Surfactant-Enabled Nanocarriers in Breast Cancer Therapy: Targeted Delivery and Multidrug Resistance Reversal.

1. Introduction

Surfactants are surface-active agents which can reduce tension between the interfaces of two phases, for instance water and oil, because they are amphiphilic compounds containing hydrophilic (water-loving) and hydrophobic (lipid-loving) moieties [ 1 , 2 ]. They can be further categorized into four broad types based on the nature of the polar head group: zwitterionic, anionic, cationic, and nonionic surfactants [ 3 , 4 , 5 ]. In pharmaceutical sciences, surfactants are of great importance as they improve the solubility, stability, and bioavailability of poorly soluble drugs in water [ 6 ]. Due to this self-assembling ability, surfactants can form diverse nanostructures such as vesicles [ 7 , 8 , 9 ], liposomes, emulsions, and micelles, which are excellent materials for drug delivery [ 10 , 11 , 12 ]. Certain surfactants exhibit antibacterial [ 13 ], anti-inflammatory [ 14 ], and anticancer activities, which makes them useful not only as solubilizing agents but as versatile drug delivery systems [ 15 , 16 , 17 , 18 ].

Surfactants have attracted increasing attention in oncology because they can penetrate through a series of barriers in cancer treatment, particularly breast cancer [ 19 , 20 ]. They enhance cellular uptake, facilitate the ease of drug passage across biological membranes, and can alter membrane fluidity to enhance drug penetration into tumor tissues [ 21 , 22 , 23 , 24 ]. In addition, certain surfactants, such as D-α-tocopheryl polyethylene glycol succinate (TPGS), have been demonstrated to inhibit efflux pumps such as P-glycoprotein (P-gp), a significant contributor to the multidrug resistance (MDR) of cancer cells [ 25 , 26 ]. Surfactants stand as vital stakeholders in the design of the next generation of drug delivery systems through their role as both a therapeutic modulator and delivery booster [ 27 , 28 ]. In addition to improved pharmacokinetics and biodistribution, their presence in nanocarriers for breast cancer therapy also brings with it the hope of targeted and controlled release, which would minimize systemic toxicity and maximize therapeutic efficiency [ 29 , 30 , 31 ].

Breast cancer continues to be one of the most common and far-reaching forms of cancer worldwide, with millions of women being diagnosed annually [ 32 ]. Breast cancer is a heterogeneous disease with varied clinical, molecular, and genetic differences that make treatment difficult. Invasive ductal carcinoma (IDC), invasive lobular carcinoma (ILC), and less common types such as inflammatory breast cancer and Paget’s disease are the primary forms of breast cancer [ 33 ]. These tumors are divided based on where they are and what the cells look like, which impacts treatment and prognoses. Breast cancer is a heterogeneous disease with numerous subtypes at the molecular level, including triple-negative breast cancer (TNBC), hormone receptor-positive (HR + ) breast cancer, and human epidermal growth factor receptor 2-positive (HER2 + ) breast cancer, each with its own implications for treatment. Notwithstanding advances in targeted treatment, early detection, and diagnostic techniques, breast cancer remains a leading cause of cancer-related morbidity and mortality.

The standard multimodal treatment modalities for breast cancer include surgery, radiation, chemotherapy, hormone therapy, targeted medicines, and, in some situations, immunotherapy [ 34 , 35 ]. Therapy outcomes, however, remain unpredictable, especially in individuals with aggressive subtypes like TNBC, which lack obvious molecular targets. Chemotherapy, the cornerstone of treatment for many kinds of breast cancer, frequently faces problems such as systemic toxicity, drug resistance, and limited drug penetration into the tumor [ 36 ]. Radiation- and chemotherapy-induced side effects also affect the quality of life for many patients 37, emphasizing the importance of using novel approaches to increase the accumulation of therapeutic drugs in the cancer region. The therapeutic usefulness of traditional drug delivery systems against breast cancer is often reduced by several issues [ 37 ]. These include the poor water solubility of hydrophobic drugs, fast clearance in the bloodstream, the lack of specificity for their distribution, and a failure to focus on their sites of tumor correctly. Due to the systemic delivery of most of the chemotherapeutic agents, high doses in non-targeting tissues can cause severe toxic effects [ 38 , 39 , 40 ]. In addition, the hydrophobicity of most anticancer drugs complicates their formulation for effective distribution. In addition, both the tumor microenvironment (TME) and the blood–brain barrier (BBB) can further limit drug penetration, creating a challenge to achieve therapeutic concentrations of the drug in the area of the tumor [ 41 ].

Surfactant-based drug delivery systems (DDSs) are a viable alternative to conventional drug administration methods that address many of the constraints associated with standard treatments [ 42 , 43 , 44 ]. Surfactants, which are amphiphilic compounds with both hydrophilic and hydrophobic sections, can greatly increase the solubility and bioavailability of medicines that are poorly water soluble [ 42 ]. These systems can create a variety of nanostructures, including nanoparticles, emulsions, liposomes, and micelles, which encapsulate therapeutic compounds, preserve them from degradation, and enhance their capacity to pass biological barriers [ 45 , 46 , 47 ]. Furthermore, surfactant-based DDSs can be designed for regulated drug release, enhancing therapeutic outcomes while minimizing side effects [ 48 , 49 ]. Improving the pharmacokinetics and biodistribution of drugs is one of the primary advantages of surfactant-based DDSs, and they are capable of ensuring that greater amounts of drug are delivered to the tumor site by restricting premature drug release and reducing the agglomeration of hydrophobic drugs [ 50 ]. In addition, surfactants can be functionalized to bind with specific receptors on cancer cells, increasing drug delivery strength and specificity. For example, ligand- or antibody-responsive overexpressed receptors on tumor cells may be assimilated into surfactant-based carriers for enhancing targeted delivery and reducing off-target injury [ 51 , 52 ]. Furthermore, surfactant-based DDSs provide the opportunity to combine multiple therapeutic agents onto one platform, i.e., immunotherapy, gene therapy, and chemotherapy [ 53 ]. This combination approach can improve treatment efficacy and address the complex and diverse character of breast cancer by addressing several facets of tumor biology at once. For instance, simultaneous administration of a chemotherapeutic drug with an immune checkpoint inhibitor or small interfering RNA (siRNA) in a surfactant-based DDS may not just reduce tumor cell proliferation but also modulate the immune system to boost anti-tumor activity [ 54 ].

Surfactant-based DDSs can potentially enhance patient compliance as well as facilitate better drug delivery. Standard chemotherapy protocols often require many cycles of treatment, which can be stressful and result in prolonged hospitalization stays [ 53 ]. On the other hand, surfactant-based systems can offer a drug’s prolonged release over time, lowering dosage frequency and enhancing patient adherence to the prescribed course of treatment. This is particularly crucial in cases of breast cancer, where the patient’s quality of life is crucial and therapy may be drawn out. Additionally, because of their adaptability, surfactant-based DDSs can be used in a wide variety of medicinal formulations, from small-molecule medications to biologics such peptides, nucleic acids, and monoclonal antibodies [ 55 ]. Due to their flexibility, surfactant-based systems can be applied in various treatment regimens, from systemic administration to targeted therapy, making them more promising for the treatment of breast cancer. Therefore, surfactant-based drug delivery methods offer a suitable alternative to conventional drug delivery methods in the treatment of breast cancer. These innovative technologies can significantly enhance the therapeutic value of anticancer drugs by addressing key issues like systemic toxicity, poor tumor targeting, and low drug solubility. A major leap towards personalized medicine can be taken with the development of surfactant-based DDSs that are tailored to specific patient needs and breast cancer types, giving a safer and more effective way of controlling the disease. The development, mechanism, and therapeutic potential of surfactant-based drug delivery methods in the therapy of breast cancer will be discussed within this review, highlighting their potential to overcome current therapy challenges and unlock more effective treatments.

The primary objective of this review is to explore the role of surfactant-based drug delivery systems in breast cancer treatment, highlighting their types, therapeutic value, molecular mechanisms, and challenges they aim to overcome. The research aims to explore how surfactants enhance drug permeability and facilitate the reversal of drug multidrug resistance (MDR) through processes like solubilization, micellization, and membrane fluidization, which yield improved outcomes in treating breast cancer ( Figure 1 ). In addition, this review aims to explore a number of surfactant-based systems, such as polymeric micelles, nanoemulsions, and liposomes, and determine the efficacy of each in delivering gene therapy, biologics, and chemotherapeutics. The FDA-approved or clinical-stage products that make use of surfactants, targeted delivery, and the biocompatibility of the systems will also be discussed in the review. In addition to investigating the current challenges and future advancements of surfactant-based systems in precision medicine, regulatory matters, and AI-based design, the research will also depict current innovations and trends.

2. Methodology

To ensure scientific rigor and relevance, the present study employed a systematic and thorough literature search strategy. High-profile scientific databases like PubMed, Scopus, Web of Science, and Google Scholar were searched for English-language, peer-reviewed articles from 2010 to 2025. A thorough list of keyword sets together with Boolean operators was employed, i.e., “surfactants”, “drug delivery systems”, “breast cancer”, “multidrug resistance”, “nanocarriers”, “micelles”, “liposomes”, and “TPGS”. The search was limited to preclinical research, clinical trials, FDA-approved drugs, and mechanism-based research on surfactant-based drug delivery systems in the treatment of breast cancer. Original research articles, reviews, and clinical publications with substantial technical advances, mechanistic insights, or translational potential were considered for inclusion. Non-English publications, editorials, commentaries, and review papers that did not contain primary data were excluded. Each study was evaluated rigorously for design robustness, usefulness to clinical application, and reproducibility of results. Selected papers were examined for data on surfactant types, drug delivery augmentation methods, formulation tactics, therapeutic effects, and safety profiles. The retrieved data were categorized into topical areas to give a consistent summary of current trends, difficulties, and future prospects in the field of surfactant-based drug delivery for breast cancer treatment.

3. Mechanistic Role of Surfactants in Drug Delivery

Surfactants, in the process of micelle formation, enhance drug delivery and reduction in multidrug resistance. These systems promote controlled release mechanisms and enhance targeted therapy, especially in cancer therapeutics. Nanomaterials also aid in the solubility, stability, and general therapeutic effect of drugs, maximizing their delivery and performance ( Table 1 ). Given their numerous applications in drug delivery systems, surfactant amphiphilic agents have received a lot of attention in the pharmaceutical sciences [ 56 , 57 , 58 ]. Micellization and solubilization are two of the most fundamental mechanisms by which surfactants enhance drug bioavailability [ 59 , 60 , 61 , 62 , 63 ]. At concentrations above their critical micelle concentration (CMC), surfactants form micelles with hydrophobic cores that trap poorly water-soluble drugs [ 64 , 65 , 66 ]. Medication solubility is enhanced, enzymatic degradation is avoided, and controlled release is facilitated by this micellar encapsulation [ 67 ]. Tween 80, Cremophor EL, and Pluronic F127, for instance, have been widely used to formulate hydrophobic anticancer drugs like docetaxel and paclitaxel, significantly enhancing their systemic bioavailability and aqueous solubility [ 68 , 69 , 70 , 71 , 72 , 73 ]. Further, such micelles can be used as nanoscale drug carriers for enhancing drug uptake across the gastrointestinal system and lymphatic uptake [ 72 ].

Surfactants improve permeability and micellar solubilization by controlling the dynamics and structure of biological membranes [ 70 ]. Surfactants that alter the lipid architecture in the stratum corneum or epithelial barriers, such as sodium lauryl sulfate (SLS), bile salts, and Labrasol, result in improved transcellular and paracellular transport [ 74 , 75 ]. These substances improve the permeability of lipid bilayers by fluidizing the membrane through their interaction with membrane phospholipids [ 76 , 77 , 78 ]. Nonionic surfactants, such as polyoxyethylene ethers, have been shown in the literature to improve the passage of both small and large molecules across epithelial cells while decreasing the order of lipid chains in membranes [ 79 , 80 , 81 ]. This characteristic is especially advantageous for applications involving transdermal and transmucosal medication administration.

3.1. Solubilization and Micellization

The ability of surfactants to form micelles and enhance the water solubility of hydrophobic drugs has been a subject of extensive research [ 68 , 69 , 82 , 83 ]. When the concentration of surfactant is greater than the critical micelle concentration (CMC), the micelle experiences micellization, which allows the hydrophilic structures to engage with the aqueous phase while the hydrophobic sections comprise the core of the micelle [ 72 , 84 , 85 , 86 , 87 ]. Based on Zhang et al. (2008), the anticancer drug paclitaxel, which is not very soluble in water, was made significantly more soluble by polymeric micelles of Pluronic block copolymers, which enhanced its therapeutic effectiveness [ 88 , 89 , 90 , 91 ]. Yoo and Park, 2001 demonstrated that doxorubicin-loaded micelles formed by PEG-poly(aspartate) block copolymers which enhance tumor accumulation using the permeable and retaining effect (EPR effect), which increased solubility and circulating time in vivo [ 92 ]. Similarly, Torchilin et al. (2001) verified that PEG-shelled stealth micelles improved drug bioavailability through improved plasma stability and decreased mononuclear phagocytic system recognition [ 42 ].

According to Jhaveri and Torchilin (2014), amphiphilic block copolymer micellar systems may be able to administer a variety of hydrophobic medications, which would increase the efficacy of combination therapy [ 93 ]. Additionally, Zhu and Jiang (2007) examined the structure–activity connections of different micelle-forming copolymers and came to the conclusion that drug loading and release kinetics were directly influenced by hydrophobicity, block length, and ionic nature [ 94 ]. According to Cai et al. (2011), Micelles that are functionalized with targeting ligands like folate or RGD peptides showed improved cellular uptake and targeted drug delivery to cancer cells [ 95 ]. Targeted systems decreased off-target toxicity but improved cytotoxicity in cancer cells. Polyhistidine segments were also used by Zhang et al. (2022) to create pH-sensitive micellar structures that break down in acidic tumor settings, enabling regulated medication release [ 96 ]. Surfactant-based micelles offer a number of benefits, including the ability to achieve targeted drug distribution, improve pharmacokinetics, and solubilize hydrophobic anticancer medications [ 84 , 85 , 86 , 87 ]. As potentially useful instruments for getting around obstacles in traditional chemotherapy formulations, these technologies are constantly developing.

3.2. Permeation Enhancement and Membrane Fluidization

Numerous studies have been conducted on the role of surfactants as permeation promoters in transdermal and mucosal drug delivery systems. Surfactants facilitate drug penetration through biological membranes by changing the fluidity and morphology of lipid bilayers [ 97 , 98 , 99 ]. Surfactants, such as polyoxyethylene ethers and sodium lauryl sulfate (SLS), alter the stratum corneum’s lipid structure and enhance skin permeability, as reported by Lemery et al. (2015) and other scientists [ 100 , 101 , 102 ]. Rege et al. (2022) discovered that nonionic surfactants, such as Tween 80, increase intestinal membrane permeability by fluidizing the lipid bilayer and momentarily breaking tight junctions [ 103 ]. Shah (2004) discovered that bile salt-type surfactants, such as sodium taurocholate, improved paracellular transport by opening up tight junctions in the nasal epithelium, which in turn greatly increased the bioavailability of peptide medications [ 104 ].

Elnaggar et al. (2014) also investigated the use of lecithin and polysorbate 80 in topical formulations [ 105 ]. Without sacrificing membrane integrity, they discovered that both surfactants improved drug flux and reduced membrane resistance. Furthermore, Sebaaly et al. (2021) hypothesized a synergistic impact after studying chitosan-coated liposomes with surfactant additives and discovering a notable improvement in mucosal penetration throughout the gastrointestinal system [ 106 ]. Mixed micelles of bile salts and phosphatidylcholine improved intestinal absorption of cyclosporin A [ 107 , 108 ], a poorly absorbed immunosuppressant, by increasing its membrane permeability and solubility. According to Cavanagh (2018), surfactants that fluidize the membranes of epithelial cells can improve drug absorption by accelerating the processes of endocytosis and transcytosis [ 109 ]. These results all point to the likelihood that surfactants facilitate new transport pathways and improve medication permeability by fluidizing lipid bilayers. However, a rigorous tuning process is required for clinical application in order to strike a compromise between membrane safety and permeability increase [ 110 ].

3.3. P-glycoprotein (P-gp) Inhibition to Reverse MDR

The efficacy of most chemotherapeutic agents is greatly compromised by multidrug resistance (MDR) in cancer, which is often due to overexpression of P-glycoprotein (P-gp). By inhibiting P-gp’s efflux activity, surfactants have emerged as effective P-gp inhibitors that enhance intracellular drug accumulation [ 111 , 112 ]. Pluronic block copolymers have been reported by Kabanov et al. (2002) to enhance membrane fluidity and inhibit P-gp ATPase activity, which can sensitize drug-resistant tumor cells [ 113 , 114 , 115 ]. According to Batrakova et al. (2003), Pluronic P85 suppressed drug resistance in MDR tumor cell lines by blocking mitochondrial function and ATP depletion, which in turn hindered drug efflux through P-gp [ 116 , 117 , 118 , 119 ]. Similarly, nonionic surfactants such as polysorbate 80 and Cremophor EL enhanced paclitaxel oral bioavailability in rats without inhibiting P-gp activity, according to Collnot et al. (2006) [ 120 , 121 ].

According to Collu and Cascella (2013), who investigated the relationship between surfactants and membrane-bound efflux pumps, surfactants can change the structure of P-gp, preventing it from binding substrates [ 122 ]. Furthermore, doxorubicin and the P-gp inhibitor verapamil were synergistically delivered by Reddy et al. (2004) using surfactants in liposomes, which restored resistance in cancer mice [ 123 , 124 ]. Bile salts, polysorbates, and PEG-derived surfactants demonstrated high P-gp inhibitory activity with little cytotoxicity, according to Kecman et al. (2020), who analyzed a number of surfactant classes [ 125 ]. Furthermore, Cremophor EL was shown by Dintaman and Silverman (1999) to enhance vinblastine entrance in Caco-2 cells in a concentration-dependent manner while suppressing P-gp transport activity [ 126 ]. Therefore, surfactants modify the membrane environment and inhibit P-gp function directly, both of which are responsible for MDR reversal ( Figure 2 ). One potential way to enhance intracellular drug loading and recover the efficacy of chemotherapeutic drugs in drug-resistant malignancies is their incorporation into nanocarrier systems.

4. Types of Surfactant-Based Systems in Breast Cancer Therapy

Surfactant-coated nanoparticles and biosensor systems improve controlled release, drug targeting, and solubility for successful cancer treatment. The systems also overcome issues such as drug resistance and tumor specificity ( Table 2 ). Given that surfactant-based systems can enhance drug solubility, stability, and drug targeting, they are being researched increasingly for the delivery of chemotherapeutic drugs in breast cancer treatment [ 127 , 128 , 129 , 130 ]. These platforms, which provide unique advantages in addressing the challenges associated with conventional chemotherapy, typically include polymeric micelles, nanoemulsions, liposomes, self-emulsifying drug delivery systems (SEDDSs), and biosurfactant-based nanocarriers [ 131 , 132 , 133 , 134 ]. As noted by Junnuthula et al. (2022), polymeric micelles, such as Pluronic micelles incorporating doxorubicin (DOX) or paclitaxel (PTX), have been shown to enhance drug solubility and provide controlled release, resulting in enhanced therapeutic efficacy and reduced toxicity [ 135 , 136 , 137 , 138 ]. Surfactants and oils come together to produce nanoemulsions and microemulsions, which are advantageous in solubilizing hydrophobic drugs [ 139 , 140 ] and retaining their stability in circulation [ 141 ].

Based on studies by Hong et al. (2014), PTX-loaded nanoemulsions can enhance the drug accumulation in tumor tissues, thus enhancing the drug’s anticancer effects [ 142 ]. Another highly explored system is surfactant-stabilized liposomes, which enhance the bioavailability of hydrophobic drugs such as DOX and possess the ability to encapsulate hydrophobic and hydrophilic drugs such that different agents may be combined for synergistic therapy [ 143 ]. By combining oils, co-surfactants, and surfactants, self-emulsifying drug delivery systems (SEDDSs) increase the oral bioavailability of poorly soluble medications by creating microemulsions that react with aqueous conditions. According to research by Jayaswal et al. (2024), PTX-loaded SEDDS greatly improved the solubility and absorption of drugs [ 144 ]. Lastly, research by Gonçalves et al. (2018) suggests the use of biosurfactant-based nanocarriers, which offer biodegradable and biocompatible drug delivery formulations and are made of natural surfactants like rhamnolipids [ 145 ]. They are less toxic than conventional synthetic surfactants and have been reported to be effective in encapsulating DOX for the treatment of breast cancer. The safety, targeting, and efficacy of therapies for breast cancer might all significantly be improved through these surfactant-based systems.

4.1. Polymeric Micelles (e.g., Pluronic Micelles with DOX, PTX)

Polymeric micelles are a well-established family of surfactant-like systems for the delivery of drugs, especially poorly soluble drugs such as paclitaxel (PTX) [ 146 , 147 ] and doxorubicin (DOX). Polymeric micelles consist of amphiphilic block copolymers, which self-assemble to form core–shell structures in water environments. While the shell consists of hydrophilic segments that ensure solubility in biological fluids, the core is typically hydrophobic, providing a stable environment for the encapsulation of hydrophobic drugs [ 148 , 149 , 150 ]. The role of pluronic block copolymers, including pluronic F127 and P85, in drug delivery is one of the most widely studied. Numerous chemotherapeutic medications, including PTX and DOX, can be efficiently encapsulated by pluronic-based micelles, according to experiments [ 151 , 152 , 153 , 154 , 155 , 156 ]. For example, Yadav et al. (2023) found that PTX-loaded Pluronic micelles decreased systemic toxicity while increasing PTX’s anticancer activity in murine breast cancer models [ 157 ]. Furthermore, by improving the distribution of PTX to tumor tissues, these micelles improved the therapeutic results in comparison to free PTX. According to a study by Majumder et al., 2020, the micellar form of DOX showed decreased cardiotoxicity and increased anticancer efficacy in vivo, demonstrating that these polymeric micelles not only improved solubility but also markedly increased DOX’s bioavailability. Additionally, research has looked into polymeric micelles’ potential to combat multidrug resistance (MDR), a significant barrier to breast cancer treatment [ 158 ]. Pluronic P85 micelles can increase the lethal action of DOX in drug-resistant MCF-7/ADR cells by inhibiting the function of P-glycoprotein (P-gp), an efflux pump that reduces intracellular drug levels, as per a study by Colakyan et al. (2006) [ 159 , 160 ]. Pluronic micelles [ 161 ] can reverse P-gp-mediated MDR by changing the membrane properties of the efflux pump, as per another study by Rathod et al. (2022). Such micelles are potential carriers in chemotherapeutic regimens for breast cancer due to their dual capacity to entrap drugs and inhibit drug resistance mechanisms.

Among the several benefits of Pluronic micelles is their biocompatibility and low toxicity profile [ 162 ]. Gothwal et al. (2016) examined the safety of Pluronic micelles and found that, in in vitro and in vivo models, they exhibited negligible toxicity, even with high doses [ 163 ]. In developing chemotherapeutic formulations, this is an important consideration because minimizing the detrimental effects of chemotherapy drugs can improve patient compliance and quality of life. The selectivity of Pluronic micelles for breast cancer cells can be further enhanced by targeting them through functionalization with targeting ligands [ 164 , 165 ]. The functionalization of Pluronic micelles with folic acid is a notable case in point. This further increases the selective delivery of anticancer drugs by targeting overexpressed folate receptors on most breast cancer cells. Some recent developments in the application of polymeric micelles for breast cancer treatment have also centered on the co-delivery of two or more drugs [ 166 , 167 , 168 , 169 , 170 ]. A dual-drug-loaded micelle system consisting of PTX and DOX was developed by Wang et al. (2016), and it has enhanced antitumor activity and synergistic effects in the treatment of breast cancer [ 171 ]. Since the two chemotherapeutic medicines were being administered simultaneously, the dosages required for each drug were lowered, decreasing the risk of side effects associated with higher dosages. Furthermore, this approach had an increased tumor growth suppression, highlighting the importance of combination drugs in improving therapeutic outcomes. Polymeric micelles are still being explored as a potential nanocarrier for breast cancer treatment in the future [ 166 , 167 , 168 ]. The objective of current research is to enhance their stability, drug-loading capacity, and ability to penetrate barriers such as poor tumor penetration and drug resistance. The integration of stimuli-sensitive elements (e.g., temperature- or pH-sensitive) within micellar drug delivery has the capability of enhancing therapeutic outcomes through controlled drug release at the tumor site [ 93 ].

Pluronic micelles, or amphiphilic block copolymers, provide a diverse platform for drug administration, particularly in cancer therapy [ 162 , 163 , 164 , 165 ]. Pluronic micelles, when functionalized with targeting ligands such as antibodies, peptides, or small molecules, can preferentially target specific receptors on breast cancer cells, such as HER2 or folate receptors [ 166 , 167 ]. This tailored administration increases drug accumulation in tumor tissue, boosting treatment efficacy while reducing systemic exposure. As a result, higher concentrations of therapeutic drugs can be confined to the tumor, which not only boosts the medicine’s efficiency but also lowers the likelihood of unpleasant side effects that are normally caused by nonspecific drug distribution. However, there are many limits to the therapeutic use of ligand-functionalized Pluronic micelles [ 168 ]. These include batch-to-batch variability in micelle formation, which can have an impact on consistency and reproducibility, as well as potential immunogenicity caused by the presence of foreign ligands. Furthermore, while targeting ligands enhance specificity, micelles still struggle with poor penetration into solid tumors, which can limit drug delivery to deeper tumor locations [ 169 ]. Furthermore, premature drug release from micelles in circulation can shorten the therapeutic window and result in off-target consequences [ 170 , 171 ]. To address these problems, recent efforts are focusing on producing stimuli-responsive micelles that release the drug selectively in the tumor microenvironment, improving penetration and increasing the therapeutic outcome while lowering the danger of premature drug leakage and adverse effects.

4.2. Nanoemulsions and Microemulsions

Due to their physicochemical differences, such as high surface area, tiny droplet size, and stability in biofluids, microemulsions and nanoemulsions are surfactant nanocarriers that have been explored in drug delivery [ 172 , 173 , 174 , 175 , 176 ]. Surfactants, oils, and co-surfactants spontaneously assemble to create these systems, which yield clear, stable, and thermodynamically stable formulations [ 177 , 178 ]. Nanoemulsions have been widely investigated for the administration of lipophilic medications, such as paclitaxel (PTX), in the treatment of breast cancer [ 179 ]. According to Jampilek and Kralova (2019), PTX-loaded nanoemulsions made of surfactants such as Tween 80 and Labrasol demonstrated improved drug solubilization and markedly increased drug bioavailability [ 180 ] in comparison to standard formulations. One of the main advantages of nanoemulsions is their capacity to improve medication penetration into tumor tissues. Jain et al. (2012) discovered that paclitaxel-loaded nanoemulsions improved cellular absorption and therapeutic efficacy in [ 180 ] breast cancer cells (MCF-7). The small droplet size and surfactant-mediated membrane fluidization, which are advantageous for drug transport across lipid bilayers, were credited by the researchers with the enhanced cellular internalization. Furthermore, it was discovered that surfactant-stabilized nanoemulsions were more stable, which is essential for preserving the drug’s therapeutic effectiveness while it is in use and directed against tumors. Because of their minuscule droplet sizes, microemulsions have also been studied as drug delivery systems for both hydrophilic and hydrophobic medications.

DOX and PTX microemulsion formulations considerably improved drug solubility and bioavailability during the treatment of breast cancer, as reported by Shaikh et al. (2021) [ 181 ]. These systems also demonstrated improved tumor targeting because they could take advantage of the EPR effect, which happens when nanoparticles prefer to aggregate in tumor tissues because of their leaky vasculature [ 182 ]. PTX-loaded microemulsions improved tumor shrinkage and extended survival rates in tumor-bearing mice in in vivo experiments when compared to free PTX, suggesting the potential of microemulsions for the treatment of breast cancer. The propensity of nanoemulsions and microemulsions to leak medications and become unstable while stored is one of the main obstacles to their clinical use. Recent studies have focused on using biocompatible surfactants, like PEGylated surfactants, to stabilize these systems. These surfactants improve formulation stability and circulation times. According to a study by Suk et al. (2016), PTX-loaded nanoemulsions stabilized by PEGylated surfactant showed improved pharmacokinetics and decreased toxicity [ 183 ]. Additionally, PEG chains added to the surfactants decreased the compositions’ immunogenicity, increasing their potential for use in a clinical setting. Combination therapy becomes a possibility due to the capacity of nanoemulsions and microemulsions to co-encapsulate multiple therapeutic agents. Singh et al. (2017) demonstrated the usage of a nanoemulsion technology for the co-delivery of paclitaxel and DOX to improve therapeutic effect against breast cancer cells [ 184 ]. Combination treatment using DOX and PTX within one nanocarrier provided greater killing of tumor cells and minimized treatment resistance risk. In the case of breast cancer treatment, this synergistic drug delivery method has been promising in overcoming the limitations of monotherapy [ 185 ]. Aside from their therapeutic applications, nanoemulsions and microemulsions have the advantage of being easily modifiable to a number of delivery routes, including topical, intravenous, and oral routes. They are ideal for enhancing the bioavailability of drugs that are poorly soluble due to their ability to provide stable, nanosized droplets under physiological conditions. To further enhance the targeting ability and therapeutic index of nanoemulsion- and microemulsion-based drug delivery systems in breast cancer treatment, future research should focus on optimizing the surfactant compositions and droplet sizes.

4.3. Liposomes Stabilized by Surfactants

Liposomes are nanocarriers with multifunctional properties composed of lipid bilayers that have the ability to encapsulate both hydrophilic and hydrophobic drugs. Due to their ability to increase drug solubility, protect drugs from degradation, and target cancer cells, they are being researched intensively for the treatment of breast cancer [ 185 , 186 ]. Liposomes’ stability and drug-release characteristics frequently need to be improved in order to increase their therapeutic usefulness. To get around these problems, liposome formulations have added surfactants to improve drug loading, prolong circulation periods, and stabilize the lipid bilayer. Liposome formulations, including surfactants like polysorbate 80, showed markedly improved stability and regulated drug release in a study by Forouhari et al. (2022), making them more efficient in delivering chemotherapeutic medicines like DOX to breast cancer cells [ 187 ]. Because surfactant-stabilized liposomes reduce lipid vesicle aggregation and produce a more uniform size distribution, they also have increased bioavailability For example, Patel et al. (2022) demonstrated that surfactant-stabilized liposomes loaded with PTX, such as Poloxamer 188, demonstrated improved tumor development and circulation half-lives in animal models of breast cancer [ 142 ]. Surfactant-modified liposomes improved therapeutic efficacy and drug deposition at the tumor site by taking advantage of the EPR effect. Additionally, adding surfactants like PEG produced a “stealth” liposome preparation that prevented early clearance and decreased reticuloendothelial system (RES) recognition [ 188 ].

Surfactants may assist liposomes in overcoming multidrug resistance (MDR) of breast cancer as well as enhancing stability and bioavailability. P-glycoprotein (P-gp) efflux pumps, which pump drugs out from cancer cells, are often the reason for MDR, a primary reason for chemotherapy failure. Based on studies conducted by Yang and Liu (2016), surfactants such as polysorbate 80 can enhance the intracellular level of chemotherapeutic drugs by suppressing P-gp activity [ 189 ]. These findings suggest that surfactant-modified liposomes hold great promise for lowering MDR in the treatment of breast cancer because they may be used both as drug resistance modulators and hydrophobic drug carriers. In addition, controlled and targeted drug delivery can be achieved through surfactant-stabilized liposome engineering. The liposomes may selectively target tumors by functionalizing their surface with targeting ligands such as folic acid, which is attached to folate receptors overexpressed on most breast cancer cells. Helmy et al. (2022) explored the use of folate-conjugated liposomes encapsulating DOX and found that these liposomes greatly enhanced tumor accumulation and cellular uptake in vitro and in vivo [ 190 ]. This strategy raises the drug’s therapeutic index while lowering the systemic toxicity associated with conventional chemotherapy.

Another important advantage of surfactant-stabilized formulations is the controlled release of drugs from liposomes [ 191 ]. The lipid composition and surfactant concentration can be changed to offer long-term sustained medication delivery through the design of release kinetics for encapsulated medicines. This lowers the rate of medication distribution and increases patient compliance. For instance, Rahman et al. (2025) found that the controlled release of PTX from surfactant-stabilized liposomes improved antitumor activity in breast cancer models while lowering the negative effects usually associated with free PTX [ 192 ]. The clinical translation of surfactant-stabilized liposomes is beset with difficulties, including scaling up manufacturing and guaranteeing consistent drug release profiles, despite the potential benefits. However, these issues will be resolved by additional developments in liposome formulation and surfactant technology. Future research will concentrate on creating stimuli-responsive liposomes, adjusting surfactant–lipid ratios, and assessing long-term stability to guarantee that such systems may be successfully used in clinical breast cancer therapy [ 193 ].

4.4. Self-Emulsifying Drug Delivery Systems (SEDDSs)

Self-emulsifying drug delivery systems (SEDDSs) are being explored as an innovative surfactant-based solution for enhancing the bioavailability of drugs with poor water solubility. When SEDDSs are subjected to aqueous environments, such as those in the gastrointestinal tract, they spontaneously form microemulsions from an oil–surfactant–co-surfactant mixture. The drug disperses quickly as a consequence of this spontaneous formation, enhancing its solubility and absorption [ 194 ]. Improving the oral bioavailability of lipophilic drugs, like PTX and DOX, that are commonly administered to treat breast cancer is a significant advantage of SEDDSs [ 195 ]. A PTX SEDDS formulation significantly enhanced drug solubility and oral bioavailability in animal models, as reported in studies by Wahi et al. (2023), and it might serve as a substitute for intravenous drug delivery [ 196 ]. SEDDS formulations are especially useful for low-solubility drugs in aqueous systems because they can solubilize high concentrations of hydrophobic drug molecules. This is particularly important for the treatment of breast cancer because many potent chemotherapy drugs, such as paclitaxel, exhibit poor water solubility. According to Rathore et al. (2023), SEDDS formulations have the ability to enhance the solubility of such drugs, leading to increased plasma levels and improved therapeutic effects [ 197 ]. SEDDSs can also reduce drug crystallization, which prevents aggregates from presenting that would otherwise reduce drug bioavailability.

Another notable feature of SEDDSs are their capacity to improve medication penetration through biological membranes. Two of the surfactants employed in SEDDSs, Tween 80 and Cremophor EL, can improve membrane fluidity and decrease gut barrier or tumor cell membrane barrier characteristics [ 198 ]. According to a study by Lakkakula et al. (2024), PTX-loaded SEDDSs improved the drug’s permeability across the intestinal wall, leading to improved systemic absorption [ 199 ]. Likewise, SEDDS formulations of DOX have been shown to increase drug absorption in breast cancer cells, potentially improving therapeutic efficacy and lowering the likelihood of resistance [ 199 ]. It is also amazing how SEDDSs can overcome drug resistance. In the treatment of breast cancer, MDR, which is typically mediated by P-gp efflux pumps, can reduce the efficacy of chemotherapy medications like DOX. The ability of SEDDSs to block or avoid P-gp activity has been investigated in recent research [ 200 , 201 ]. SEDDS formulations of DOX improved intracellular drug absorption in MDR cell lines, according to Riaz et al. (2023), indicating that surfactants might affect P-gp activity and increase the lethal effects of chemotherapeutic medications [ 201 ].

Furthermore, SEDDSs can be customized to be administered orally and parenterally, allowing for greater flexibility in the course of treatment. The use of SEDDSs is a promising method for oral delivery of breast cancer treatment because of its capacity to encapsulate hydrophobic medications and protect them from deterioration while being transported through the gastrointestinal tract. As established by Wahi et al. (2023), the use of a lipid-based SEDDS formulation for oral administration of PTX not only increased drug solubility but also lowered the rate of administration compared to conventional PTX formulations, hence improving patient compliance [ 196 ]. Notwithstanding the benefits, there are still issues with the development of SEDDS for the treatment of breast cancer, namely with regard to formulation stability, scale-up procedures, and long-term shelf life. Future studies will concentrate on optimizing surfactant blends and enhancing the stability and controlled-release properties of SEDDS formulations in an attempt to enhance therapeutic effects [ 202 ]. All things considered, SEDDSs present a tenable strategy for improving the effectiveness of medications with low solubility in the treatment of breast cancer.

4.5. Biosurfactant-Based Nanocarriers

Natural amphiphilic molecules known as biosurfactants have attracted significant attention to drug delivery due to their low toxicity, biocompatibility, and biodegradability [ 203 ]. These surfactants, which are secreted by bacteria and fungus, have the ability to spontaneously form micelles and nanoparticles that can encapsulate a variety of therapeutic substances. Biosurfactant-derived nanocarriers present a promising approach to treating breast cancer since they are less immunogenic, more stable, and more drug-soluble than synthetic surfactants [ 204 ]. Studies by Ceresa et al. (2023) have demonstrated that rhamnolipid-derived micelles may encapsulate hydrophobic medications such as paclitaxel, providing a substitute for formulations that use synthetic surfactants [ 131 ]. One of the main advantages of biosurfactant-based nanocarriers is their biocompatibility, which allows for systemic circulation for extended periods of time without experiencing appreciable toxicity. According to a study by Wadhawan et al. (2022) [ 205 ], rhamnolipid micelles loaded with DOX demonstrated improved biocompatibility and preserved therapeutic efficacy in breast cancer cells with lower cytotoxicity than their synthetic equivalents. The fact that these natural surfactants are biodegradable, that is, the body will metabolize them without allowing them to build up in tissues, is a significant advantage over synthetic surfactants that may have harmful long-term effects.

In addition, more effective drug targeting and delivery could be achieved through biosurfactant-based nanocarriers. The cancer cell selectivity of the nanocarriers can be enhanced by modifying the biosurfactant micelle surface with targeting ligands such as folate or antibodies. For example, studies by Yoo and Park, 2004 showed that DOX can be delivered specifically to folate receptor-positive breast cancer cells through folate-conjugated rhamnolipid micelles, increasing treatment outcomes [ 206 ]. Biosurfactant-based systems are ideal candidates for precision therapy in the treatment of breast cancer because they are biocompatible and targetable. The ability of biosurfactants to modify biological processes, such as enhancing the absorption of drugs and bypassing multidrug resistance (MDR), has been explored in addition to their application in drug delivery. Naughton et al. (2019) state that biosurfactants like sophorolipids have been found to enhance intracellular drug delivery in drug-resistant cancer cell lines by blocking the P-gp efflux pump [ 207 ]. Biosurfactant-based nanocarriers have one of the most significant advantages of being able to reverse MDR, making them a preferred option for maximizing the efficacy of chemotherapy in the event of resistant breast cancer [ 207 ].

Moreover, biosurfactants have the ability to enhance nanoparticle stability and loading capacity due to their surfactant properties. By inhibiting nanocarriers from agglomeration, biosurfactants can enhance the stability of nanocarriers in biological media. Compared to traditional surfactant formulations, Bezza et al. (2020) demonstrated that biosurfactant-stabilized nanoparticles exhibited enhanced stability and longer release profiles [ 208 ]. Sequestering a high therapeutic load in stable nanocarriers is essential to make chemotherapy both effective and less harmful. The cost and large-scale production of biosurfactant-based nanocarriers pose challenges despite the promising prospects. Current research is focused, however, on scaling up biosurfactant production and optimizing the production processes. Biosurfactant-controlled drug delivery systems could be an effective tool for improving the outcomes of breast cancer treatment after these problems are addressed [ 209 , 210 , 211 ].

5. FDA-Approved or Clinical Stage Surfactant-Containing Formulations

Surfactant-based drug delivery systems enhance drug solubility, stability, and targeting, and thus therapeutic effects. A number of such systems are approved by the FDA, whereas others are being tested in the clinical setting for treating cancer ( Table 3 and Table 4 ). These systems help to evade drug resistance and optimize treatment. Many formulations with surfactants have successfully received FDA approval or clinical use, which shows the promise of surfactants in enhancing drug delivery for various diseases, including cancer. Doxil (liposomal doxorubicin), a surfactant-stabilized liposomal formulation, especially with polyethyleneglycol (PEG), is one of the best-documented examples [ 212 , 213 , 214 , 215 , 216 , 217 ]. Through the application of the enhanced permeability and retention (EPR) effect to target tumor tissues more effectively, Doxil, an FDA-approved drug, significantly improves the pharmacokinetics of doxorubicin, enhancing its solubility and reducing systemic toxicity [ 218 ]. When surfactants are used to prepare liposomes, hydrophobic drugs can be encapsulated for controlled and sustained release, which improves the efficacy of cancer therapy [ 219 ]. Abraxane (albumin-bound paclitaxel), another FDA-approved, surfactant-containing formulation, employs albumin as a stabilizing molecule in a surfactant-free formulation. The formulation confers a significant advantage in treating non-small-cell lung cancer and breast cancer by enhancing the solubility of paclitaxel and enabling its delivery to tumor cells through receptor-mediated endocytosis [ 220 , 221 ].

Clinical trials are also testing formulations based on surfactants to give new treatments. For example, clinical-stage lipid-based formulations based on surfactants, like Marqibo (liposomal vincristine sulfate), are being studied for the treatment of lymphoma, leukemia, and other cancers [ 222 ]. The formulation enhances vincristine’s pharmacokinetics by decreasing its quick clearance and neurotoxic adverse effects [ 223 , 224 ]. Furthermore, a variety of micelles and surfactant-containing nanoemulsions are undergoing clinical testing to improve the bioavailability and delivery targeting of medications that are poorly soluble in water, such as curcumin and paclitaxel [ 225 , 226 , 227 ]. Nanoemulsion-based formulations, like those employed in the Cemiplimab clinical study, are being investigated to more effectively deliver therapeutic proteins and small molecules to target tissues, in addition to improving drug stability and circulation time [ 228 , 229 , 230 , 231 , 232 , 233 , 234 ]. Clinical-stage and FDA-approved formulations demonstrate the important role surfactants play in enhancing drug distribution and getting around the drawbacks of conventional chemotherapy [ 38 , 39 ]. Surfactants help solubilize hydrophobic medications, shield them from degradation, and allow for targeted administration to particular sites, all of which increase efficacy and decrease toxicity [ 40 ]. Furthermore, surfactant-containing systems are useful because they may encapsulate a variety of drugs, such as proteins, nucleic acids, and tiny molecules, expanding their use in the treatment of numerous malignancies and other illnesses [ 235 ]. The ongoing development and improvement of these formulations may advance pharmaceutical administration procedures and offer patients safer and more efficient treatment options.

5.1. Genexol ® (Polymeric Micelle Formulation of Paclitaxel)

Genexol ® is a polymeric micelle formulation of paclitaxel designed to overcome the drawbacks of conventional paclitaxel formulations [ 236 ]. This formulation increases paclitaxel’s aqueous solubility and stability by entrapping it in polyethyleneglycol (PEG)-poly(D,L-lactide) block copolymers [ 237 ]. Genexol ® (Samyang Biopharmaceuticals Corporation, Seoul, South Korea) was designed to enhance the therapeutic efficacy of paclitaxel and reduce its toxicities, particularly when used to treat ovarian and breast cancers [ 238 ]. Paclitaxel’s half-life is prolonged and its bioavailability is enhanced by the formulation of micelles, which prevents the drug from degrading too rapidly in the blood [ 239 ]. The micellar nanoparticles are small enough to allow the increased permeability and retention (EPR) effect, which enhances cancer cell targeting and allows selective tumor tissue accumulation [ 240 ].

Genexol ® has demonstrated encouraging outcomes in a number of clinical trials. In a Phase III trial of patients with metastatic breast cancer, Genexol ® was just as effective as traditional paclitaxel, with a marked decrease in hypersensitivity responses and neutropenia [ 240 ]. Additionally, Genexol ® showed a better pharmacokinetic profile than traditional paclitaxel, which resulted in fewer adverse effects and greater tolerance [ 241 ]. Nevertheless, despite its benefits, Genexol ® has drawbacks. The formulation’s long-term stability, especially under different storage conditions, may have an impact on the stability of its therapeutic effects, which is one of the primary issues [ 242 ]. Furthermore, the PEG micelle component may cause immunological side effects in specific patient populations, which could affect the drug’s long-term use [ 243 ].

Clinical trials have investigated the possibility of combining Genexol ® with different anticancer medications [ 244 ]. When used in combination with cisplatin or trastuzumab, for instance, Genexol ® has been demonstrated to increase the cytotoxicity of paclitaxel and improve overall treatment results in a variety of solid tumors [ 245 ]. In an effort to enhance cancer treatment plans and enhance patient outcomes, clinical trials of these combinations are still being investigated. Future clinical trials will concentrate on improving micelle formulation in order to address stability concerns and enhance patient outcomes for patients with various cancer types. The creation of dual-drug-loaded micelles is one method for co-administering paclitaxel with other targeted or chemotherapeutic medications in a single micellar platform; this could potentially have a synergistic effect [ 246 ].

5.2. Emerging TPGS-Based Micellar Drugs in Trials

Tocopheryl polyethylene glycol succinate (TPGS)-based micelles have proven to be a promising method for addressing hydrophobic drugs’ solubility problem in cancer treatment [ 247 , 248 , 249 ]. Vitamin E derivative TPGS acts as a surfactant to enhance the solubility, bioavailability, and systemic toxicity of poorly soluble drugs [ 250 ]. Preclinical and clinical investigations have assessed TPGS-based micelles as drug delivery formulations of a variety of drugs, including paclitaxel and other anticancer therapeutics [ 251 ]. Micelles formed by TPGS exploit TPGS’s ability to solubilize hydrophobic drugs but maintain their stability in aqueous environments. The micelles also allow release of the drug within the target location and enhance cellular uptake by endocytosis [ 252 ]. By promoting selective accumulation in cancer tissues through the EPR effect, the application of TPGS in drug delivery systems enhances the therapeutic efficacy of chemotherapy [ 253 ].

Numerous preclinical investigations have shown that TPGS-based micelles can reduce adverse effects and increase the effectiveness of chemotherapeutic medications, for example, TPGS micelles have been successfully used to encapsulate chemotherapeutic medications such as doxorubicin and paclitaxel, and these micelles have demonstrated enhanced anticancer efficacy [ 254 , 255 , 256 ]. By increasing drug solubility and lowering the necessary dosages, these medication formulations improve patient compliance and lower toxicities. Clinical trials have shown encouraging safety and efficacy outcomes for formulations based on TPGS. For instance, clinical research using paclitaxel-loaded TPGS micelles showed better pharmacokinetic profiles, including improved tumor-targeting capabilities and less severe side effects such as hypersensitivity reactions, when compared to the conventional paclitaxel formulation [ 257 , 258 ].

Despite the advantages, TPGS-based micellar formulations have problems when used in clinical settings. One of the main worries with TPGS is its possible immunogenicity, especially since cancer patients are often given it [ 259 ]. Furthermore, when TPGS-based micelles are manufactured at scale, consistency and cost issues could arise, which would prevent their widespread application in clinical settings [ 260 ]. The main goal of the current research on TPGS-based micelles is to improve the drug release profiles and targeting properties. Nanotechnology advancements like stimuli-responsive drug release systems are being used in TPGS-based formulations to distribute drugs in a regulated and targeted manner in response to environmental stimuli like pH or temperature [ 261 ]. The development of TPGS-based micelles may improve the therapeutic results of cancer treatment and lessen its adverse effects. FDA clinical trials for surfactant-based nanomedicines are highlighted in Figure 3 . In the treatment of cancer, the products improve drug targeting, solubility, and bioavailability. They aim to address the issues of drug resistance and improve the efficacy of treatment.

TPGS-based micelles, which are prepared with D-α-tocopheryl polyethylene glycol succinate (TPGS), have gained considerable interest because they have the ability to enhance drug solubility and bioavailability. Their ability to bring about immunogenicity, however, is a major deterrent to their use in the clinic. Recent data have proved that PEGylated molecules like TPGS have the ability to generate anti-PEG antibodies, resulting in accelerated blood clearance (ABC) and hypersensitivity reactions on repeated dosing [ 253 , 254 , 255 ]. The amphiphilic character of TPGS is also a concern with regard to complement activation-related pseudoallergy (CARPA), particularly at high doses or chronic dosing. Although TPGS has been found to possess an acceptable safety profile in preclinical studies, comprehensive immunotoxicity evaluations are only limited, and additional studies are required to prove safety in a broad spectrum of patient populations. From a production standpoint, large-scale production of TPGS-micelles is also hampered by batch-to-batch reproducibility issues, particularly with respect to particle size, drug loading efficiency, and stability [ 256 ]. Micellization is highly sensitive to the solvent system, concentration, and preparation procedure, and scale-up is certainly no easy process [ 257 , 258 ]. Furthermore, regulatory avenues are uncertain, considering that TPGS is both an active ingredient with an effect on pharmacokinetics and a functional excipient. Such dual functionality makes classification based on current FDA or EMA guidelines challenging, and the outcome is that it might have to be characterized and controlled with more stringent standards than typical excipients. Harmonized nanomedicine approval guidelines are also not in place, further complicating the picture and potentially slowing clinical deployment of TPGS–micellar systems in the face of promising therapeutic outcomes [ 261 , 262 ].

6. Targeted Delivery Approaches

Surfactant-mediated drug-releasing strategies from nanocarrier systems encompass enhancing drug solubility, modifying cellular membranes, and inhibiting efflux pumps. Surfactants stabilize nanocarriers, facilitate drug loading, and allow for controlled or site-specific release. This approach enhances therapy efficacy, especially for multidrug-resistant tumors ( Figure 4 ). To achieve the highest therapeutic effects and minimize systemic side effects, targeted drug-delivery systems are designed to direct therapeutic molecules to specific cells or tissues. In oncology, where conventional chemotherapy often leads to severe side effects due to the nonspecific distribution of drugs in the body, the ability to deliver drug action to a particular location is incredibly beneficial [ 263 ]. Targeted drug delivery has been achieved through many strategies, including the application of liposomes, nanoparticles, and antibody–drug conjugates, each having shown potential in preclinical and clinical studies [ 264 ]. These systems usually make use of the biological properties of tumors, such as their increased permeability and retention (EPR) effect, to allow for improved drug accumulation in the tumor region [ 265 ]. One of the most popular methods for delivering drugs to a specific location is through surface-modified nanoparticles. For instance, nanoparticles containing specific ligands or antibodies may bind to overexpressed receptors on tumor cells to enable the exact administration of the therapeutic ingredient [ 266 ]. This method increases the drug’s effectiveness while lowering the risk of systemic toxicity. In the well-known instance of using HER2-targeted liposomes to deliver chemotherapeutic medicines for the treatment of breast cancer, trastuzumab coupled to the liposomal surface enhanced drug delivery and clinical results [ 267 ].

The regulated release of drugs is another benefit of targeted delivery systems based on nanoparticles. When encapsulated in nanocarriers, which may release the drug in response to particular stimuli like temperature or pH changes frequently found in the tumor microenvironment, drugs can be protected from premature degradation [ 268 ]. These methods make it possible to apply the medication more effectively, which improves therapeutic results and lessens adverse effects. Paclitaxel, for instance, can be given in pH-sensitive nanoparticles, which introduce the medication into the acidic tumor environment and increases the drug’s lethality against cancer cells [ 269 ]. A further promising method for targeted drug delivery is the use of antibody–drug conjugates, or ADCs. ADCs, which are composed of monoclonal antibodies associated with these medications, enable the selective delivery of potent cytotoxic agents to cancer cells exhibiting the particular target antigen [ 270 ]. This strategy has already produced FDA-approved treatments for HER2-positive breast cancer, such as trastuzumab emtansine (Kadcyla ® (Roche, Basel, Switzerland)) [ 271 ]. ADCs’ high levels of specificity reduce the collateral harm that traditional chemotherapy usually causes to healthy cells and tissues.

Although targeted medication delivery systems have advanced significantly, there are still a number of obstacles to overcome. One of the biggest obstacles is tumor heterogeneity, which makes it more difficult to successfully target every cancer cell because various parts of a tumor express varying amounts of the target receptor [ 272 ]. Furthermore, the immune reaction to the antibodies or nanoparticles may cause the drug delivery system to be eliminated before it reaches the target, which would decrease the treatment’s overall efficacy [ 273 ]. Research continues to develop ways in which one can bypass such limitations, such as developing delivery systems that are multi-targeted or utilizing stealth technology in order to evade immune detection [ 274 ]. All things considered, targeted drug delivery techniques have transformed the science of drug therapy as a whole by providing better and more accurate ways to deliver medications to their intended locations of action. Clinical treatments based on liposomes, ADCs, and nanoparticles have demonstrated significant promise in lowering adverse effects and improving therapeutic results. More research and clinical trials are required to improve these systems and address the ongoing issues with their use, which will eventually result in even more potent treatments for cancer and other diseases.

6.1. Ligand-Functionalized Surfactant-Based Systems (e.g., Folic Acid, HER2 Antibodies)

Drug delivery via ligand-functionalized surfactants has emerged as an effective strategy to enhance the efficacy and selectivity of targeted therapy. Such systems involve the encapsulation of pharmaceutical compounds with surfactants, which are amphiphilic molecules capable of forming lipid layers or micelles. The systems have the ability to transport drugs to cells overexpressing specific receptors, like HER2, by incorporating ligands such as folic acid or antibodies against these receptors. This enhances treatment effectiveness and reduces off-target toxicity [ 275 ]. Improved treatment results have been obtained when therapeutic drugs are concentrated in the targeted tissues, such as cancer cells, due to the targeting capability provided by ligands such as folic acid, which can bind with the folate receptor, or HER2 antibodies, which target HER2-positive cells specifically [ 276 ]. Since folate receptors are broadly overexpressed on a range of cancer cell types, such as breast, ovarian, and colon cancers, folic acid-targeting surfactant-based systems are particularly useful in cancer therapy [ 277 ]. Such systems are able to utilize the increased folate uptake of the tumor to deliver chemotherapeutic drugs, such as doxorubicin (DOX) or paclitaxel, to the tumor site directly by conjugating surfactant-based carriers with folic acid [ 278 ]. As per research, this approach can raise the level of medication that builds up in tumor tissues, enhancing the therapeutic index and reducing the adverse effects that are normally related to conventional chemotherapy [ 279 ].

Likewise, HER2-targeted surfactant-based delivery systems have shown tremendous potential in the therapy of HER2-positive cancers, such as certain types of gastric and breast cancer. Such drug delivery systems have the ability to bind selectively to HER2 receptors overexpressed on the surface of cancer cells by functionalizing surfactants with antibodies against HER2 [ 280 ]. This allows the encapsulated drug to be released predominantly at the site of the tumor [ 281 ]. This tailored strategy improves clinical outcomes for HER2-positive tumors by minimizing damage to healthy cells and optimizing the therapeutic efficacy of the encapsulated medication, such as doxorubicin or trastuzumab [ 282 ]. Ligand-functionalized surfactant-based systems provide improved drug targeting, stability, and controlled release characteristics. Depending on the tumor microenvironment’s acidic or enzymatic conditions, the encapsulated drug can be administered, and surfactant micelles or vesicles can shield it from early deterioration while in circulation [ 283 ]. This regulated release technique lessens systemic side effects and increases the treatment’s therapeutic efficacy by guaranteeing that the medication is exclusively active at the intended site [ 284 ].

One of the ways that ligand-targeting and surfactant-based delivery systems can be used to introduce several therapeutic treatments is by combining chemotherapy with gene therapy or immunotherapy. For instance, surfactant-based carriers functionalized with folic acid or HER2 antibodies have been used to co-deliver chemotherapy drugs and siRNA, enabling synergistic effects across several therapeutic modalities [ 285 ]. This approach facilitates the use of combination medications, which can circumvent drug resistance and enhance the overall therapeutic response [ 286 ]. Although ligand-functionalized surfactant-based systems have a lot of potential, several issues must be resolved to maximize their practical usefulness. These include concerns about the ligands’ immunogenicity, the stability of the ligand–receptor interaction, and the requirement for effective production procedures. Furthermore, intratumoral variability in target receptor expression, such as HER2, limits the therapeutic potential of targeted medications in certain patient groups [ 287 , 288 ]. It will need more research and clinical testing to overcome these obstacles and fully utilize ligand-functionalized surfactant-based drug delivery systems.

6.2. Dual-Delivery Systems (e.g., DOX + siRNA)

Dual-delivery platforms are a sophisticated method of drug delivery that has attracted a lot of attention lately. They involve the simultaneous co-delivery of multiple medicinal agents. Conjugating nucleic acids like siRNA with traditional chemotherapeutic treatments like doxorubicin (DOX) can greatly increase the therapeutic effectiveness of anticancer medications [ 287 , 288 , 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 , 297 , 298 , 299 , 300 , 301 ]. By intercalating DNA and blocking topoisomerase II, DOX is a potent chemotherapeutic drug that causes DNA damage and apoptosis in tumor cells [ 302 ]. However, its usefulness is frequently restricted by severe systemic toxicity and drug resistance. However, siRNA offers an alternative mode of action that can get around these restrictions by mutating particular genes linked to drug resistance or the development of cancer. The goal of designing a dual-delivery system is to concurrently target a few pathways that give cancer cells their ability to survive. For instance, co-delivery of DOX and siRNA against multidrug resistance (MDR) proteins, such as P-glycoprotein (P-gp), has been demonstrated to sensitize drug-resistant cancer cells to DOX treatment, hence overcoming drug resistance and improving overall therapeutic efficiency [ 303 ]. Dual-delivery systems, in contrast to traditional medications, can produce synergistic benefits by transporting both therapeutic substances via a single delivery method. This leads to better medication results and fewer adverse effects [ 304 ].

Because they provide a consistent and regulated release platform for DOX and siRNA, nanoparticles are essential in the administration of dual therapy. To guarantee their simultaneous release at the tumor site, DOX and siRNA have been encapsulated in various nanoparticles, including liposomes, micelles, and polymeric nanoparticles [ 305 , 306 , 307 , 308 , 309 , 310 , 311 ]. The nanoparticles may be surface-functionalized with certain ligands or antibodies, such as folic acid or HER2-targeted antibodies, to improve targeting efficacy and increase drug accumulation within the tumor environment [ 312 ]. This focused strategy is especially helpful in resolving the problem of non-specific distribution, which frequently results in off-target toxicities and reduced effectiveness of traditional drug delivery methods. The potential for synergistic effects is one of the main benefits of dual-delivery methods. For example, siRNA can be used to decrease genes that encourage treatment resistance, whereas DOX directly affects the cancer cells. This combination can increase the effectiveness of chemotherapeutic medications against cancer cells and offer a more effective long-term treatment plan by decreasing tumor recurrence [ 313 ]. Research has demonstrated that co-administration of DOX with siRNA-targeting genes such as drug efflux pumps or anti-apoptotic proteins dramatically improves response to treatment in a variety of cancer models [ 314 ].

Another significant benefit of dual-delivery systems is the controlled release of both drug substances. A more efficient and sustained therapeutic effect can be achieved through the design of nanoparticles that simultaneously release siRNA and DOX [ 315 ]. For instance, the use of pH-responsive nanoparticles enables the regulated administration of siRNA and DOX in the acidic environment of tumors, guaranteeing that both medications reach the tumor cells at the best possible moment [ 316 ]. By lowering the possibility of early release and the resulting harm to healthy tissues, this improves the treatment’s overall safety profile. Despite their potential, clinical translation and the creation of dual-delivery systems present difficulties. Among the primary problems are the intricate formulation and the challenge of attaining consistent and reliable co-delivery of both therapeutic medications. Furthermore, resolving siRNA’s intrinsic instability and guaranteeing the effective cellular uptake of siRNA and DOX continue to be formidable obstacles [ 317 ]. Future studies must concentrate on enhancing these systems’ stability, target efficacy, and controlled release behavior in order to optimize their therapeutic potential.

7. Overcoming Multidrug Resistance (MDR)

Surfactant-carriers suppress drug efflux pumps such as P-glycoprotein and increase membrane permeability. Surfactant-carriers enhance intracellular drug uptake and stabilize drug delivery systems ( Figure 5 ). This results in re-established drug sensitivity and enhanced cancer treatment efficacy. In the treatment of breast cancer, surfactant-based nanocarriers enhance drug solubility, stability, and targeted delivery. Surfactant-carriers enhance intracellular drug retention and counteract multidrug resistance (MDR) by inhibiting efflux pumps such as P-glycoprotein ( Table 5 and Table 6 ). These technologies minimize toxicity and side effects as well as enhance therapeutic outcomes. Multidrug resistance (MDR) is the biggest hindrance in cancer treatment, making most chemotherapeutic treatments fail. MDR is mainly due to overexpression of efflux pumps such as P-glycoprotein (P-gp), which actively exports anticancer drugs from cells, restricting drug buildup and effectiveness [ 318 , 319 , 320 , 321 , 322 , 323 , 324 ]. This can be further enhanced by alterations in drug targets, modified apoptosis mechanisms, and increased DNA repair processes [ 325 , 326 , 327 ]. Scientists have been focusing on developing methods to either inhibit these efflux pumps or increase drug delivery to bypass these resistance processes to combat MDR. One approach is the employment of drug delivery systems using nanoparticles, which are able to encapsulate drugs and deliver them directly to the site of the tumor [ 328 , 329 ]. This increases the deposition of drugs within cancer cells and reduces their binding to efflux pumps in normal tissues by increasing the solubility and bioavailability of anticancer drugs; nanoparticles like liposomes [ 330 ], micelles, and polymeric nanoparticles have shown promise against MDR. Through the modulation of the release of their payload, such nanoparticles are able to ensure long-term drug concentrations within the tumor environment and reduce the risk of efflux pump-dependent resistance [ 331 , 332 ]. As an illustration, evidence has been put forward to the effect that the delivery of liposomal formulations of doxorubicin is capable of circumventing P-gp-driven efflux through the encapsulation of the drug in a lipid bilayer that prevents direct drug interaction with the pump and increases intracellular drug accumulation [ 333 ].

Apart from enhancing drug delivery, the inhibition of P-gp and other drug efflux pumps is another essential approach to overcome MDR. A number of compounds have been found to inhibit the functioning of these pumps, thus reversing the resistance of cancer cells to chemotherapy. In drug-resistant cancer cell lines, for example, it has been found that the calcium channel antagonist verapamil is an inhibitor of P-gp activity and enhances the cytotoxicity of drugs like doxorubicin [ 348 , 349 ]. More recent studies have also explored the use of naturally occurring compounds like curcumin that have the capacity to modulate the expression and activity of efflux pumps and small molecules that specifically inhibit P-gp, such as tariquidar and zosuquidar [ 350 ]. While concerns regarding their safety and toxicity remain to be dealt with in the clinical context, these inhibitors can effectively bypass drug resistance when administered in combination with conventional chemotherapy [ 351 ]. Utilizing multidrug resistance modulators, which have the ability to alter gene expression associated with resistance in cancer cells, is another interesting approach. The downregulation of P-gp or other resistance-associated protein expression by gene therapy methods is one such case. To revive the sensitivity of cancer cells to chemotherapeutic drugs, P-gp and other drug resistance-related genes have been accurately knocked down by employing RNA interference (RNAi) and CRISPR-Cas9 gene editing [ 352 ]. It is possible to enhance the effectiveness of existing drugs without having to develop new chemotherapeutic drugs by using these technologies to specifically target the molecular pathways responsible for MDR [ 353 ].

To overcome MDR, combined therapy that hits multiple resistance pathways has also been proposed. Scientists attempt to render cancer cells more responsive to treatment and less prone to developing resistance by combining chemotherapeutic agents with inhibitors of resistance pathways, i.e., P-gp inhibitors or apoptosis modulators. For example, preclinical models of MDR cancer have shown enhanced antitumor activity when doxorubicin is used in combination with a P-gp inhibitor or an apoptosis inducer [ 354 ]. Clinical trials are ongoing to study these combinatory strategies, with the aim of finding feasible methods to overcome MDR and improve the efficacy of cancer therapy. While promising developments have been seen in combating MDR, there remain some challenges to be addressed before these strategies can be applied in the clinical context. Major hurdles involve the potential toxicity of resistance inhibitors, complexity of resistance mechanisms, and diversity of malignancies [ 355 ]. In addition, to ensure efficacy and safety, extensive preclinical and clinical studies are required to develop novel drug delivery strategies and resistance modulators. In search of optimal approaches to reverse MDR and maximize the efficacy of cancer therapies in the clinic, continued investigation is needed.

7.1. Role of Surfactants Like TPGS, Tween 80, and Brij 35 in Efflux Pump Inhibition

One major challenge in cancer therapy is multidrug resistance (MDR), where cancer cells are resistant to numerous chemotherapy agents. MDR is primarily brought about by efflux transporters, particularly the ATP-binding cassette (ABC) family of transporters, which export anticancer drugs from cells, reducing their intracellular levels and efficacy [ 335 , 356 , 357 ]. Surfactants like Tween 80, Brij 35, and d-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS) have been recognized as potential efflux pump inhibitors (EPIs) that could assist in reversing MDR. The capability of TPGS, a derivative of vitamin E, to inhibit P-glycoprotein (P-gp), a recognized efflux pump, is established. TPGS has been shown in studies to reverse drug resistance by enhancing the intracellular concentration of chemotherapeutic drugs such as doxorubicin and paclitaxel by inhibiting the ATPase activity of P-gp [ 337 , 343 ]. Similarly, it has been proven that the nonionic surfactant Tween 80 suppresses P-gp-efflux in a variety of cell lines, enhancing the efficacy of chemotherapeutic drugs [ 344 ]. Experiments have indicated that another nonionic surfactant, Brij 35, may enhance the cytotoxicity of anticancer drugs in drug-resistant cell lines by modifying the activity of efflux pumps [ 338 ].

The physicochemical properties of the surfactants, e.g., hydrophilic-lipophilic balance (HLB), are also the reasons for the ability of surfactants to inhibit efflux pumps. For example, TPGS may interact with the cell membrane lipid bilayer and change P-gp activity due to its high HLB. Besides enhancing drug uptake, such interaction prevents drugs from actively effluxing out of the cell [ 358 ]. The ability of surfactants to alter the fluidity of the membrane and inhibit the efflux pump is crucial for enhancing medication retention in cells. Nonionic surfactants like Tween 80 and Brij 35 are also more desirable for clinical application because they are less toxic to healthy cells compared to other efflux pump inhibitors [ 359 , 360 ]. Their capability to bypass chemoresistance is also evidenced through their differential effect on MDR cells [ 361 ]. In addition, clinical trials have indicated promising results when surfactants and anticancer drugs are co-administered. For example, the ability of TPGS and paclitaxel in combination to overcome P-gpmediated drug resistance in cancer cells has been explored in clinical situations [ 336 ]. As per clinical trials using surfactant–drug formulations, surfactants have the ability to enhance the bioavailability and therapeutic effects of the medications substantially. Surfactants such as TPGS possess beneficial pharmacokinetic properties enabling them to escape efflux-mediated resistance and thus are an effective strategy in combating MDR in anticancer therapy [ 362 , 363 ]. Drug-resistant cancer patients can be improved with the treatment if surfactants are incorporated into drug formulations.

7.2. Mechanisms of MDR Reversal with Surfactant-Carriers

Surfactants increase drug solubility, block efflux pumps, and raise membrane permeability. They enable greater intracellular drug retention in MDR cells. This approach enhances therapeutic effectiveness and helps counteract multidrug resistance ( Figure 6 ). Surfactant-carriers are increasingly being utilized as a strategy to overcome MDR by not only blocking efflux pumps but also by increasing the bioavailability and cellular accumulation of chemotherapeutic agents [ 364 , 365 ]. Surfactant interaction with cell membranes is the process through which surfactant-carriers induce reversal of MDR [ 366 , 367 ]. Surfactants, being amphiphilic, are able to dismantle the plasma membrane lipid bilayer, facilitating increased drug molecule permeability that otherwise would be pumped out by pumps like P-gp. The increased membrane permeability facilitates chemotherapy drugs to accumulate within the cells, which ensures drug retention and bypasses mechanisms of resistance [ 368 ]. Surfactants also have the role of being solubilizing agents, which enhance the solubility of poorly soluble anticancer drugs and facilitate easier transport across membranes [ 339 ].

Another reason why surfactants and chemotherapeutic drugs act together is the formation of surfactant–drug complexes, which are more readily taken up by cancer cells than free drugs. Increased intracellular drug levels may be attained through encapsulating hydrophobic drugs within micellar assemblies that bypass the efflux pump barriers [ 345 ]. When surfactant and drug molecules combine to create mixed micelles, hydrophobic drugs are stabilized and made more soluble, enhancing their prospects for the treatment of MDR-resistant cancers [ 346 ]. In addition, by altering the transcriptional activity of efflux pump protein-encoding genes or by influencing the efflux pump proteins themselves, surfactants are able to alter efflux pump protein expression levels, leading to a reduction in their activity and enhanced retention of drugs [ 369 ]. Surfactant-carriers can interfere with other cellular mechanisms that have been involved in drug resistance in addition to their role in suppressing the efflux pump. For instance, it has been shown that surfactant use influences signaling pathways that are also connected with MDR, including those that involve breast cancer resistance protein (BCRP) and multidrug resistance proteins (MRPs). Surfactants have the ability to increase the reversal of MDR by specifically targeting these proteins [ 340 ]. Surfactant carriers can also affect intracellular drug distribution and can be targeted at various subcellular compartments, including the nucleus, where most anticancer drugs act, and make the pharmaceuticals more evenly distributed within the cells. This comprehensive approach reduces the challenges posed by MDR and enhances the overall efficacy of the treatment regimen [ 370 ].

Surfactants’ use as carriers has also promoted the development of targeted drug delivery systems aimed at specifically tackling MDR. The occurrence of off-target effects can be reduced by targeting the drug–surfactant complex to specific sites of tumors through the modification of surfactant molecules to incorporate targeting ligands, i.e., peptides or antibodies. Besides enhancing the tumor drug concentration, these surfactant-carrier targeting systems decrease the systemic toxicity associated with conventional chemotherapy [ 341 ]. Raising the therapeutic index of drug delivery systems based on surfactants has been shown to be feasible by targeting specific receptors that are overexpressed on cancer cells, i.e., folate receptors or epidermal growth factor receptors (EGFRs) [ 347 ]. This customized drug delivery system holds much potential for conquering MDR and enhancing the selectivity and effectiveness of chemotherapeutic drugs. Overall, because surfactant-carriers can specifically target some cancer cells, increase drug solubility and stability, and inhibit efflux pumps, they represent a convenient means of combating MDR. Surfactants in combination with chemotherapeutic medicines might enhance the effectiveness of cancer therapy, particularly in the ability to overcome resistance. For them to maximize their potential in reversing MDR and improving patient outcomes in cancer therapy, additional research into surfactant formulation optimization and clinical validation are needed [ 342 ].

8. Biocompatibility and Toxicological Profile

When developing surfactant-based drug delivery systems, biocompatibility and toxicological characteristics are crucial ( Table 7 ), particularly when surfactants are being utilized to treat cancer and combat multidrug resistance (MDR). Because surfactants like TPGS, Tween 80, and Brij 35 are frequently given systemically, biocompatibility is crucial to proving their safety in vivo. According to studies, TPGS has been extensively investigated for its high biocompatibility and low toxicity, and it is said to be well tolerated in animal models [ 371 ]. Since nonionic surfactants Brij 35 and Tween 80 have shown reduced cytotoxicity in a number of in vitro and in vivo investigations, they are both viable options for drug administration [ 372 , 373 ]. Notwithstanding this possibility, the toxicity profiles of any drug can be altered by dosage and administration methods. Among the negative effects caused by extremely high concentrations or extended exposure to these surfactants are hemolysis and inflammation, which emphasizes the necessity of optimizing formulation conditions in order to reduce toxicity [ 374 ]. Furthermore, it is clear that large dosages of surfactants, such as Tween 80, may be harmful to kidney and liver function; therefore, careful dosing control is necessary to prevent systemic toxicity [ 375 ]. Therefore, assessing organ-specific toxicities as well as acute and chronic toxicity is necessary to ensure the safe and efficient clinical use of surfactant carrier systems. Lastly, despite the promising biocompatibility profiles of surfactants like TPGS, Tween 80, and Brij 35, more toxicological testing is necessary to guarantee their safety for use in overcoming MDR, and comprehensive research is necessary to establish long-term safety within human clinical trials.

8.1. Cytotoxicity Studies and Dose-Limiting Toxicities

Cytotoxicity studies are a crucial component of assessing the safety and effectiveness of surfactant-based drug delivery systems, particularly when surfactants are employed in anticancer therapy to combat multidrug resistance (MDR) [ 376 ]. Determining the possible negative effects of surfactants on healthy cells and tissues is the aim of these investigations. In several cell lines, the cytotoxicity profiles of surfactants such TPGS, Tween 80, and Brij 35 have been identified. Research has indicated that TPGS dosages up to 0.5% ( w / v ) are well tolerated in in vitro cell models and have demonstrated encouraging outcomes in improving drug retention at therapeutic levels without significantly harming normal cells [ 377 ]. However, it should be mentioned that elevated surfactant levels may result in dose-dependent cytotoxicity. For example, it has been shown that elevated Tween 80 levels can have cytotoxic effects, such as cell membrane rupture and changes in cell viability [ 378 ]. To prevent exacerbating the toxicity to healthy tissues, surfactants and chemotherapeutic drugs may also have additive or synergistic effects that need to be carefully considered [ 379 ]. Using their understanding of cytotoxicity profiles, scientists can tailor surfactant formulation and dosage to maximize therapeutic efficacy while reducing negative effects on healthy cells.

The development of medication delivery methods that include surfactants raises serious concerns regarding DLTs, which are side effects that, because of their severity, make it impossible to increase a drug’s dosage further and may even cause treatment to be stopped. In surfactant–drug combos, DLTs may result from the combined toxicity of the surfactant and the chemotherapeutic medication. For instance, while TPGS has been demonstrated to increase the bioavailability of doxorubicin and paclitaxel, excessive dosages of the drug have been linked in animal models to hepatotoxicity, gastrointestinal toxicity, and blood enzyme rise [ 380 ]. Likewise, overdosing on Tween 80 has been linked to nephrotoxicity and liver damage [ 381 ]. These DLTs highlight how crucial it is to identify the ideal dosage range for drug–surfactant mixes in order to reduce adverse effects. Clinically investigated surfactant-based drug delivery systems require close patient monitoring for toxicity, especially when bigger dosages or longer treatment are administered. Preclinical research is frequently used to determine safe and effective dosages, and additional surfactant formulation adjustments can lower DLTs by lowering toxicity without compromising therapeutic efficacy [ 382 ].

8.2. Biodegradable and GRAS-Listed Surfactants

Biodegradable surfactants have attracted the attention of drug delivery system researchers, especially for use in the treatment of MDR in cancer care [ 383 ]. Surfactants that break down into harmless metabolites are desirable since they lower the likelihood of long-term body accumulation. Due to their biocompatibility and biodegradability, poly(lactic acid)-derived biodegradable surfactants, such as poly(lactic-co-glycolic acid) (PLGA), have been used in diverse drug delivery formulations [ 384 ]. Even though PLGA-based surfactants degrade over time, no possibility of bioaccumulation or toxicity exists for this formulation. They are ideal for sustained drug delivery systems due to their biodegradability, which can release the drug slowly over time without requiring additional treatments. In addition, by promoting more drug retention in cancer cells and less exposure to healthy cells, these surfactants can be designed so as to target a specific tissue, enhancing their value in breaking MDR [ 385 ]. As a result, biodegradable surfactants are suitable candidates for safer and more effective MDR reversal methods with their controlled release properties and biocompatibility.

Whether a surfactant is included by regulatory organizations such as the U.S. Food and Drug Administration (FDA) as Generally Recognized as Safe (GRAS) is another factor in deciding which one to use in delivering medication. Surfactants which have been scientifically proven to be safe for their intended application in food, drugs, or cosmetics are known as GRAS-listed surfactants. Due to their safety profile, nonionic surfactants such as Tween 80 and GRAS-listed surfactants are often used in drugs [ 386 ]. At proper amounts, Tween 80 has been extensively researched for its lack of toxicity and potential to enhance the solubility and bioavailability of drugs that poorly dissolve without causing significant adverse effects [ 387 ]. Brij 35 is another GRAS-listed nonionic surfactant, which has exhibited negligible cytotoxicity when subjected to in vitro and in vivo experiments. Its applications in enhancing therapeutic effect and overcoming MDR without inducing side effects have also motivated investigations on its application in drug delivery systems [ 388 ]. GRAS-listed surfactants are suitable for clinical translation and long-term therapy because they provide an added layer of safety and regulatory assurance.

Because they meet the sustainability and safety standards needed for widespread use in medical applications, GRAS-listed and biodegradable surfactants are particularly sought-after [ 389 ]. Because they cannot build up in the body, their capacity to break down into non-toxic byproducts lowers the possibility of harmful long-term effects, including organ toxicity or chronic inflammation [ 390 ]. Furthermore, the minimal environmental impact of surfactants due to natural degradation is one of the main elements driving the pharmaceutical industry’s increased desire for green chemistry solutions. Because they can significantly improve the hydrophobic medication’s solubility, stability, and controlled release in drug delivery systems, surfactants are especially useful in combating MDR [ 391 , 392 ].

8.3. Biodegradability and the Environmental Impact of Surfactants

Although biodegradable surfactants provide several advantages in medication administration, it is important to take the environment into account as well. The overall sustainability and safety of biodegradable surfactants may even be impacted by their environmental persistence. Certain biodegradable surfactants, such those derived from natural oils and fatty acids, have been demonstrated to break down more quickly and produce less harmful consequences than synthetic surfactants [ 393 , 394 ]. However, the rate at which certain surfactants biodegrade can be affected by environmental variables like pH, temperature, and microbial activity. It is essential to assess the in vivo and environmental degradation profiles of surfactants used in drug administration to make sure they do not present long-term risks to ecosystems. Ongoing research on surfactant biodegradation pathways and environmental toxicity will be crucial to the development of sustainable medication delivery methods with fewer negative effects on biology and the environment [ 395 ].

Using GRAS-listed and biodegradable surfactants in drug delivery formulations is one method of avoiding MDR while upholding strict safety regulations. Clinical usage of surfactants such as TPGS, Tween 80, and Brij 35 is possible due to their low toxicity and good tolerance at therapeutic concentrations [ 396 ]. More research is required to evaluate their cytotoxicity, dose-limiting toxicities, and biodegradation characteristics in preclinical and clinical contexts. The creation of safer surfactant–drug formulations will require striking the ideal balance between maximizing therapeutic efficacy and reducing toxicity to healthy tissues. By concentrating on biodegradable and ecologically friendly surfactants, scientists can create cancer therapies and develop other therapeutic areas that are more effective and sustainable while also increasing the overall efficacy of MDR reversal methods [ 397 , 398 ].

9. Recent Trends and Innovations in Stimuli-Responsive Surfactant Systems

Stimuli-sensitive surfactants or smart surfactants have recently been a breakthrough family of materials ( Figure 7 ) due to their ability to alter structural and physicochemical properties upon exposure to external environmental signals such as pH, temperature, and redox [ 399 , 400 , 401 , 402 ]. It is possible to design surfactants that can selectively respond to specific environmental stimuli [ 403 , 404 ], and hence, these surfactants are suitable for various biomedical and industrial applications ( Table 8 ). Recent work has pointed to the development of surfactants with pH-sensitive moieties, which are extremely useful for drug delivery systems in cancer chemotherapy [ 403 , 404 ]. Ding et al. (2022) reported that pH-sensitive surfactants may deliver chemotherapeutic agents into acidic tumor microenvironments with lower pH values than normal tissue [ 405 ]. In addition, temperature-sensitive surfactants, which can exhibit phase transitions at certain temperatures, have been of interest in controlled drug release systems. Verkhovskii et al. (2023) found that such surfactants are applied in smart hydrogels for localized and temperature-induced drug release, enhancing the therapeutic effect [ 406 ].

Redox-responsive surfactants, however, are finding increased use in those applications wherein the release of bioactive chemicals is facilitated by reduction or oxidation of certain chemical bonds [ 407 ]. Disulfide-containing surfactants, for example, have been utilized to design nanoparticles that, upon contact with the reducing microenvironment of tumor cells or inflammatory tissue, release their payload [ 408 ]. Shende and Deshpande, 2020 assert that by minimizing off-target effects and enhancing the therapeutic index, redox-responsive surfactant systems may enhance drug delivery’s specificity and efficacy [ 409 ]. Targeting hard-to-reach locations such as the brain or inflamed tissues is easier with this targeted release, triggered by changes in redox conditions. In addition, surfactant systems’ responsiveness to numerous stimuli, such as pH and redox, offers the opportunity to maximize drug release processes, broadening their application in precision medicine.

9.1. Co-Delivery of Chemotherapeutics and Immune Agents

The concurrent delivery of chemotherapeutic drugs and immune-modulatory drugs has received considerable interest in cancer therapy with the synergistic benefits it has to provide [ 410 ]. Combining immunotherapies, which stimulate the immune system of the body against tumors, with chemotherapy, which specifically kills the cancer cells, is a promising method to circumvent the limitations of single-agent monotherapy [ 411 ]. Surfactants are very important to this co-delivery approach, particularly in the development of nanocarriers capable of simultaneously encapsulating both types of drugs. Kandasamy et al.’s study in 2023 demonstrated that surfactant-stabilized micelles could co-deliver a checkpoint inhibitor and the chemotherapy agent doxorubicin, which enhanced tumor regression and reduced systemic toxicity [ 412 ]. Successful delivery of immunological and chemotherapeutic drugs to the tumor site relies on the surfactant’s ability to solubilize hydrophobic drugs and protect them from premature degradation. The use of surfactant systems for co-delivery may not only enhance drug efficacy but also overcome the problem of tumor immune suppression. For instance, surfactant-based nanoparticles may enhance the overall treatment outcome by encapsulating immune stimulators and chemotherapeutics in one formulation, such as cytokines or adjuvants. Liu et al. (2024) explored the use of surfactant-functionalized lipid nanoparticles to co-deliver paclitaxel and an immune checkpoint inhibitor [ 413 ]. The results showed a significant increase in immune cell activation at the tumor site along with enhanced tumor-targeted delivery. The tumor microenvironment was effectively transformed by this bimodal approach, which additionally directly cytotoxically destroyed the cancer cells and induced an anti-tumor immune response. Through synergistic co-delivery, these findings demonstrate the value of surfactant-based nanocarriers in revolutionizing cancer treatment.

9.2. Surfactants in Photodynamic and Gene Therapy

Two newer therapeutic methods being explored increasingly for their ability to target and treat tumors selectively with minimal side effects are photodynamic therapy (PDT) and gene therapy [ 414 , 415 ]. Surfactants have been found to be key players in both PDT and gene therapy as they can facilitate the solubilization and controlled release of therapeutic agents like photosensitizers and nucleic acids. The stability and bioavailability of photosensitizers that are photoactivated to produce reactive oxygen species (ROS) targeted at killing cancer cells are enhanced in PDT through the use of surfactants. Recent advances have focused on making the selectivity and efficacy of PDT better through surfactant-coated nanoparticles that can efficiently deliver these photosensitizers to tumor cells [ 416 , 417 ]. For instance, Castillo et al. (2017) reported that upon exposure to light activation, surfactant-stabilized micelles of Porphyrin-based photosensitizer exhibited improved cellular uptake and retention with more efficacious therapeutic outcomes [ 418 ].

Surfactants are utilized in gene therapy to assist in delivering genetic material into target cells, such as plasmids, siRNAs, and CRISPR-Cas9 reagents [ 419 ]. Cationic-headed surfactants are often utilized to co-associate with nucleic acids to form nanoparticles that may penetrate cell membranes. The use of surfactant-based nanoparticles [ 420 ] for the delivery of CRISPR-Cas9 systems for gene editing within cancer cells was highlighted in a recent study by Wu et al. (2024). By protecting the cargo from enzymatic degradation [ 420 , 421 ], the surfactants enhanced gene editing efficacy and enhanced the stability and cellular internalization of the CRISPR reagents. In addition, surfactant-based systems may be designed to respond to specific stimuli, for example, temperature or pH, in a controlled manner to deliver their gene therapy payloads. These developments render surfactant-based carriers a fundamental tool in the delivery of efficient and targeted PDT and gene therapy strategies.

9.3. Surfactant-Mediated Tumor Targeting

Surfactant-based systems’ capacity to obtain selective tumor targeting is a decisive aspect of their success as drug delivery systems [ 421 ]. Leverage on some characteristics of tumor cells, including their altered surface charge, receptor overexpression, and the unique characteristics of the vasculature of tumors, is involved in the multifaceted procedure of tumor targeting [ 422 ]. Surfactant systems may be engineered to enhance tumor passive and active targeting, as recent studies indicate. To deposit the therapeutic payload precisely in the location of the tumor, for example, surfactant-modified nanoparticles may be ligand-functionalized and attach to receptors overexpressed on the surface of tumor cells [ 423 ]. As per a Pisani, 2022 study, folic acid-coated surfactant-functionalized liposomes selectively targeted cancer cells that had the expression of the folate receptor, resulting in greater drug concentration in tumors [ 424 ]. The enhanced permeability and retention (EPR) effect, which allows nanoparticles to accumulate within tumor tissues due to their leaky vasculature, can also be exploited by surfactant-based systems as well as receptor-mediated targeting [ 425 ]. By improving the stability and size distribution of nanoparticles, surfactants can increase their extravasation into tumors while decreasing absorption by healthy tissues. Recent advancements in surfactant formulations have produced hybrid nanoparticles, which mix liposomes, micelles, and dendrimers for the best possible drug delivery. According to research by Lee et al., these surfactant hybrids improve the pharmacokinetic profile of the encapsulated medications and improve tumor-specific delivery, resulting in more effective treatment with fewer systemic side effects [ 426 , 427 ].

Despite their promise for cutting-edge therapeutic applications, surfactant-based systems’ clinical translation and development continue to face numerous obstacles [ 428 ]. The requirement for exact control over the physicochemical characteristics of surfactant formulations in order to guarantee constant performance is one of the main obstacles. Understanding surfactants’ interactions with biological systems, such as the immune system, cytotoxicity, and biocompatibility, is crucial to maximizing their safety and effectiveness [ 429 ]. Scalability and reproducibility are also essential for the commercialization of surfactant-based nanocarriers, which are sometimes hindered by intricate and expensive production procedures [ 430 ]. Researchers like Chen et al. (2023) have emphasized the significance of creating standardized protocols in surfactant formulation in order to address these issues and enhance consistency in treatment results [ 431 ].

The development of surfactant systems that can guarantee site-specific and regulated drug release in vivo is another crucial problem. Although stimuli-responsive surfactants have demonstrated potential for initiating medication release under specific circumstances, it is still challenging to guarantee the exact moment and site of release. Future research will probably concentrate on increasing the sensitivity of surfactant systems to several stimuli at once, such as pH, temperature, and redox conditions, in order to accomplish more dependable and effective drug delivery [ 432 ]. As the sector develops, it is anticipated that new surfactant-based materials with enhanced targeting efficiency, stability, and therapeutic efficacy will be created.

10. Challenges and Future Prospects in Surfactant Metal Complexes for Biomedical Applications

10.1. Scale-Up, Reproducibility, and Storage Stability

The development of surfactant–metal complex systems for biomedical applications is significantly hampered by the difficulty of scaling up and repeating their synthesis. Although these complexes can be successfully synthesized in a lab setting, a number of obstacles must be removed before they can be produced commercially. Nanoparticles must have regulated size, shape, and composition in order to be successful, especially in medication delivery systems. Asymmetric treatment results and toxicity issues may result from variations in these factors. Temperature, reaction duration, and solvent selection are among of the variables that can affect the synthesis process’s repeatability throughout scaling [ 433 , 434 , 435 ]. Furthermore, storage stability is a major concern because many surfactant–metal complexes can degrade over time, particularly when exposed to environmental factors such humidity, light, and temperature variations [ 436 ]. Important steps to improve the long-term stability of such complexes include the creation of protective coatings or more sophisticated formulations that inhibit oxidation or hydrolysis and may reduce their bioactivity [ 87 , 90 ].

10.2. Regulatory Aspects

Surfactant–metal complexes used in biological applications have a complex and developing legal framework. These materials, which are frequently regarded as a novel type of nanomaterials, must pass stringent testing and authorization procedures before they can be widely used in therapeutic settings. Regulatory agencies like the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have developed frameworks for evaluating nanomaterials, but the regulations pertaining to surfactant-metal complexes are still being developed [ 437 ]. Toxicity tests, such as genotoxicity, immunotoxicity, and acute and chronic toxicity, should be performed to evaluate the safety of these complexes. Their biocompatibility with human tissue should also be thoroughly examined. Concerns regarding the consistency of their safety and effectiveness as well as regulatory obstacles are exacerbated by the diversity in surfactant–metal complex production. As research advances, a more uniform method of generating and evaluating these complexes will be needed to satisfy regulatory standards [ 438 ].

10.3. Precision Medicine and AI-Assisted Surfactant System Design

The development of surfactant–metal complexes for precision medicine holds great promise for the use of artificial intelligence (AI). Artificial intelligence (AI) has the potential to optimize these systems by searching through large datasets to find the best surfactants, metal pairings, and nanoparticle formulations for specific patients [ 439 ]. Additionally, scientists can use machine learning techniques to forecast the interactions between biological systems and surfactant–metal complexes, which can improve the effectiveness of treatments for particular disorders [ 440 ]. By taking patient genetic and phenotypic variations into account, AI can further assist in customizing drug delivery systems, guaranteeing that surfactant–metal complexes are made for maximum efficacy and minimal adverse effects [ 441 ]. AI-based models can also help predict the stability, biodegradation, and bioavailability of these complexes, ensuring their long-term efficacy in medical applications [ 442 , 443 , 444 , 445 ]. However, the creation of AI-supported systems must be carried out carefully since accurate model training necessitates both big datasets and high-quality experimental information.

There are still significant concerns about the possible toxicity and biocompatibility of surfactant–metal complexes, despite their great potential for biomedical applications. The way that nanoparticles interact with biological systems is greatly influenced by their size and surface chemistry. Stabilizing surfactants for metal nanoparticles might occasionally trigger immunological reactions that result in inflammation or cytotoxicity [ 446 , 447 , 448 ]. Furthermore, the metal ions that the nanoparticles release have the ability to build up in tissues and have toxicological effects, such as organ damage and oxidative stress [ 444 ]. Biocompatibility testing is essential to guarantee that the surfactant–metal complexes do not cause negative reactions when given to people. Future studies should concentrate on creating more biocompatible surfactants or altering the metal complexes’ surface characteristics in order to reduce toxicity while preserving therapeutic efficacy. Longer-term in vivo studies are also necessary to examine the potential accumulation of metal complexes in organs and tissues, which could eventually pose a health risk [ 449 , 450 ].

The transition of surfactant–metal complexes from laboratory-scale synthesis to clinical settings presents a second significant obstacle. Although these complexes appear promising in vitro, they frequently behave differently in vivo because of factors like metabolism, clearance rates, and biodistribution [ 445 ]. Manufacturing must be scalable without sacrificing the surfactant–metal complex’s structural integrity or functionality in order to advance these systems to clinical trials. Additionally, large-scale production methods need to be economical and ecologically responsible. Utilizing green chemistry concepts, such as bio-inspired or low-toxic reagents, during the synthesis of surfactant–metal complexes can lower manufacturing costs and their environmental impact [ 87 , 88 , 89 , 90 ]. Large-scale production involves taking into account the production and regulatory limitations, for example, complying with good manufacturing practices (GMPs). Ensuring that such products can be mass-produced without compromising their safety and quality is critical as scientists strive to optimize the synthesis and formulation process.

Looking forward, continued interdisciplinary research is crucial to the future of surfactant–metal complexes in biomedical applications. To surpass the current challenges and achieve the full potential of these materials, collaboration among chemists, biologists, and engineers will be important. Accelerated exploration of new surfactant–metal complex combinations will be facilitated by new material synthesis methods, such as automated synthesis platforms and high-throughput screening. In addition, there can be synergistic benefits to integrating nanomedicine with advanced technologies such as gene therapy, immunotherapy, and regenerative medicine. The future development of surfactant-assisted nanocarriers in the treatment of breast cancer will revolutionize the accuracy, efficacy, and safety of treatment. Surfactants play a pivotal role in stabilizing nanocarrier systems, improving drug solubility, and targeting drugs to tumor cells with minimal off-target toxicity [ 450 ]. Future development will focus on the development of smart, stimulus-sensitive surfactants for controlled drug release against the tumor microenvironment’s specific conditions, i.e., pH or enzyme levels. Additionally, the use of biocompatible and biodegradable surfactants will widen the clinical utility of these nanocarriers by reducing systemic toxicity and immunogenicity [ 451 ]. Future research can also explore the co-encapsulation of therapeutic drugs and diagnostic probes in a single nanocarrier for real-time monitoring and targeted therapy. With ongoing advancements in nanotechnology and molecular biology, surfactant-assisted nanocarriers are set to become a keystone in the next generation of breast cancer treatments. To enhance the precision and specificity of genetic treatments, surfactant–metal complexes, for instance, might be used as drug delivery vehicles for gene-editing tools. The development and optimization of surfactant–metal complexes for specific biological functions will increasingly rely on AI and computational modeling methods as they evolve. A promising future for the development of highly personalized and targeted therapies is offered by the integration of AI, precision medicine, and nanotechnology.

11. Conclusions

Surfactant-based drug delivery systems are a novel approach to breast cancer treatment that address some of the fundamental limitations of traditional chemotherapeutic drugs. Surfactants are amphiphilic, which allows them to act as permeability enhancers, solubilizers, and MDR modulators, all of which are especially important in the treatment of aggressive and drug-resistant breast cancer. They are effective vehicles in modern oncological treatment because they can produce nanoscale carriers, protect labile medicines, and promote tumor deposition through passive and active targeting methods. Clinical translation has demonstrated the safety and therapeutic efficacy of surfactant-containing formulations, as proven by medications like Genexol ® , with successful clinical results. Recent precision medicine objectives are closely matched with improvements in ligand-mediated targeting and dual-delivery techniques, which further improve therapy precision and treatment synergy. Furthermore, surfactants’ functional profiles are being expanded through their incorporation into modern technologies such as gene therapy, phototherapy, and stimuli-responsive systems. Nonetheless, there remain significant barriers to overcome before they can reach their full clinical potential. These include pharmacokinetic predictability, long-term storage stability, production scalability, and regulatory framework uniformity. Because of the cytotoxicity of certain synthetic surfactants, safer, biodegradable alternatives must be developed and approved by regulators. Advances in biosurfactant technology and computational design tools such as machine learning and AI-guided formulation hold the key to overcoming these impediments. In short, drug delivery methods that are surfactant-based have evolved into a robust and incredibly versatile platform for the treatment of breast cancer. These technologies improve treatment outcomes through the integration of nanotechnology, pharmacokinetics, and tailored medicine. They also usher in a new age of cancer therapies that will be characterized by enhanced patient compliance, reduced systemic toxicity, and improved selectivity.

Acknowledgments

I extend sincere thanks to the Dean, Department of General Medicine, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamilnadu, India, for their valuable guidance and encouragement. Canva software was used to design the figures.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Author Contributions

Original draft preparation, review, editing, and writing and supervision: K.N. conceptualization, methodology, data curation and validation: A.J. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The datasets generated and analyzed during this study are available from the corresponding author upon reasonable request.

Conflicts of Interest

The authors declare no conflicts of interest.

References

1. Moulik S.P. Chakraborty I. Rakshit A.K. Role of surface-active materials (amphiphiles and surfactants) in the formation of nanocolloidal dispersions, and their applications J. Surfactants Deterg. 2022 25 703 727 10.1002/jsde.12612

2. Dutta A.K. Introductory Chapter: Surfactants Surfactants Detrgent IntechOpen London, UK 2019 1 9781839628962

3. Nagaraj K. Sakthinathan S. Arunachalam S. Effect of hydrophobicity on intercalative binding of some surfactant copper (II) complexes with tRNA Monatshefte Für Chem.-Chem. Mon. 2014 145 1897 1902 10.1007/s00706-014-1267-9

4. Kronberg B. Holmberg K. Lindman B. Types of Surfactants, their Synthesis, and Applications Surface Chemistry of Surfactants and Polymers Wiley Online Library Hoboken, NJ, USA 2014 10.1002/9781118695968.ch1

5. Ghosh S. Ray A. Pramanik N. Self-Assembly of Surfactants: An Overview on General Aspects of Amphiphiles Biophys. Chem. 2020 265 106429 10.1016/j.bpc.2020.106429 32693319

6. Sekhon B.S. Surfactants: Pharmaceutical and medicinal aspects J. Pharm. Technol. Res. Manag. 2013 1 43 68 10.15415/jptrm.2013.11004

7. Jia F. Su S. Zhang R. Wu Y. Main Fabrication Methods of Micellar Nanoparticles for Nanoscale Tumor Therapy through the Self-Assembly of Amphiphilic Copolymers Curr. Chin. Sci. 2022 2 263 274 10.2174/2210298102666220317104331

8. Varma L.T. Singh N. Gorain B. Choudhury H. Tambuwala M.M. Kesharwani P. Shukla R. Recent Advances in Self-Assembled Nanoparticles for Drug Delivery Curr. Drug Deliv. 2020 17 279 291 10.2174/1567201817666200210122340 32039683

9. Ruiz M. Gantner M. Talevi A. Applications of Nanosystems to Anticancer Drug Therapy (Part II. Dendrimers, Micelles, Lipid-Based Nanosystems) Recent Patents on Anti-Cancer Drug Discov. 2013 9 99 128 10.2174/1574891X113089990038 23578193

10. Afzal S. Lone M.S. Kaur P. Ahanger F.A. Nazir N. Dar A.A. Surfactant and Polymer-Based Self-Assemblies for Encapsulation, Protection, and Release of Nutraceuticals Handbook of Nutraceuticals and Natural Products: Biological, Medicinal, and Nutritional Properties and Applications John Wiley & Sons Hoboken, NJ, USA 2022 363 402 10.1002/9781119746843.ch16

11. Aziz Z. Ahmad A. Mohd-Setapar S. Hassan H. Lokhat D. Kamal M. Ashraf G. Recent Advances in Drug Delivery of Polymeric Nano-Micelles Curr. Drug Metab. 2017 18 16 29 10.2174/1389200217666160921143616 27654898

12. Mukhopadhyay D. Sano C. Al Sawaftah N. El-Awady R. Husseini G.A. Paul V. Ultrasound-mediated cancer therapeutics delivery using micelles and liposomes: A review Recent Pat. Anti-Cancer Drug Discovery. 2021 16 498 520 10.2174/1574892816666210706155110 34911412

13. Bjerk T.R. Severino P. Jain S. Marques C. Silva A.M. Pashirova T. Souto E.B. Biosurfactants: Properties and applications in drug delivery, biotechnology and ecotoxicology Bioengineering 2021 8 115 10.3390/bioengineering8080115 34436118 PMC8389267

14. Gosala R. Raghunandhakumar S. Subramanian B. Modulating Drug Delivery with Nano-Selenium Capped Chitosan Reverse Micelles for Anticancer Potential J. Drug Deliv. Sci. Technol. 2025 108 106860 10.1016/j.jddst.2025.106860

15. Mousavi S.J. Heydari P. Javaherchi P. Kharazi A.Z. Zarrabi A. Alginate-based nanocomposite incorporating chitosan nanoparticles: A dual-drug delivery system for infection control and wound regeneration J. Drug Deliv. Sci. Technol. 2025 107 106755 10.1016/j.jddst.2025.106755

16. Moghaddam S.H. Vatankhah A. Oroojalian F. Kesharwani P. Sahebkar A. Liposomes as Immunotherapeutic Carriers: A Game-Changer in Cancer Therapy J. Drug Deliv. Sci. Technol. 2025 107 106847 10.1016/j.jddst.2025.106847

17. Anestopoulos I. Kiousi D.E. Klavaris A. Galanis A. Salek K. Euston S.R. Pappa A. Panayiotidis M.I. Surface Active Agents and Their Health-Promoting Properties: Molecules of Multifunctional Significance Pharmaceutics 2020 12 688 10.3390/pharmaceutics12070688 32708243 PMC7407150

18. Ceresa C. Fracchia L. Fedeli E. Porta C. Banat I.M. Recent advances in biomedical, therapeutic and pharmaceutical applications of microbial surfactants Pharmaceutics 2021 13 466 10.3390/pharmaceutics13040466 33808361 PMC8067001

19. Kaur P. Garg T. Rath G. Murthy R.S.R. Goyal A.K. Surfactant-Based Drug Delivery Systems for Treating Drug-Resistant Lung Cancer Drug Deliv. 2014 23 717 728 10.3109/10717544.2014.935530 25013959

20. Katari O. Kumar K. Bhamble S. Jain S. Gemini Surfactants as Next-Generation Drug Carriers in Cancer Management Expert Opin. Drug Deliv. 2024 21 1029 1051 10.1080/17425247.2024.2384037 39039919

21. Baby S. Alyami N.M. Aljawdah H.M. Alharbi S.A. Arulselvan P. Jaganathan S.K. Hussein-Al-Ali S.H. Muruganantham B. Chlorogenic Acid Functionalized Tin Oxide-Sodium Alginate Hybrid Nanomaterials Induce Oxidative Stress-Mediated Apoptosis in Breast Cancer MDA-MB-231 Cells Indian J. Pharm. Educ. Res. 2025 59 757 766 10.5530/ijper.20257391

22. Ghahremanloo A. Asgharzadeh F. Gheybi F. Hosseini H. Hashemy S.I. Sahebkar A. Synergistic anticancer effects of liposomal doxorubicin and aprepitant combination therapy in breast cancer: Preclinical insights and therapeutic potential J. Drug Deliv. Sci. Technol. 2025 105 106620 10.1016/j.jddst.2025.106620

23. Kaur P. Garg T. Rath G. Murthy R.S.R. Goyal A.K. Development, Optimization and Evaluation of Surfactant-Based Pulmonary Nanolipid Carrier System of Paclitaxel for the Management of Drug Resistance Lung Cancer Using Box-Behnken Design Drug Deliv. 2014 23 1912 1925 10.3109/10717544.2014.993486 25544602

24. Morales J.O. Peters J.I. Williams R.O. Surfactants: Their critical role in enhancing drug delivery to the lungs Ther. Deliv. 2011 2 623 641 10.4155/tde.11.15 22833979

25. Rathod S. Desai H. Patil R. Sarolia J. Non-ionic surfactants as a P-glycoprotein (P-gp) efflux inhibitor for optimal drug delivery a concise outlook Aaps Pharmscitech 2022 23 55 10.1208/s12249-022-02211-1 35043278

26. Xue F. Lu L. Drug-Based Reversal of Drug Resistance in Hepatocellular Carcinoma (HCC) Using TPGS J. Biosci. Med. 2024 12 161 172 10.4236/jbm.2024.129016

27. Desai N. Rana D. Patel M. Bajwa N. Prasad R. Vora L.K. Nanoparticle Therapeutics in Clinical Perspective: Classification, Marketed Products, and Regulatory Landscape Small 2025 10.1002/smll.202502315 PMC12288819 40454890

28. Islam J. Hazarika H. Roy P.K. Patowary P. Chattopadhyay P. Pathak Y.V. Zaman K. Regulatory Perspectives and Concerns Related to Nanoparticle-Based Lung Delivery Handbook of Lung Targeted Drug Delivery Systems CRC Press Boca Raton, FL, USA 2021 591 609 10.1201/9781003046547-43

29. Sharma R.B. Tomar S. Kaushal S. Kaur A. the Role of Multiscale Approaches for the Rational Design of Nanoparticulate Drug Delivery System: Recent Advances Computational Drug Delivery IGI Global Scientific Publishing Hershey, PA, USA 2024 19 38 10.1515/9783111208671-002

30. Salkho N.M. Turki R.Z. Guessoum O. Martins A.M. Vitor R.F. Husseini G.A. Liposomes as a Promising Ultrasound-Triggered Drug Delivery System in Cancer Treatment Curr. Mol. Med. 2018 17 668 688 10.2174/1566524018666180416100142 29663885

31. Bodkhe M. Chalke T. Kulkarni S.J. Goswami A. Micelles: Synthesis, Characterization Methods, and Applications Discovery, Disruption, and Future Implications of Nanomaterials IGI Global Scientific Publishing Hershey, PA, USA 2024 101 144 10.4018/979-8-3693-4397-5.ch004

32. Arnold M. Morgan E. Rumgay H. Mafra A. Singh D. Laversanne M. Vignat J. Gralow J.R. Cardoso F. Siesling S. Current and future burden of breast cancer: Global statistics for 2020 and 2040 Breast 2022 66 15 23 10.1016/j.breast.2022.08.010 36084384 PMC9465273

33. Wilkinson L. Gathani T. Understanding breast cancer as a global health concern Br. J. Radiol. 2022 95 20211033 10.1259/bjr.20211033 34905391 PMC8822551

34. Luveta J. Parks R.M. Heery D.M. Cheung K.L. Johnston S.J. Invasive lobular breast cancer as a distinct disease: Implications for therapeutic strategy Oncol. Ther. 2020 8 1 11 10.1007/s40487-019-00105-0 32700069 PMC7359988

35. McCart Reed A.E. Kalinowski L. Simpson P.T. Lakhani S.R. Invasive lobular carcinoma of the breast: The increasing importance of this special subtype Breast Cancer Res. 2021 23 6 10.1186/s13058-020-01384-6 33413533 PMC7792208

36. Mir M.A. Novel Approaches in Metronomic Chemotherapy for Breast Cancer Treatment CRC Press Boca Raton, FL, USA 2024

37. Lee J.H. Nan A. Combination drug delivery approaches in metastatic breast cancer J. Drug Deliv. 2012 2012 915375 10.1155/2012/915375 22619725 PMC3350970

38. Yang L.Y. Lei S.Z. Xu W.J. Lai Y. Zhang Y. Wang Y. Wang Z.L. Rising above: Exploring the therapeutic potential of natural product-based compounds in human cancer treatment Tradit. Med. Res. 2025 10 18 10.53388/TMR20240618001

39. Valente S. Roesch E. Breast cancer survivorship J. Surg. Oncol. 2024 130 8 15 10.1002/jso.27627 38534002

40. Zhou L. Zou M. Xu Y. Lin P. Lei C. Xia X. Nano drug delivery system for tumor immunotherapy: Next-generation therapeutics Front. Oncol. 2022 12 864301 10.3389/fonc.2022.864301 35664731 PMC9160744

41. Arvanitis C.D. Ferraro G.B. Jain R.K. The blood–brain barrier and blood–tumour barrier in brain tumours and metastases Nat. Rev. Cancer 2020 20 26 41 10.1038/s41568-019-0205-x 31601988 PMC8246629

42. Torchilin V.P. Structure and design of polymeric surfactant-based drug delivery systems J. Control. Release 2001 73 137 172 10.1016/S0168-3659(01)00299-1 11516494

43. Niemarkt H.J. Hütten M.C. Kramer B.W. Surfactant for Respiratory Distress Syndrome: New Ideas on a Familiar Drug with Innovative Applications Neonatology 2017 111 408 414 10.1159/000458466 28538236 PMC5516408

44. Herting E. Härtel C. Göpel W. Less Invasive Surfactant Administration: Best Practices and Unanswered Questions Curr. Opin. Pediatr. 2020 32 228 234 10.1097/MOP.0000000000000878 32068592 PMC7077956

45. Nagaraj K. Arunachalam S. Synthesis, CMC determination and influence of the micelles, β-cyclodextrin, ionic liquids and liposome (dipalmitoylphosphatidylcholine) vesicles on the kinetics of an outer-sphere electron transfer reaction J. Incl. Phenom. Macrocycl. Chem. 2014 79 425 435 10.1007/s10847-013-0365-3

46. Nagaraj K. Sakthinathan S. Chiu T.W. Kamalesu S. Lokhandwala S. Parekh N.M. Karuppiah C. States of Aggregation and Phase Transformation Behavior of Metallosurfactant Complexes by Hexacyanoferrate (II): Thermodynamic and Kinetic Investigation of ETR in Ionic Liquids and Liposome Vesicles Biomimetics 2022 7 221 10.3390/biomimetics7040221 36546921 PMC9775953

47. Chimote G. Banerjee R. Evaluation of Antitubercular Drug-Loaded Surfactants as Inhalable Drug-Delivery Systems for Pulmonary Tuberculosis J. Biomed. Mater. Res. Part A 2009 89A 281 292 10.1002/jbm.a.31959 18431766

48. Nagaraj K. Kamalesu S. Kosamiya A.H. Kaliyaperumal R. Uthra C. Bakhsh E.M. Khan S.B. Radha S. Karthikeyan A. Karuppiah C. Biophysical studies of single and double alkyl chain metallosurfactants in presence of ionic liquids as additive on its binding to calf thymus DNA Inorg. Chem. Commun. 2023 157 111362 10.1016/j.inoche.2023.111362

49. Saha U. De R. Das B. Interactions between loaded drugs and surfactant molecules in micellar drug delivery systems: A critical review J. Mol. Liq. 2023 382 121906 10.1016/j.molliq.2023.121906

50. Kesharwani R. Jaiswal P. Patel D.K. Yadav P.K. Lipid-based drug delivery system (LBDDS): An emerging paradigm to enhance oral bioavailability of poorly soluble drugs Biomed. Mater. Devices 2023 1 648 663 10.1007/s44174-022-00041-0

51. Raj S. Khurana S. Choudhari R. Kesari K.K. Kamal M.A. Garg N. Ruokolainen J. Das B.C. Kumar D. Specific targeting cancer cells with nanoparticles and drug delivery in cancer therapy Seminars in Cancer Biology Academic Press Cambridge, UK 2021 Volume 69 166 177 10.1016/j.semcancer.2019.11.002 31715247

52. Chehelgerdi M. Chehelgerdi M. Allela O.Q.B. Pecho R.D.C. Jayasankar N. Rao D.P. Thamaraikani T. Vasanthan M. Viktor P. Lakshmaiya N. Progressing Nanotechnology to Improve Targeted Cancer Treatment: Overcoming Hurdles in Its Clinical Implementation Mol. Cancer 2023 22 169 10.1186/s12943-023-01865-0 37814270 PMC10561438

53. Verma R. Rao L. Nagpal D. Yadav M. Kumar V. Kumar V. Kumar H. Parashar J. Bansal N. Kumar M. Emerging nanotechnology-based therapeutics: A new insight into promising drug delivery system for lung cancer therapy Recent Pat. Nanotechnol. 2024 18 395 414 10.2174/1872210517666230613154847 37537775

54. Kumar K. Rani V. Mishra M. Chawla R. New paradigm in combination therapy of siRNA with chemotherapeutic drugs for effective cancer therapy Curr. Res. Pharmacol. Drug Discov. 2022 3 100103 10.1016/j.crphar.2022.100103 35586474 PMC9108887

55. Quadir S.S. Saharan V. Choudhary D. Harish Jain C.P. Joshi G. Nano-strategies as oral drug delivery platforms for treatment of cancer: Challenges and future perspectives AAPS PharmSciTech 2022 23 152 10.1208/s12249-022-02301-0 35606661

56. Yang R. Zhang G.G. Zemlyanov D.Y. Purohit H.S. Taylor L.S. Drug release from surfactant-containing amorphous solid dispersions: Mechanism and role of surfactant in release enhancement Pharm. Res. 2023 40 2817 2845 10.1007/s11095-023-03502-3 37052841

57. Guagliardo R. Perez-Gil J. De Smedt S. Raemdonck K. Pulmonary surfactant and drug delivery: Focusing on the role of surfactant proteins J. Control. Release 2018 291 116 126 10.1016/j.jconrel.2018.10.012 30321577

58. Ismail R. Baaity Z. Csóka I. Regulatory Status Quo and Prospects for Biosurfactants in Pharmaceutical Applications Drug Discov. Today 2021 26 1929 1935 10.1016/j.drudis.2021.03.029 33831583

59. Qi S. Roser S. Edler K.J. Pigliacelli C. Rogerson M. Weuts I. Van Dycke F. Stokbroekx S. Insights into the role of polymer-surfactant complexes in drug solubilisation/stabilisation during drug release from solid dispersions Pharm. Res. 2013 30 290 302 10.1007/s11095-012-0873-7 22983643

60. Feng D. Peng T. Huang Z. Singh V. Shi Y. Wen T. Lu M. Quan G. Pan X. Wu C. Polymer–Surfactant System Based Amorphous Solid Dispersion: Precipitation Inhibition and Bioavailability Enhancement of Itraconazole Pharmaceutics 2018 10 53 10.3390/pharmaceutics10020053 29695136 PMC6027051

61. Gibaldi M. Feldman S. Mechanisms of surfactant effects on drug absorption J. Pharm. Sci. 1970 59 579 589 10.1002/jps.2600590502 4911055

62. de Freitas Araújo Reis M.Y. de Araújo Régo R.I. Rocha B.P. Guedes G.G. Ramalho Í.M.d.M. Cavalcanti A.L.d.M. Guimarães G.P. Damasceno B.P.d.L. A general approach on surfactants use and properties in drug delivery systems Curr. Pharm. Des. 2021 27 4300 4314 10.2174/1381612827666210526091825 34042031

63. Saboo S. Bapat P. Moseson D.E. Kestur U.S. Taylor L.S. Exploring the role of surfactants in enhancing drug release from amorphous solid dispersions at higher drug loadings Pharm. 2021 13 735 10.3390/pharmaceutics13050735 PMC8156319 34067666

64. Bhadoriya S.S. Madoriya N. Biosurfactants: A New Pharmaceutical Additive for Solubility Enhancement and Pharmaceutical Development Biochem. Pharmacol. Open Access 2013 2 10.4172/2167-0501.1000113

65. Parvaiz A.B. Ghulam M.R. Aijaz A.D. Effect of Surfactant Mixing on Partitioning of Model Hydrophobic Drug, Naproxen, between Aqueous and Micellar Phases J. Phys. Chem. B 2009 113 997 1006 10.1021/jp807229c 19123827

66. Rangel-Yagui C.O. Pessoa A. Jr. Tavares L.C. Micellar solubilization of drugs J. Pharm. Pharm. Sci. 2005 8 147 165 16124926

67. Nagaraj K. Senthil Murugan K. Thangamuniyandi P. Sakthinathan S. Synthesis, micellization behaviour, DNA/RNA binding and biological studies of a surfactant cobalt (III) complex with dipyrido [3, 2-a: 2′, 4′-c](6, 7, 8, 9-tetrahydro) phenazine J. Fluoresc. 2014 24 1701 1714 10.1007/s10895-014-1457-1 25260810

68. Akash M.S.H. Rehman K. Recent progress in biomedical applications of Pluronic (PF127): Pharmaceutical perspectives J. Control. Release. 2015 209 120 138 10.1016/j.jconrel.2015.04.032 25921088

69. Jaquilin R. Oluwafemi O.S. Thomas S. Oyedeji A.O. Recent Advances in Drug Delivery Nanocarriers Incorporated in Temperature-Sensitive Pluronic F-127–a Critical Review J. Drug Deliv. Sci. Technol. 2022 72 103390 10.1016/j.jddst.2022.103390

70. Chen L. Sha X. Jiang X. Chen Y. Ren Q. Fang X. Pluronic P105/F127 mixed micelles for the delivery of docetaxel against Taxol-resistant non-small cell lung cancer: Optimization and in vitro, in vivo evaluation Int. J. Nanomed. 2013 8 73 84 10.2147/IJN.S38221 PMC3540961 23319859

71. Raval A. Pillai S.A. Bahadur A. Bahadur P. Systematic characterization of Pluronic ® micelles and their application for solubilization and in vitro release of some hydrophobic anticancer drugs J. Mol. Liq. 2017 230 473 481 10.1016/j.molliq.2017.01.065

72. Bhalodi K. Kothari C. Butani S. Next-generation cancer nanotherapeutics: Pluronic ® F127 based mixed micelles for enhanced drug delivery Naunyn-Schmiedeberg’s Arch. Pharmacol. 2024 398 3241 3270 10.1007/s00210-024-03582-x 39527309

73. Zhang W. Shi Y. Chen Y. Ye J. Sha X. Fang X. Multifunctional Pluronic P123/F127 mixed polymeric micelles loaded with paclitaxel for the treatment of multidrug resistant tumors Biomaterials 2011 32 2894 2906 10.1016/j.biomaterials.2010.12.039 21256584

74. Nie S. Hsiao W.W. Pan W. Yang Z. Thermoreversible Pluronic ® F127-based hydrogel containing liposomes for the controlled delivery of paclitaxel: In vitro drug release, cell cytotoxicity, and uptake studies Int. J. Nanomed. 2011 6 151 166 10.2147/IJN.S15057 PMC3075891 21499415

75. Soo P.L. Dunne M. Liu J. Allen C. Nano-sized advanced delivery systems as parenteral formulation strategies for hydrophobic anti-cancer drugs Nanotechnol. Drug Deliv. 2009 349 383 10.1007/978-0-387-77668-2_12

76. Maher S. Geoghegan C. Brayden D.J. Safety of surfactant excipients in oral drug formulations Adv. Drug Deliv. Rev. 2023 202 115086 10.1016/j.addr.2023.115086 37739041

77. Roussel L. Abdayem R. Gilbert E. Pirot F. Haftek M. Influence of excipients on two elements of the stratum corneum barrier: Intercellular lipids and epidermal tight junctions Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement: Drug Manipulation Strategies and Vehicle Effects Springer Berlin, Germany 2015 69 90

78. Chakravarthy P.S.A. Popli P. Challa R.R. Vallamkonda B. Singh I. Swami R. Bile salts: Unlocking the potential as bio-surfactant for enhanced drug absorption J. Nanopart. Res. 2024 26 76 10.1007/s11051-024-05985-6

79. Jiao J. Polyoxyethylated nonionic surfactants and their applications in topical ocular drug delivery Adv. Drug Deliv. Rev. 2008 60 1663 1673 10.1016/j.addr.2008.09.002 18845195

80. Casiraghi A. Selmin F. Minghetti P. Cilurzo F. Montanari L. Nonionic surfactants: Polyethylene glycol (peg) ethers and fatty acid esters as penetration enhancers Percutaneous Penetration Enhancers Chemical Methods in Penetration Enhancement: Modification of the Stratum Corneum Springer Berlin, Germany 2015 251 271 10.1007/978-3-662-47039-8_15

81. Moghadam S.H. Saliaj E. Wettig S.D. Dong C. Ivanova M.V. Huzil J.T. Foldvari M. Effect of chemical permeation enhancers on stratum corneum barrier lipid organizational structure and interferon alpha permeability Mol. Pharm. 2013 10 2248 2260 10.1021/mp300441c 23587061

82. Klaus A. Tiddy G.J.T. Touraud D. Schramm A. Stühler G. Drechsler M. Kunz W. Phase Behavior of an Extended Surfactant in Water and a Detailed Characterization of the Dilute and Semidilute Phases Langmuir 2009 26 5435 5443 10.1021/la903899w 20000427

83. Nagaraj K. Ragu M. Ganesan M. Kinetics and thermodynamics study on electron transfer in microheterogeneous media: A comparative study J. Iran. Chem. Soc. 2016 13 575 582 10.1007/s13738-015-0768-8

84. Vinarov Z. Katev V. Radeva D. Tcholakova S. Denkov N.D. Micellar Solubilization of Poorly Water-Soluble Drugs: Effect of Surfactant and Solubilizate Molecular Structure Drug Dev. Ind. Pharm. 2017 44 677 686 10.1080/03639045.2017.1408642 29164955

85. Lawrence M.J. Surfactant Systems: Their Use in Drug Delivery Chem. Soc. Rev. 1994 23 417 424 10.1039/cs9942300417

86. Xu W. Ling P. Zhang T. Polymeric Micelles, a Promising Drug Delivery System to Enhance Bioavailability of Poorly Water-Soluble Drugs J. Drug Deliv. 2013 2013 340315 10.1155/2013/340315 23936656 PMC3712247

87. Nagaraj K. Thangamuniyandi P. Kamalesu S. Lokhandwala S. Parekh N.M. Panda S.R. Sakthinathan S. Chiu T.W. Chelladurai K. Karthikeyan A. Metallo-Surfactant assisted silver nanoparticles: A new approach for the colorimetric detection of amino acids Spectrochim. Acta Part A Mol. Biomol. Spectrosc. 2023 296 122693 10.1016/j.saa.2023.122693 37028097

88. Nagaraj K. Priyanshi J. Govindasamy C. Sivakumar A.S. Kamalesu S. Naman J. Dixitkumar M. Lokhandwala S. Parekh N.M. Radha S. Effect of hydrophobicity and size of the ligands on the intercalative binding interactions of some metallo-surfactants containing π-conjugated systems with yeast tRNA J. Biomol. Struct. Dyn. 2024 42 3949 3957 10.1080/07391102.2023.2216783 37254288

89. Chiappetta D.A. Sosnik A. Poly(Ethylene Oxide)–Poly(Propylene Oxide) Block Copolymer Micelles as Drug Delivery Agents: Improved Hydrosolubility, Stability and Bioavailability of Drugs Eur. J. Pharm. Biopharm. 2007 66 303 317 10.1016/j.ejpb.2007.03.022 17481869

90. He C.-X. He Z.-G. Gao J.-Q. Microemulsions as Drug Delivery Systems to Improve the Solubility and the Bioavailability of Poorly Water-Soluble Drugs Expert Opin. Drug Deliv. 2010 7 445 460 10.1517/17425241003596337 20201713

91. Wang Y. Li Y. Zhang L. Fang X. Pharmacokinetics and biodistribution of paclitaxel-loaded pluronic P105 polymeric micelles Arch. Pharmacal. Res. 2008 31 530 538 10.1007/s12272-001-1189-2 18449513

92. Yoo H.S. Park T.G. Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA–PEG block copolymer J. Control. Release 2001 70 63 70 10.1016/S0168-3659(00)00340-0 11166408

93. Jhaveri A.M. Torchilin V.P. Multifunctional polymeric micelles for delivery of drugs and siRNA Front. Pharmacol. 2014 5 77 10.3389/fphar.2014.00077 24795633 PMC4007015

94. Zhu J. Jiang W. Self-assembly of block copolymers in selective solvents Chem. Phys. Res. Trend 2007 252 65 116

95. Cai L.L. Liu P. Li X. Huang X. Ye Y.Q. Chen F.Y. Yuan H. Hu F.Q. Du Y.Z. RGD peptide-mediated chitosan-based polymeric micelles targeting delivery for integrin-overexpressing tumor cells Int. J. Nanomed. 2011 6 3499 3508 10.2147/IJN.S26670 PMC3265222 22282676

96. Zhang Y. Kim I. Lu Y. Xu Y. Yu D.G. Song W. Intelligent poly (l-histidine)-based nanovehicles for controlled drug delivery J. Control. Release 2022 349 963 982 10.1016/j.jconrel.2022.08.005 35944751

97. Deshmukh S.A.R.K. van Sint Annaland M. Kuipers J.A.M. Effect of fluidization conditions on the membrane permeation rate in a membrane assisted fluidized bed Chem. Eng. J. 2003 96 125 131 10.1016/j.cej.2003.08.012

98. De Jong J.F. van Sint Annaland M. Kuipers J.A.M. Experimental study on the effects of gas permeation through flat membranes on the hydrodynamics in membrane-assisted fluidized beds Chem. Eng. Sci. 2011 66 2398 2408 10.1016/j.ces.2011.02.059

99. De Jong J.F. van Sint Annaland M. Kuipers J.A.M. Experimental study on the hydrodynamic effects of gas permeation through horizontal membrane tubes in fluidized beds Powder Technol. 2013 241 74 84 10.1016/j.powtec.2013.03.014

100. Lémery E. Briançon S. Chevalier Y. Bordes C. Oddos T. Gohier A. Bolzinger M.A. Skin toxicity of surfactants: Structure/toxicity relationships Colloids Surf. A Physicochem. Eng. Asp. 2015 469 166 179 10.1016/j.colsurfa.2015.01.019

101. Faucher J.A. Goddard E.D. Kulkarni R.D. Effect of polyoxyethylated materials on the interaction of surfactants with skin J. Am. Oil Chem. Soc. 1979 56 776 782 10.1007/BF02663061

102. Jakasa I. Verberk M.M. Bunge A.L. Kruse J. Kezic S. Increased permeability for polyethylene glycols through skin compromised by sodium lauryl sulphate Exp. Dermatol. 2006 15 801 807 10.1111/j.1600-0625.2006.00478.x 16984262

103. Rege B.D. Kao J.P. Polli J.E. Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers Eur. J. Pharm. Sci. 2002 16 237 246 10.1016/S0928-0987(02)00055-6 12208453

104. Shah R.B. Oral Delivery and Formulation of Salmon Calcitonin: Protection from Serine Proteases with Ovomucoids Texas Tech University Lubbock, TX, USA 2004

105. Elnaggar Y.S. El-Refaie W.M. El-Massik M.A. Abdallah O.Y. Lecithin-based nanostructured gels for skin delivery: An update on state of art and recent applications J. Control. Release 2014 180 10 24 10.1016/j.jconrel.2014.02.004 24531009

106. Sebaaly C. Trifan A. Sieniawska E. Greige-Gerges H. Chitosan-coating effect on the characteristics of liposomes: A focus on bioactive compounds and essential oils: A review Processes 2021 9 445 10.3390/pr9030445

107. Pavlović N. Goločorbin-Kon S. Ðanić M. Stanimirov B. Al-Salami H. Stankov K. Mikov M. Bile acids and their derivatives as potential modifiers of drug release and pharmacokinetic profiles Front. Pharmacol. 2018 9 1283 10.3389/fphar.2018.01283 30467479 PMC6237018

108. Beauchesne P.R. Chung N.S. Wasan K.M. Cyclosporine A: A review of current oral and intravenous delivery systems Drug Dev. Ind. Pharm. 2007 33 211 220 10.1080/03639040601155665 17454054

109. Cavanagh R. An Investigation into Mechanisms of Non-Ionic Surfactant Effect on Epithelial Cells Ph.D. Thesis University of Nottingham Nottingham, UK 2018

110. Teodori E. Braconi L. Bua S. Lapucci A. Bartolucci G. Manetti D. Romanelli M.N. Dei S. Supuran C.T. Coronnello M. Dual P-glycoprotein and CA XII inhibitors: A new strategy to reverse the P-gp mediated multidrug resistance (MDR) in cancer cells Molecules 2020 25 1748 10.3390/molecules25071748 32290281 PMC7181201

111. Zhang H. Xu H. Ashby C.R. Jr. Assaraf Y.G. Chen Z.S. Liu H.M. Chemical molecular-based approach to overcome multidrug resistance in cancer by targeting P-glycoprotein (P-gp) Med. Res. Rev. 2021 41 525 555 10.1002/med.21739 33047304

112. Li X.Q. Wang L. Lei Y. Hu T. Zhang F.L. Cho C.H. To K.K. Reversal of P-gp and BCRP-mediated MDR by tariquidar derivatives Eur. J. Med. Chem. 2015 101 560 572 10.1016/j.ejmech.2015.06.049 26197160

113. Kabanov A.V. Lemieux P. Vinogradov S. Alakhov V. Pluronic ® block copolymers: Novel functional molecules for gene therapy Adv. Drug Deliv. Rev. 2002 54 223 233 10.1016/S0169-409X(02)00018-2 11897147

114. Kabanov A.V. Alakhov V.Y. Pluronic ® block copolymers in drug delivery: From micellar nanocontainers to biological response modifiers Crit. Rev. Ther. Drug Carr. Syst. 2002 19 1 72 10.1615/CritRevTherDrugCarrierSyst.v19.i1.10 12046891

115. Kabanov A.V. Batrakova E.V. Alakhov V.Y. Pluronic ® block copolymers for overcoming drug resistance in cancer Adv. Drug Deliv. Rev. 2002 54 759 779 10.1016/S0169-409X(02)00047-9 12204601

116. Batrakova E.V. Li S. Alakhov V.Y. Elmquist W.F. Miller D.W. Kabanov A.V. Sensitization of cells overexpressing multidrug-resistant proteins by pluronic P85 Pharm. Res. 2003 20 1581 1590 10.1023/A:1026179132599 14620511 PMC3070744

117. Batrakova E.V. Li S.H.U. Alakhov V.Y. Miller D.W. Kabanov A.V. Optimal structure requirements for pluronic block copolymers in modifying P-glycoprotein drug efflux transporter activity in bovine brain microvessel endothelial cells J. Pharmacol. Exp. Ther. 2003 304 845 854 10.1124/jpet.102.043307 12538842

118. Batrakova E.V. Li S. Li Y. Alakhov V.Y. Elmquist W.F. Kabanov A.V. Distribution kinetics of a micelle-forming block copolymer Pluronic P85 J. Control. Release 2004 100 389 397 10.1016/j.jconrel.2004.09.002 15567504

119. Batrakova E.V. Li S. Brynskikh A.M. Sharma A.K. Li Y. Boska M. Gong N. Mosley R.L. Alakhov V.Y. Gendelman H.E. Effects of pluronic and doxorubicin on drug uptake, cellular metabolism, apoptosis and tumor inhibition in animal models of MDR cancers J. Control. Release 2010 143 290 301 10.1016/j.jconrel.2010.01.004 20074598 PMC3089980

120. Collnot E.M. Modulation of the apical efflux transporter P-glycoprotein by Vitamin E TPGS: Structure-activity relationships and mechanism of inhibition Mol. Biol. 2007 10.22028/D291-22375

121. Collnot E.M. Baldes C. Wempe M.F. Hyatt J. Navarro L. Edgar K.J. Schaefer U.F. Lehr C.M. Influence of vitamin E TPGS poly (ethylene glycol) chain length on apical efflux transporters in Caco-2 cell monolayers J. Control. Release 2006 111 35 40 10.1016/j.jconrel.2005.11.005 16410030

122. Collu F. Cascella M. Multidrug resistance and efflux pumps: Insights from molecular dynamics simulations Curr. Top. Med. Chem. 2013 13 3165 3183 10.2174/15680266113136660224 24200357

123. Reddy L.H. Sharma R.K. Chuttani K. Mishra A.K. Murthy R.R. Etoposide-incorporated tripalmitin nanoparticles with different surface charge: Formulation, characterization, radiolabeling, and biodistribution studies AAPS J. 2004 6 55 64 10.1208/aapsj060323 15760108 PMC2751248

124. Reddy L.H. Murthy R.S. Pharmacokinetics and biodistribution studies of doxorubicin loaded poly (butyl cyanoacrylate) nanoparticles synthesized by two different techniques Biomed. Pap. 2004 148 161 166 10.5507/bp.2004.029 15744366

125. Kecman S. Škrbić R. Cengic A.B. Mooranian A. Al-Salami H. Mikov M. Golocorbin-Kon S. Potentials of human bile acids and their salts in pharmaceutical nano delivery and formulations adjuvants Technol. Health Care 2020 28 325 335 10.3233/THC-191845 31594273

126. Dintaman J.M. Silverman J.A. Inhibition of P-glycoprotein by D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) Pharm. Res. 1999 16 1550 1556 10.1023/A:1015000503629 10554096

127. Apostolou M. Fatokun A.A. Assi S. Khan I. Targeted lipid-based drug delivery systems for lung cancer therapy Appl. Sci. 2024 14 6759 10.3390/app14156759

128. Abdelaziz H.M. Gaber M. Abd-Elwakil M.M. Mabrouk M.T. Elgohary M.M. Kamel N.M. Kabary D.M. Freag M.S. Samaha M.W. Mortada S.M. Inhalable particulate drug delivery systems for lung cancer therapy: Nanoparticles, microparticles, nanocomposites and nanoaggregates J. Control. Release 2018 269 374 392 10.1016/j.jconrel.2017.11.036 29180168

129. Choudhury H. Pandey M. Gorain B. Chatterjee B. Madheswaran T. Md S. Mak K.K. Tambuwala M. Chourasia M.K. Kesharwani P. Nanoemulsions as effective carriers for the treatment of lung cancer Nanotechnology-Based Targeted Drug Delivery Systems for Lung Cancer Academic Press Cambridge, UK 2019 217 247

130. Gothwal A. Khan I. Gupta U. Polymeric Micelles: Recent Advancements in the Delivery of Anticancer Drugs Pharm. Res. 2015 33 18 39 10.1007/s11095-015-1784-1 26381278

131. Ceresa C. Fracchia L. Sansotera A.C. De Rienzo M.A.D. Banat I.M. Harnessing the potential of biosurfactants for biomedical and pharmaceutical applications Pharm. Res. 2023 15 2156 10.3390/pharmaceutics15082156 PMC10457971 37631370

132. Rodrigues L.R. Microbial Surfactants: Fundamentals and Applicability in the Formulation of Nano-Sized Drug Delivery Vectors J. Colloid Interface Sci. 2015 449 304 316 10.1016/j.jcis.2015.01.022 25655712

133. Verma R. Kumar K. Bhatt S. Yadav M. Kumar M. Tagde P. Rajinikanth P.S. Tiwari A. Tiwari V. Nagpal D. Untangling breast cancer: Trailing towards nanoformulations-based drug development Recent Pat. Nanotechnol. 2025 19 76 98 10.2174/1872210517666230731091046 37519201

134. Ohadi M. Shahravan A. Dehghan N. Eslaminejad T. Banat I.M. Dehghannoudeh G. Potential Use of Microbial Surfactant in Microemulsion Drug Delivery System: A Systematic Review Drug Des. Dev. Ther. 2020 14 541 550 10.2147/DDDT.S232325 PMC7008186 32103896

135. Haddad R. Alrabadi N. Altaani B. Li T. Paclitaxel drug delivery systems: Focus on nanocrystals’ surface modifications Polymers 2022 14 658 10.3390/polym14040658 35215570 PMC8875890

136. Manjappa A.S. Kumbhar P.S. Patil A.B. Disouza J.I. Patravale V.B. Polymeric mixed micelles: Improving the anticancer efficacy of single-copolymer micelles Crit. Rev. Ther. Drug Carr. Syst. 2019 36 1 58 10.1615/CritRevTherDrugCarrierSyst.2018020481 30806205

137. Junnuthula V. Kolimi P. Nyavanandi D. Sampathi S. Vora L.K. Dyawanapelly S. Polymeric micelles for breast cancer therapy: Recent updates, clinical translation and regulatory considerations Pharmaceutics 2022 14 1860 10.3390/pharmaceutics14091860 36145608 PMC9501124

138. Avramović N. Mandić B. Savić-Radojević A. Simić T. Polymeric nanocarriers of drug delivery systems in cancer therapy Pharmaceutics 2020 12 298 10.3390/pharmaceutics12040298 32218326 PMC7238125

139. Shaker D.S. Ishak R.A.H. Ghoneim A. Elhuoni M.A. Nanoemulsion: A Review on Mechanisms for the Transdermal Delivery of Hydrophobic and Hydrophilic Drugs Sci. Pharm. 2019 87 17 10.3390/scipharm87030017

140. Gudiña E.J. Rangarajan V. Sen R. Rodrigues L.R. Potential Therapeutic Applications of Biosurfactants Trends Pharmacol. Sci. 2013 34 667 675 10.1016/j.tips.2013.10.002 24182625

141. Elshikh M. Marchant R. Banat I.M. Biosurfactants: Promising Bioactive Molecules for Oral-Related Health Applications FEMS Microbiol. Lett. 2016 363 fnw213 10.1093/femsle/fnw213 27619892

142. Li B. Tan T. Chu W. Zhang Y. Ye Y. Wang S. Qin Y. Tang J. Cao X. Co-Delivery of Paclitaxel (PTX) and Docosahexaenoic Acid (DHA) by Targeting Lipid Nanoemulsions for Cancer Therapy Drug Deliv. 2021 29 75 88 10.1080/10717544.2021.2018523 PMC8735879 34964421

143. Naderinezhad S. Amoabediny G. Haghiralsadat F. Co-delivery of hydrophilic and hydrophobic anticancer drugs using biocompatible pH-sensitive lipid-based nano-carriers for multidrug-resistant cancers RSC Adv. 2017 7 30008 30019 10.1039/C7RA01736G

144. Jayaswal N. Srivastava S. Kumar S. Sridhar S.B. Khalid A. Najmi A. Zoghebi K. Alhazmi H.A. Mohan S. Tambuwala M.M. Precision arrows: Navigating breast cancer with nanotechnology siRNA Int. J. Pharm. 2024 662 124403 10.1016/j.ijpharm.2024.124403 38944167

145. Khare U. Sharma P. Kumar A. Applications of Surfactants in Pharmaceutical Formulation Development of Conventional and Advanced Delivery Systems Int. J. Pharmacogn. 155 IJP 2019 6 155 163 10.13040/IJPSR.0975-8232.IJP.6(5).155-63

146. Chen Y. Zhang W. Huang Y. Gao F. Sha X. Fang X. Pluronic-based functional polymeric mixed micelles for co-delivery of doxorubicin and paclitaxel to multidrug resistant tumor Int. J. Pharm. 2015 488 44 58 10.1016/j.ijpharm.2015.04.048 25899286

147. Cho H. Lai T.C. Tomoda K. Kwon G.S. Polymeric micelles for multi-drug delivery in cancer Aaps Pharmscitech 2015 16 10 20 10.1208/s12249-014-0251-3 25501872 PMC4309804

148. Jhaveri A. Deshpande P. Torchilin V. Stimuli-Sensitive Nanopreparations for Combination Cancer Therapy J. Control. Release 2014 190 352 370 10.1016/j.jconrel.2014.05.002 24818767

149. Cheng X. Lv X. Xu J. Zheng Y. Wang X. Tang R. Pluronic micelles with suppressing doxorubicin efflux and detoxification for efficiently reversing breast cancer resistance Eur. J. Pharm. Sci. 2020 146 105275 10.1016/j.ejps.2020.105275 32087259

150. Wang F. Zhang D. Zhang Q. Chen Y. Zheng D. Hao L. Duan C. Jia L. Liu G. Liu Y. Synergistic effect of folate-mediated targeting and verapamil-mediated P-gp inhibition with paclitaxel-polymer micelles to overcome multi-drug resistance Biomaterials 2011 32 9444 9456 10.1016/j.biomaterials.2011.08.041 21903258

151. Yadav K.S. Soni G. Choudhary D. Khanduri A. Bhandari A. Joshi G. Microemulsions for Enhancing Drug Delivery of Hydrophilic Drugs: Exploring Various Routes of Administration Med. Drug Discov. 2023 20 100162 10.1016/j.medidd.2023.100162

152. He Z. Wan X. Schulz A. Bludau H. Dobrovolskaia M.A. Stern S.T. Montgomery S.A. Yuan H. Li Z. Alakhova D. A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity Biomaterials 2016 101 296 309 10.1016/j.biomaterials.2016.06.002 27315213 PMC5035646

153. Mustafa G. Hassan D. Ruiz-Pulido G. Pourmadadi M. Eshaghi M.M. Behzadmehr R. Tehrani F.S. Rahdar A. Medina D.I. Pandey S. Nanoscale drug delivery systems for cancer therapy using paclitaxel—A review of challenges and latest progressions J. Drug Deliv. Sci. Technol. 2023 84 104494 10.1016/j.jddst.2023.104494

154. Yadav P.K. Saklani R. Tiwari A.K. Verma S. Chauhan D. Yadav P. Rana R. Kalleti N. Gayen J.R. Rath S.K. Ratiometric codelivery of Paclitaxel and Baicalein loaded nanoemulsion for enhancement of breast cancer treatment Int. J. Pharm. 2023 643 123209 10.1016/j.ijpharm.2023.123209 37422142

155. Zhang X. Chen W. Bai J. Jin L. Kang X. Zhang H. Wang Z. Pluronic P123 Modified Nano Micelles Loaded with Doxorubicin Enhanced Tumor-Suppressing Effect on Drug-Resistant Breast Cancer Cells Aging 2020 12 8289 8300 10.18632/aging.103138 32396524 PMC7244042

156. Majumder N. G Das N. Das S.K. Polymeric micelles for anticancer drug delivery Ther. Deliv. 2020 11 613 635 10.4155/tde-2020-0008 32933425

157. Kesharwani S.S. Kaur S. Tummala H. Sangamwar A.T. Overcoming multiple drug resistance in cancer using polymeric micelles Expert Opin. Drug Deliv. 2018 15 1127 1142 10.1080/17425247.2018.1537261 30324813

158. Cao A. Ma P. Yang T. Lan Y. Yu S. Liu L. Sun Y. Liu Y. Multifunctionalized Micelles Facilitate Intracellular Doxorubicin Delivery for Reversing Multidrug Resistance of Breast Cancer Mol. Pharm. 2019 16 2502 2510 10.1021/acs.molpharmaceut.9b00094 30998372

159. Colakyan K. Modulation of Efflux of Xenobiotics in Multidrug Resistant (MDR) Cancer Cell Lines by Pluronic Block Copolymers Institut National de la Recherche Scientifique Québec, QC, Canada 2006

160. Modok S. Mellor H. Callaghan R. Modulation of Multidrug Resistance Efflux Pump Activity to Overcome Chemoresistance in Cancer Curr. Opin. Pharmacol. 2006 6 350 354 10.1016/j.coph.2006.01.009 16690355

161. Bogman K. Erne-Brand F. Alsenz J. Drewe J. The role of surfactants in the reversal of active transport mediated by multidrug resistance proteins J. Pharm. Sci. 2003 92 1250 1261 10.1002/jps.10395 12761814

162. Gerardos A.M. Balafouti A. Stergios P. Mixed Copolymer Micelles for Nanomedicine Nanomanufacturing 2023 3 233 247 10.3390/nanomanufacturing3020015

163. Wang L. Zhang D.-Z. Wang Y.-X. Bioflavonoid Fisetin Loaded α-Tocopherol-Poly(Lactic Acid)-Based Polymeric Micelles for Enhanced Anticancer Efficacy in Breast Cancers Pharm. Res. 2017 34 453 461 10.1007/s11095-016-2077-z 28004315

164. Gao H. Zhang J. Kleijn T.G. Wu Z. Liu B. Ma Y. Ding B. Yin D. Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases Oncol. Res. 2024 32 769 10.32604/or.2023.044276 38560569 PMC10972726

165. Li X. Yu Y. Ji Q. Qiu L. Targeted delivery of anticancer drugs by aptamer AS 1411 mediated Pluronic F127/cyclodextrin-linked polymer composite micelles Nanomed. Nanotechnol. Biol. Med. 2015 11 175 184 10.1016/j.nano.2014.08.013 25218928

166. Choudhury H. Pandey M. Wen L.P. Cien L.K. Xin H. Yee A.N. Lee N.J. Gorain B. Amin M.C.I.M. Pichika M.R. Folic acid conjugated nanocarriers for efficient targetability and promising anticancer efficacy for treatment of breast cancer: A review of recent updates Curr. Pharm. Des. 2020 26 5365 5379 10.2174/1381612826666200721000958 32693762

167. Pawar A. Singh S. Rajalakshmi S. Shaikh K. Bothiraja C. Development of Fisetin-Loaded Folate Functionalized Pluronic Micelles for Breast Cancer Targeting Artif. Cells Nanomed. Biotechnol. 2018 46 (Suppl. S1) 347 361 10.1080/21691401.2018.1423991 29334247

168. Guan J. Zhou Z.Q. Chen M.H. Li H.Y. Tong D.N. Yang J. Yao J. Zhang Z.Y. Folate-conjugated and pH-responsive polymeric micelles for target-cell-specific anticancer drug delivery Acta Biomater. 2017 60 244 255 10.1016/j.actbio.2017.07.018 28713015

169. Narmani A. Rezvani M. Farhood B. Darkhor P. Mohammadnejad J. Amini B. Refahi S. Abdi Goushbolagh N. Folic Acid Functionalized Nanoparticles as Pharmaceutical Carriers in Drug Delivery Systems Drug Dev. Res. 2019 80 404 424 10.1002/ddr.21545 31140629

170. Yuan Y. Cai T. Xia X. Zhang R. Chiba P. Cai Y. Nanoparticle delivery of anticancer drugs overcomes multidrug resistance in breast cancer Drug Deliv. 2016 23 3350 3357 10.1080/10717544.2016.1178825 27098896

171. Wang Y. Zhang H. Hao J. Li B. Li M. Xiuwen W. Lung cancer combination therapy: Co-delivery of paclitaxel and doxorubicin by nanostructured lipid carriers for synergistic effect Drug Deliv. 2016 23 1398 1403 10.3109/10717544.2015.1055619 26079530

172. Arredondo-Ochoa T. Silva-Martínez G.A. Microemulsion based nanostructures for drug delivery Front. Nanotechnol. 2022 3 753947 10.3389/fnano.2021.753947

173. Vijayalakshmi K. Vidhyulatha N. Aldawood S. Manjulabai A. Aboorva M. Manjula R. Velmurugan G. Nagaraj K. Computational and experimental investigation of biogenic zinc oxide nanoparticles synthesized from Clausena dentata leaf extract for α-amylase inhibition and K562 leukemia cell therapy Food Biosci. 2025 68 106371 10.1016/j.fbio.2025.106371

174. Nagaraj K. Kamalesu S. State-of-the-art surfactants as biomedical game changers: Unlocking their potential in drug delivery, diagnostics, and tissue engineering Int. J. Pharm. 2025 676 125590 10.1016/j.ijpharm.2025.125590 40228615

175. Shah F. Nagaraj K. Kamalesu S. Radhakrishnan L. Venkatachalapathy R. Advancing Nutraceuticals in a Promising Frontier in Modern Healthcare Food Humanit. 2024 3 100462 10.1016/j.foohum.2024.100462

176. Moulik S.P. Rakshit A.K. Naskar B. Physical chemical properties of surfactants in solution and their applications: A comprehensive account J. Surfactants Deterg. 2024 27 895 925 10.1002/jsde.12757

177. Tripathy D.B. Kesarwani S. Gupta A. Chhabra P. Nano-Surfactants: Types, Synthesis, Properties, and Potential Applications Multifunct. Mater. Eng. Biol. Appl. 2025 17 441 459

178. Wang Y. Yu L. Han L. Sha X. Fang X. Difunctional Pluronic Copolymer Micelles for Paclitaxel Delivery: Synergistic Effect of Folate-Mediated Targeting and Pluronic-Mediated Overcoming Multidrug Resistance in Tumor Cell Lines Int. J. Pharm. 2007 337 63 73 10.1016/j.ijpharm.2006.12.033 17289311

179. Jampilek J. Kralova K. Natural biopolymeric nanoformulations for brain drug delivery Nanocarriers for Brain Targeting Apple Academic Press Palm Bay, FL, USA 2019 131 204

180. Jain V. Swarnakar N.K. Mishra P.R. Verma A. Kaul A. Mishra A.K. Jain N.K. Paclitaxel loaded PEGylated gleceryl monooleate based nanoparticulate carriers in chemotherapy Biomaterials 2012 33 7206 7220 10.1016/j.biomaterials.2012.06.056 22809646

181. Chaurasia M. Singh R. Sur S. Flora S.J.S. A review of FDA approved drugs and their formulations for the treatment of breast cancer Front. Pharmacol. 2023 14 1184472 10.3389/fphar.2023.1184472 37576816 PMC10416257

182. Pandey S. Shaikh F. Gupta A. Tripathi P. Yadav J.S. A recent update: Solid lipid nanoparticles for effective drug delivery Adv. Pharm. Bull. 2021 12 17 10.34172/apb.2022.007 35517874 PMC9012924

183. Suk J.S. Xu Q. Kim N. Hanes J. Ensign L.M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery Adv. Drug Deliv. Rev. 2016 99 28 51 10.1016/j.addr.2015.09.012 26456916 PMC4798869

184. Singh S.K. Singh S. Lillard J.W. Jr. Singh R. Drug delivery approaches for breast cancer Int. J. Nanomed. 2017 12 6205 6218 10.2147/IJN.S140325 PMC5576701 28883730

185. Johnsson M. Edwards K. Interactions between nonionic surfactants and sterically stabilized phophatidyl choline liposomes Langmuir 2000 16 8632 8642 10.1021/la000190r

186. Tai K. He X. Yuan X. Meng K. Gao Y. Yuan F. A comparison of physicochemical and functional properties of icaritin-loaded liposomes based on different surfactants Colloids Surf. A Physicochem. Eng. Asp. 2017 518 218 231 10.1016/j.colsurfa.2017.01.019

187. Forouhari S. Beygi Z. Mansoori Z. Hajsharifi S. Heshmatnia F. Gheibihayat S.M. Liposomes: Ideal drug delivery systems in breast cancer Biotechnol. Appl. Biochem. 2022 69 1867 1884 10.1002/bab.2253 34505736

188. Muntimadugu E. Kumar R. Saladi S. Rafeeqi T.A. Khan W. CD44 targeted chemotherapy for co-eradication of breast cancer stem cells and cancer cells using polymeric nanoparticles of salinomycin and paclitaxel Colloids Surf. B Biointerfaces 2016 143 532 546 10.1016/j.colsurfb.2016.03.075 27045981

189. Yang X. Liu K. P-gp inhibition-based strategies for modulating pharmacokinetics of anticancer drugs: An update Curr. Drug Metab. 2016 17 806 826 10.2174/1389200217666160629112717 27364832

190. Helmy L.A. Abdel-Halim M. Hassan R. Sebak A. Farghali H.A. Mansour S. Tammam S.N. The other side to the use of active targeting ligands; the case of folic acid in the targeting of breast cancer Colloids Surf. B Biointerfaces 2022 211 112289 10.1016/j.colsurfb.2021.112289 34954516

191. Patel R. Lacerda Q. Oeffinger B.E. Eisenbrey J.R. Rochani A.K. Kaushal G. Wessner C.E. Wheatley M.A. Development of a dual drug-loaded, surfactant-stabilized contrast agent containing oxygen Polymers 2022 14 1568 10.3390/polym14081568 35458319 PMC9027498

192. Ur Rahman M. Hussain H.R. Akram H. Sarfraz M. Nouman M. Khan J.A. Ishtiaq M. Niosomes as a targeted drug delivery system in the treatment of breast cancer: Preparation, classification and mechanisms of cellular uptake J. Drug Target. 2025 33 916 932 10.1080/1061186X.2025.2468750 39964023

193. Wei X. Song M. Li W. Huang J. Yang G. Wang Y. Multifunctional nanoplatforms co-delivering combinatorial dual-drug for eliminating cancer multidrug resistance Theranostics 2021 11 6334 10.7150/thno.59342 33995661 PMC8120214

194. Salawi A. Self-emulsifying drug delivery systems: A novel approach to deliver drugs Drug Deliv. 2022 29 1811 1823 10.1080/10717544.2022.2083724 35666090 PMC9176699

195. Chaurawal N. Misra C. Raza K. Lipid-based nanocarriers loaded with taxanes for the management of breast cancer: Promises and challenges Curr. Drug Targets 2022 23 544 558 10.2174/1389450122666210824144304 34431461

196. Wahi A. Bishnoi M. Raina N. Singh M.A. Verma P. Gupta P.K. Kaur G. Tuli H.S. Gupta M. Recent updates on nano-phyto-formulations based therapeutic intervention for cancer treatment Oncol. Res. 2023 32 19 10.32604/or.2023.042228 38188681 PMC10767243

197. Rathore C. Hemrajani C. Sharma A.K. Gupta P.K. Jha N.K. Aljabali A.A. Gupta G. Singh S.K. Yang J.C. Dwivedi R.P. Self-nanoemulsifying drug delivery system (SNEDDS) mediated improved oral bioavailability of thymoquinone: Optimization, characterization, pharmacokinetic, and hepatotoxicity studies Drug Deliv. Transl. Res. 2023 13 292 307 10.1007/s13346-022-01193-8 35831776 PMC9726673

198. Shehata E.M. Elnaggar Y.S. Galal S. Abdallah O.Y. Self-emulsifying phospholipid pre-concentrates (SEPPs) for improved oral delivery of the anti-cancer genistein: Development, appraisal and ex-vivo intestinal permeation Int. J. Pharm. 2016 511 745 756 10.1016/j.ijpharm.2016.07.078 27492016

199. Lakkakula J. Srilekha G.K.P. Kalra P. Varshini S.A. Penna S. Exploring the promising role of chitosan delivery systems in breast cancer treatment: A comprehensive review Carbohydr. Res. 2024 545 109271 10.1016/j.carres.2024.109271 39270442

200. Nguyen T.T.L. Duong V.A. Maeng H.J. Pharmaceutical formulations with P-glycoprotein inhibitory effect as promising approaches for enhancing oral drug absorption and bioavailability Pharmaceutics 2021 13 1103 10.3390/pharmaceutics13071103 34371794 PMC8309061

201. Riaz S. Riaz A. Younus A. Mubin M. Ashraf M. Application of Bionanomaterials for Cancer Therapy Sustainable Nanomaterials for Biomedical Engineering Apple Academic Press Palm Bay, FL, USA 2023 307 341

202. Nikolakakis I. Partheniadis I. Self-emulsifying granules and pellets: Composition and formation mechanisms for instant or controlled release Pharmaceutics 2017 9 50 10.3390/pharmaceutics9040050 29099779 PMC5750656

203. Katiyar S.S. Kushwah V. Dora C.P. Jain S. Novel biosurfactant and lipid core-shell type nanocapsular sustained release system for intravenous application of methotrexate Int. J. Pharm. 2019 557 86 96 10.1016/j.ijpharm.2018.12.043 30584909

204. Malik J.A. Ansari J.A. Ahmed S. Khan A. Ahemad N. Anwar S. Nano-drug delivery system: A promising approach against breast cancer Ther. Deliv. 2023 14 357 381 10.4155/tde-2023-0020 37431741

205. Wadhawan A. Singh J. Sharma H. Handa S. Singh G. Kumar R. Barnwal R.P. Pal Kaur I. Chatterjee M. Anticancer biosurfactant-loaded PLA–PEG nanoparticles induce apoptosis in human MDA-MB-231 breast cancer cells ACS Omega 2022 7 5231 5241 10.1021/acsomega.1c06338 35187338 PMC8851644

206. Esmaeili F. Ghahremani M.H. Ostad S.N. Atyabi F. Seyedabadi M. Malekshahi M.R. Amini M. Dinarvand R. Folate-Receptor-Targeted Delivery of Docetaxel Nanoparticles Prepared by PLGA–PEG–Folate Conjugate J. Drug Target. 2008 16 415 423 10.1080/10611860802088630 18569286

207. Naughton P.J. Marchant R. Naughton V. Banat I.M. Microbial biosurfactants: Current trends and applications in agricultural and biomedical industries J. Appl. Microbiol. 2019 127 12 28 10.1111/jam.14243 30828919

208. Bezza F.A. Tichapondwa S.M. Chirwa E.M. Synthesis of biosurfactant stabilized silver nanoparticles, characterization and their potential application for bactericidal purposes J. Hazard. Mater. 2020 393 122319 10.1016/j.jhazmat.2020.122319 32120206

209. Hussein H.A. Abdullah M.A. Biosurfactant as a vehicle for targeted antitumor and anticancer drug delivery Green Sustainable Process for Chemical and Environmental Engineering and Science Academic Press Cambridge, UK 2022 299 317

210. Katiyar S.S. Ghadi R. Kushwah V. Dora C.P. Jain S. Lipid and biosurfactant based core–shell-type nanocapsules having high drug loading of paclitaxel for improved breast cancer therapy ACS Biomater. Sci. Eng. 2020 6 6760 6769 10.1021/acsbiomaterials.0c01290 33320604

211. Akiyode O.A. The Physico-Chemical and Biological Analysis of Microbial Biosurfactants (BSs) for Applications towards Cancer Therapies, Wound Healing Dressings and Drug Delivery Ph.D. Thesis University of Greenwich London, UK 2017

212. Sardesai S. Biniwale M. Wertheimer F. Garingo A. Ramanathan R. Evolution of surfactant therapy for respiratory distress syndrome: Past, present, and future Pediatr. Res. 2017 81 240 248 10.1038/pr.2016.203 27706130

213. Lawrence M.J. Surfactant Systems: Microemulsions and Vesicles as Vehicles for Drug Delivery Eur. J. Drug Metab. Pharmacokinet. 1994 19 257 269 10.1007/BF03188929 7867669

214. Dri D.A. Marianecci C. Carafa M. Gaucci E. Gramaglia D. Surfactants, nanomedicines and nanocarriers: A critical evaluation on clinical trials Pharmaceutics 2021 13 381 10.3390/pharmaceutics13030381 33805639 PMC7999832

215. Kaliyaperumal R. Nagaraj K. Sakthikumar K. Albeshr M.F. Velmurugan G. Green Synthesis and Characterization of ZnO/α-Fe2O3 Nanocomposites Using Hydrocotyle umbellata Leaf Extract and Evaluation of Their Antimicrobial Properties Appl. Organomet. Chem. 2025 39 e70121 10.1002/aoc.70121

216. Shah N.N. Merchant M.S. Cole D.E. Jayaprakash N. Bernstein D. Delbrook C. Richards K. Widemann B.C. Wayne A.S. Vincristine sulfate liposomes injection (VSLI, Marqibo ® ): Results from a phase I study in children, adolescents, and young adults with refractory solid tumors or leukemias Pediatr. Blood Cancer 2016 63 997 1005 10.1002/pbc.25937 26891067 PMC6689398

217. Savla R. Browne J. Plassat V. Wasan K.M. Wasan E.K. Review and analysis of FDA approved drugs using lipid-based formulations Drug Dev. Ind. Pharm. 2017 43 1743 1758 10.1080/03639045.2017.1342654 28673096

218. Gabizon A.A. Gabizon-Peretz S. Modaresahmadi S. La-Beck N.M. Thirty years from FDA approval of pegylated liposomal doxorubicin (Doxil/Caelyx): An updated analysis and future perspective BMJ Oncol. 2025 4 e000573 10.1136/bmjonc-2024-000573 PMC11751825 39885941

219. Rommasi F. Esfandiari N. Liposomal nanomedicine: Applications for drug delivery in cancer therapy Nanoscale Res. Lett. 2021 16 95 10.1186/s11671-021-03553-8 34032937 PMC8149564

220. Talluri S.V. Kuppusamy G. Karri V.V.S.R. Tummala S. Madhunapantula S.V. Lipid-based nanocarriers for breast cancer treatment–comprehensive review Drug Deliv. 2016 23 1291 1305 10.3109/10717544.2015.1092183 26430913

221. Marwah H. Dewangan H.K. Advancements in solid lipid nanoparticles and nanostructured lipid carriers for breast cancer therapy Curr. Pharm. Des. 2024 30 2922 2936 10.2174/0113816128319233240725103706 39150028

222. Silva S.G. Alves C. Cardoso A.M.S. Jurado A.S. de Lima M.C.P. Vale M.L.C. Marques E.F. Synthesis of Gemini Surfactants and Evaluation of Their Interfacial and Cytotoxic Properties: Exploring the Multifunctionality of Serine as Headgroup Eur. J. Org. Chem. 2013 2013 1758 1769 10.1002/ejoc.201201396

223. Halliday H.L. Recent clinical trials of surfactant treatment for neonates Neonatology 2006 89 323 329 10.1159/000092869 16770072

224. Shukla R. Singh A. Singh K.K. Vincristine-based nanoformulations: A preclinical and clinical studies overview Drug Deliv. Transl. Res. 2024 14 1 16 10.1007/s13346-023-01389-6 PMC10746576 37552393

225. Ganta S. Devalapally H. Amiji M. Curcumin enhances oral bioavailability and anti-tumor therapeutic efficacy of paclitaxel upon administration in nanoemulsion formulation J. Pharm. Sci. 2010 99 4630 4641 10.1002/jps.22157 20845461

226. Migden M.R. Rischin D. Schmults C.D. Guminski A. Hauschild A. Lewis K.D. Chung C.H. Hernandez-Aya L. Lim A.M. Chang A.L.S. PD-1 blockade with cemiplimab in advanced cutaneous squamous-cell carcinoma N. Engl. J. Med. 2018 379 341 351 10.1056/NEJMoa1805131 29863979

227. Kim H. Kwak M. Structures and applications of nucleic acid-based micelles for cancer therapy Int. J. Mol. Sci. 2023 24 1592 10.3390/ijms24021592 36675110 PMC9861421

228. Stagaard R. Jensen A. Schauer T. Bay M.L. Tavanez A.R. Wielsøe S. Peletier M. Strøbech J.E. Oria V.O. Zornhagen K.W. Exercise boost after surgery improves survival in model of metastatic breast cancer Front. Immunol. 2025 16 1533798 10.3389/fimmu.2025.1533798 40066446 PMC11891249

229. Rogé M. Kirova Y. Lévêque E. Guigo M. Johnson A. Nebbache R. Del Campo E.R. Lazarescu I. Servagi S. Mervoyer A. Impact of Radiation Therapy Modalities on Loco-regional Control in Inflammatory Breast Cancer Int. J. Radiat. Oncol. Biol. Phys. 2024 120 496 507 10.1016/j.ijrobp.2024.04.010 38621608

230. Shi X.Y. Bao X. Li Y. Yin C.L. Theanine combined with cisplatin inhibits the proliferation and metastasis of TNBC cells through Akt signaling pathway Tradit. Med. Res. 2023 8 25 10.53388/TMR20221025001

231. Culhane R. Zaborowski A.M. Hill A.D. Menopausal Hormone Therapy in Breast Cancer Survivors Cancers 2024 16 3267 10.3390/cancers16193267 39409888 PMC11475154

232. Wang Z. Yang L. Natural-product-based, carrier-free, noncovalent nanoparticles for tumor chemo-photodynamic combination therapy Pharmacol. Res. 2024 203 107150 10.1016/j.phrs.2024.107150 38521285

233. Dvir K. Giordano S. Leone J.P. Immunotherapy in breast cancer Int. J. Mol. Sci. 2024 25 7517 10.3390/ijms25147517 39062758 PMC11276856

234. Li T. Chen Y.C. Ao P. Heterogeneous Evolution of Breast Cancer Cells-An Endogenous Molecular-Cellular Network Study Biology 2024 13 564 10.3390/biology13080564 39194502 PMC11352015

235. Melo E.P. Aires-Barros M.R. Cabral J.M.S. Reverse Micelles and Protein Biotechnology Biotechnol. Annu. Review 2001 7 87 129 10.1016/s1387-2656(01)07034-x 11686050

236. Kim S.C. Kim D.W. Shim Y.H. Bang J.S. Oh H.S. Kim S.W. Seo M.H. In vivo evaluation of polymeric micellar paclitaxel formulation: Toxicity and efficacy J. Control. Release 2001 72 191 202 10.1016/S0168-3659(01)00275-9 11389998

237. Sławomir W. Koper A. Śledziñska P. Bebyn M. Koper K. Innovative Strategies for Effective Paclitaxel Delivery: Recent Developments and Prospects J. Oncol. Pharm. Pract. 2024 30 367 384 10.1177/10781552231208978 38204196

238. Nam S.H. Lee S.W. Lee Y.J. Kim Y.M. Safety and tolerability of weekly Genexol-PM, a Cremophor-Free polymeric micelle formulation of paclitaxel, with carboplatin in gynecologic cancer: A phase I study Cancer Res. Treat. Off. J. Korean Cancer Assoc. 2023 55 1346 1354 10.4143/crt.2022.1436 PMC10582543 37189263

239. Ma P. Mumper R.J. Paclitaxel nano-delivery systems: A comprehensive review J. Nanomed. Nanotechnol. 2013 4 1000164 10.4172/2157-7439.1000164 24163786 PMC3806207

240. Zi Y. Yang K. He J. Wu Z. Liu J. Zhang W. Strategies to enhance drug delivery to solid tumors by harnessing the EPR effects and alternative targeting mechanisms Adv. Drug Deliv. Rev. 2022 188 114449 10.1016/j.addr.2022.114449 35835353

241. Lim W.T. Tan E.H. Toh C.K. Hee S.W. Leong S.S. Ang P.C.S. Wong N.S. Chowbay B. Phase I pharmacokinetic study of a weekly liposomal paclitaxel formulation (Genexol ® -PM) in patients with solid tumors Ann. Oncol. 2010 21 382 388 10.1093/annonc/mdp315 19633055

242. Elhissi A.M. Mahmood R. Parveen I. Vali A. Najlah M. Phoenix D.A. Ahmed W. Taxane anticancer formulations: Challenges and achievements Adv. Med. Surg. Eng. 2020 347 358 10.1016/B978-0-12-819712-7.00018-8

243. Lee H. Soo P.L. Liu J. Butler M. Allen C. Polymeric micelles for formulation of anti-cancer drugs Nanotechnology for Cancer Therapy CRC Press Boca Raton, FL, USA 317 355

244. Lee J. Kim J. Chang E. Choi W. Lee K. Yoon H. Jung S. Park M. Yoon J. Kim S. A Phase II Trial of Neoadjuvant Chemotherapy with Genexol ® (Paclitaxel) and Epirubicin for Locally Advanced Breast Cancer J. Breast Cancer 2014 17 344 10.4048/jbc.2014.17.4.344 25548582 PMC4278053

245. Moretton M.A. Bernabeu E. Grotz E. Gonzalez L. Zubillaga M. Chiappetta D.A. A glucose-targeted mixed micellar formulation outperforms Genexol in breast cancer cells Eur. J. Pharm. Biopharm. 2017 114 305 316 10.1016/j.ejpb.2017.02.005 28192249

246. Serras A. Faustino C. Pinheiro L. Functionalized Polymeric Micelles for Targeted Cancer Therapy: Steps from Conceptualization to Clinical Trials Pharmaceutics 2024 16 1047 10.3390/pharmaceutics16081047 39204392 PMC11359152

247. Tan S. Zou C. Zhang W. Yin M. Gao X. Tang Q. Recent developments in d-α-tocopheryl polyethylene glycol-succinate-based nanomedicine for cancer therapy Drug Deliv. 2017 24 1831 1842 10.1080/10717544.2017.1406561 29182031 PMC8241040

248. Wong C.N. Lee S.K. Lim Y.M. Yang S.B. Chew Y.L. Chua A.L. Liew K.B. Recent Advances in Vitamin E TPGS-Based Organic Nanocarriers for Enhancing the Oral Bioavailability of Active Compounds: A Systematic Review Pharmaceutics 2025 17 485 10.3390/pharmaceutics17040485 40284480 PMC12030195

249. Mehata A.K. Setia A. Malik A.K. Hassani R. Dailah H.G. Alhazmi H.A. Albarraq A.A. Mohan S. Muthu M.S. Vitamin E TPGS-based nanomedicine, nanotheranostics, and targeted drug delivery: Past, present, and future Pharmaceutics 2023 15 722 10.3390/pharmaceutics15030722 36986583 PMC10054265

250. Yang C. Wu T. Qi Y. Zhang Z. Recent advances in the application of vitamin E TPGS for drug delivery Theranostics 2018 8 464 10.7150/thno.22711 29290821 PMC5743561

251. Liu Y. Wang W. Yang J. Zhou C. Sun J. pH-sensitive polymeric micelles triggered drug release for extracellular and intracellular drug targeting delivery Asian J. Pharm. Sci. 2013 8 159 167 10.1016/j.ajps.2013.07.021

252. Shi Y. van der Meel R. Chen X. Lammers T. The EPR Effect and Beyond: Strategies to Improve Tumor Targeting and Cancer Nanomedicine Treatment Efficacy Theranostics 2020 10 7921 7924 10.7150/thno.49577 32685029 PMC7359085

253. Maeda H. Nakamura H. Fang J. The EPR effect for macromolecular drug delivery to solid tumors: Improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo Adv. Drug Deliv. Rev. 2013 65 71 79 10.1016/j.addr.2012.10.002 23088862

254. Feng S.S. Zhao L. Zhang Z. Bhakta G. Win K.Y. Dong Y. Chien S. Chemotherapeutic engineering: Vitamin E TPGS-emulsified nanoparticles of biodegradable polymers realized sustainable paclitaxel chemotherapy for 168 h in vivo Chem. Eng. Sci. 2007 62 6641 6648 10.1016/j.ces.2007.08.006

255. Muthu M.S. Avinash Kulkarni S. Liu Y. Feng S.S. Development of docetaxel-loaded vitamin E TPGS micelles: Formulation optimization, effects on brain cancer cells and biodistribution in rats Nanomedicine 2012 7 353 364 10.2217/nnm.11.111 22329606

256. Kutty R.V. Feng S.S. Cetuximab conjugated vitamin E TPGS micelles for targeted delivery of docetaxel for treatment of triple negative breast cancers Biomaterials 2013 34 10160 10171 10.1016/j.biomaterials.2013.09.043 24090836

257. Chen T.E. Tu L. Wang G. Qi N. Wu W. Zhang W. Feng J. Multi-functional chitosan polymeric micelles as oral paclitaxel delivery systems for enhanced bioavailability and anti-tumor efficacy Int. J. Pharm. 2020 578 119105 10.1016/j.ijpharm.2020.119105 32018019

258. Zhang Z. Mei L. Feng S.S. Paclitaxel drug delivery systems Expert Opin. Drug Deliv. 2013 10 325 340 10.1517/17425247.2013.752354 23289542

259. Farooq M.A. Trevaskis N.L. TPGS decorated liposomes as multifunctional nano-delivery systems Pharm. Res. 2023 40 245 263 10.1007/s11095-022-03424-6 36376604 PMC9663195

260. Yan H. Du X. Wang R. Zhai G. Progress in the Study of D-α-Tocopherol Polyethylene Glycol 1000 Succinate (TPGS) Reversing Multidrug Resistance Colloids Surf. B Biointerfaces 2021 205 111914 10.1016/j.colsurfb.2021.111914 34130211

261. Rathod S. Bahadur P. Tiwari S. Nanocarriers Based on Vitamin E-TPGS: Design Principle and Molecular Insights into Improving the Efficacy of Anticancer Drugs Int. J. Pharm. 2021 592 120045 10.1016/j.ijpharm.2020.120045 33212172

262. Zuo R. Zhang J. Song X. Hu S. Gao X. Wang J. Ji H. Ji C. Peng L. Si H. Encapsulating halofuginone hydrobromide in TPGS polymeric micelles enhances efficacy against triple-negative breast cancer cells Int. J. Nanomed. 2021 16 1587 1600 10.2147/IJN.S289096 PMC7924253 33664573

263. Senapati S. Mahanta A.K. Kumar S. Maiti P. Controlled drug delivery vehicles for cancer treatment and their performance Signal Transduct. Target. Ther. 2018 3 7 10.1038/s41392-017-0004-3 29560283 PMC5854578

264. Chen Z. Kankala R.K. Yang Z. Li W. Xie S. Li H. Chen A.Z. Zou L. Antibody-based drug delivery systems for cancer therapy: Mechanisms, challenges, and prospects Theranostics 2022 12 3719 10.7150/thno.72594 35664074 PMC9131265

265. Wu J. The enhanced permeability and retention (EPR) effect: The significance of the concept and methods to enhance its application J. Pers. Med. 2021 11 771 10.3390/jpm11080771 34442415 PMC8402171

266. Abd Ellah N.H. Abouelmagd S.A. Surface functionalization of polymeric nanoparticles for tumor drug delivery: Approaches and challenges Expert Opin. Drug Deliv. 2017 14 201 214 10.1080/17425247.2016.1213238 27426638

267. Khan D.R. Webb M.N. Cadotte T.H. Gavette M.N. Use of targeted liposome-based chemotherapeutics to treat breast cancer Breast Cancer Basic Clin. Res. 2015 9 1 5 10.4137/BCBCR.S29421 PMC4533644 26309409

268. Chen B. Dai W. He B. Zhang H. Wang X. Wang Y. Zhang Q. Current multistage drug delivery systems based on the tumor microenvironment Theranostics 2017 7 538 10.7150/thno.16684 28255348 PMC5327631

269. Saadat M. Mostafaei F. Mahdinloo S. Abdi M. Zahednezhad F. Zakeri-Milani P. Valizadeh H. Drug delivery of pH-Sensitive nanoparticles into the liver cancer cells J. Drug Deliv. Sci. Technol. 2021 63 102557 10.1016/j.jddst.2021.102557

270. Abdollahpour-Alitappeh M. Lotfinia M. Gharibi T. Mardaneh J. Farhadihosseinabadi B. Larki P. Faghfourian B. Sepehr K.S. Abbaszadeh-Goudarzi K. Abbaszadeh-Goudarzi G. Antibody–drug conjugates (ADCs) for cancer therapy: Strategies, challenges, and successes J. Cell. Physiol. 2019 234 5628 5642 10.1002/jcp.27419 30478951

271. Najjar M.K. Manore S.G. Regua A.T. Lo H.W. Antibody-drug conjugates for the treatment of HER2-positive breast cancer Genes 2022 13 2065 10.3390/genes13112065 36360302 PMC9691220

272. Oostra D.R. Macrae E.R. Role of trastuzumab emtansine in the treatment of HER2-positive breast cancer Breast Cancer Targets Ther. 2014 6 103 113 10.2147/BCTT.S67297 PMC4112743 25114588

273. Mitchell M.J. Billingsley M.M. Haley R.M. Wechsler M.E. Peppas N.A. Langer R. Engineering precision nanoparticles for drug delivery Nat. Rev. Drug Discov. 2021 20 101 124 10.1038/s41573-020-0090-8 33277608 PMC7717100

274. Lopes J. Lopes D. Motallebi M. Ye M. Xue Y. Vieira A.C. Singh S.K. Dua K. Veiga F. Sethi G. Biomembrane-coated nanosystems as next-generation delivery systems for the treatment of gastrointestinal cancers Bioeng. Transl. Med. 2025 e70006 10.1002/btm2.70006 PMC12284443 40708975

275. Kunjiappan S. Pavadai P. Vellaichamy S. Ram Kumar Pandian S. Ravishankar V. Palanisamy P. Govindaraj S. Srinivasan G. Premanand A. Sankaranarayanan M. Surface receptor-mediated targeted drug delivery systems for enhanced cancer treatment: A state-of-the-art review Drug Dev. Res. 2021 82 309 340 10.1002/ddr.21758 33170541

276. Tagde P. Kulkarni G.T. Mishra D.K. Kesharwani P. Recent Advances in Folic Acid Engineered Nanocarriers for Treatment of Breast Cancer J. Drug Deliv. Sci. Technol. 2020 56 101613 10.1016/j.jddst.2020.101613

277. Prabhu R.H. Patravale V.B. Joshi M.D. Polymeric nanoparticles for targeted treatment in oncology: Current insights Int. J. Nanomed. 2015 10 1001 1018 10.2147/IJN.S56932 PMC4324541 25678788

278. Liu Y. Sun J. Cao W. Yang J. Lian H. Li X. Sun Y. Wang Y. Wang S. He Z. Dual targeting folate-conjugated hyaluronic acid polymeric micelles for paclitaxel delivery Int. J. Pharm. 2011 421 160 169 10.1016/j.ijpharm.2011.09.006 21945183

279. Liu Y. Sun J. Lian H. Cao W. Wang Y. He Z. Folate and CD44 receptors dual-targeting hydrophobized hyaluronic acid paclitaxel-loaded polymeric micelles for overcoming multidrug resistance and improving tumor distribution J. Pharm. Sci. 2014 103 1538 1547 10.1002/jps.23934 24619562

280. Tai W. Mahato R. Cheng K. The role of HER2 in cancer therapy and targeted drug delivery J. Control. Release 2010 146 264 275 10.1016/j.jconrel.2010.04.009 20385184 PMC2918695

281. Fatima I. Rahdar A. Sargazi S. Barani M. Hassanisaadi M. Thakur V.K. Quantum dots: Synthesis, antibody conjugation, and HER2-receptor targeting for breast cancer therapy J. Funct. Biomater. 2021 12 75 10.3390/jfb12040075 34940554 PMC8708439

282. Swain S.M. Shastry M. Hamilton E. Targeting HER2-positive breast cancer: Advances and future directions Nat. Rev. Drug Discov. 2023 22 101 126 10.1038/s41573-022-00579-0 36344672 PMC9640784

283. Entzian K. Aigner A. Drug delivery by ultrasound-responsive nanocarriers for cancer treatment Pharmaceutics 2021 13 1135 10.3390/pharmaceutics13081135 34452096 PMC8397943

284. Ding C. Li Z. A review of drug release mechanisms from nanocarrier systems Mater. Sci. Eng. C 2017 76 1440 1453 10.1016/j.msec.2017.03.130 28482511

285. Wang H. Huang Y. Combination therapy based on nano codelivery for overcoming cancer drug resistance Med. Drug Discov. 2020 6 100024 10.1016/j.medidd.2020.100024

286. Oh D.Y. Bang Y.J. HER2-targeted therapies a role beyond breast cancer Nat. Rev. Clin. Oncol. 2020 17 33 48 10.1038/s41571-019-0268-3 31548601

287. Di Cosimo S. Baselga J. Management of breast cancer with targeted agents: Importance of heterogenicity Nat. Rev. Clin. Oncol. 2010 7 139 147 10.1038/nrclinonc.2009.234 20125090

288. Zardavas D. Irrthum A. Swanton C. Piccart M. Clinical Management of Breast Cancer Heterogeneity Nat. Rev. Clin. Oncol. 2015 12 381 394 10.1038/nrclinonc.2015.73 25895611

289. Li J. Wang Y. Zhu Y. Oupický D. Recent advances in delivery of drug–nucleic acid combinations for cancer treatment J. Control. Release 2013 172 589 600 10.1016/j.jconrel.2013.04.010 23624358 PMC3783568

290. Qiu C. Wu Y. Shi Q. Guo Q. Zhang J. Meng Y. Wang C. Xia F. Wang J. Xu C. Advanced Strategies for Nucleic Acids and Small-Molecular Drugs in Combined Anticancer Therapy Int. J. Biol. Sci. 2023 19 789 810 10.7150/ijbs.79328 36778126 PMC9910002

291. Paskeh M.D.A. Saebfar H. Mahabady M.K. Orouei S. Hushmandi K. Entezari M. Hashemi M. Aref A.R. Hamblin M.R. Ang H.L. Overcoming Doxorubicin Resistance in Cancer: SiRNA-Loaded Nanoarchitectures for Cancer Gene Therapy Life Sci. 2022 298 120463 10.1016/j.lfs.2022.120463 35259354

292. Saad M. Garbuzenko O.B. Minko T. Co-Delivery of SiRNA and an Anticancer Drug for Treatment of Multidrug-Resistant Cancer Nanomedicine 2008 3 761 776 10.2217/17435889.3.6.761 19025451 PMC2628713

293. Gandhi N.S. Tekade R.K. Chougule M.B. Nanocarrier Mediated Delivery of SiRNA/MiRNA in Combination with Chemotherapeutic Agents for Cancer Therapy: Current Progress and Advances J. Control. Release 2014 194 238 256 10.1016/j.jconrel.2014.09.001 25204288 PMC4254052

294. Pinedo H.M. Smorenburg C.H. Drugs Affecting Growth of Tumours Springer Science & Business Media Dordrecht, The Netherlands 2007

295. Buzun K. Bielawska A. Bielawski K. Gornowicz A. DNA Topoisomerases as Molecular Targets for Anticancer Drugs J. Enzym. Inhib. Med. Chem. 2020 35 1781 1799 10.1080/14756366.2020.1821676 PMC7534307 32975138

296. Agudelo D. Bourassa P. Bérubé G. Tajmir-Riahi H.-A. Intercalation of Antitumor Drug Doxorubicin and Its Analogue by DNA Duplex: Structural Features and Biological Implications Int. J. Biol. Macromol. 2014 66 144 150 10.1016/j.ijbiomac.2014.02.028 24560949

297. Sritharan S. Sivalingam N. A Comprehensive Review on Time-Tested Anticancer Drug Doxorubicin Life Sci. 2021 278 119527 10.1016/j.lfs.2021.119527 33887349

298. Demoulin B. Hermant M. Castrogiovanni C. Staudt C. Dumont P. Resveratrol Induces DNA Damage in Colon Cancer Cells by Poisoning Topoisomerase II and Activates the ATM Kinase to Trigger P53-Dependent Apoptosis Toxicol. Vitr. 2015 29 1156 1165 10.1016/j.tiv.2015.04.015 25952326

299. Yuan Y. Liu J. Yu X. Liu X. Cheng Y. Zhou C. Li M. Shi L. Deng Y. Liu H. Tumor-Targeting PH/Redox Dual-Responsive Nanosystem Epigenetically Reverses Cancer Drug Resistance by Co-Delivering Doxorubicin and GCN5 SiRNA Acta Biomater. 2021 135 556 566 10.1016/j.actbio.2021.09.002 34496281

300. Creixell M. Peppas N.A. Co-Delivery of SiRNA and Therapeutic Agents Using Nanocarriers to Overcome Cancer Resistance Nano Today 2012 7 367 379 10.1016/j.nantod.2012.06.013 26257819 PMC4527553

301. Walker J.V. Nitiss J.L. DNA topoisomerase II as a target for cancer chemotherapy Cancer Investig. 2002 20 570 589 10.1081/CNV-120002156 12094551

302. Xu J. Li R. Yan D. Zhu L. Biomimetic Modification of SiRNA/Chemo Drug Nanoassemblies for Targeted Combination Therapy in Breast Cancer ACS Appl. Mater. Interfaces 2024 16 59765 59776 10.1021/acsami.4c11064 39447113

303. Kargari Aghmiouni D. Khoee S. Dual-drug delivery by anisotropic and uniform hybrid nanostructures: A comparative study of the function and substrate–drug interaction properties Pharmaceutics 2023 15 1214 10.3390/pharmaceutics15041214 37111700 PMC10142803

304. Zare M. Pemmada R. Madhavan M. Shailaja A. Ramakrishna S. Kandiyil S.P. Donahue J.M. Thomas V. Encapsulation of MiRNA and SiRNA into Nanomaterials for Cancer Therapeutics Pharmaceutics 2022 14 1620 10.3390/pharmaceutics14081620 36015246 PMC9416290

305. Subhan M.A. Torchilin V.P. Efficient nanocarriers of siRNA therapeutics for cancer treatment Transl. Res. 2019 214 62 91 10.1016/j.trsl.2019.07.006 31369717

306. Mainini F. Eccles M.R. Lipid and Polymer-Based Nanoparticle SiRNA Delivery Systems for Cancer Therapy Molecules 2020 25 2692 10.3390/molecules25112692 32532030 PMC7321291

307. Ullah A. Khan M. Zhang Y. Shafiq M. Ullah M. Abbas A. Xianxiang X. Chen G. Diao Y. Advancing Therapeutic Strategies with Polymeric Drug Conjugates for Nucleic Acid Delivery and Treatment Int. J. Nanomed. 2025 20 25 52 10.2147/IJN.S429279 PMC11717654 39802382

308. Cheng W. Liang C. Wang X. Tsai H.-I. Liu G. Peng Y. Nie J. Huang L. Mei L. Zeng X. A Drug-Self-Gated and Tumor Microenvironment-Responsive Mesoporous Silica Vehicle: “Four-In-One” Versatile Nanomedicine for Targeted Multidrug-Resistant Cancer Therapy Nanoscale 2017 9 17063 17073 10.1039/C7NR05450E 29085938

309. Sitia L. Sevieri M. Signati L. Bonizzi A. Chesi A. Mainini F. Corsi F. Mazzucchelli S. HER-2-targeted nanoparticles for breast cancer diagnosis and treatment Cancers 2022 14 2424 10.3390/cancers14102424 35626028 PMC9139811

310. Miller K.D. Nogueira L. Mariotto A.B. Rowland J.H. Yabroff K.R. Alfano C.M. Jemal A. Kramer J.L. Siegel R.L. Cancer treatment and survivorship statistics, 2019 CA A Cancer J. Clin. 2019 69 363 385 10.3322/caac.21565 31184787

311. Sanati M. Figueroa-Espada C.G. Han E.L. Mitchell M.J. Yavari S.A. A Bioengineered Nanomaterials for SiRNA Therapy of Chemoresistant Cancers ACS Nano 2024 10.1021/acsnano.4c11259 39666006

312. Liu S. Li L. Zhang X. Meng Q. Nanotherapies from an oncologist doctor’s view Smart Mater. Med. 2023 4 183 198 10.1016/j.smaim.2022.07.005

313. Meng F. Zhong Y. Cheng R. Deng C. Zhong Z. pH-sensitive polymeric nanoparticles for tumor-targeting doxorubicin delivery: Concept and recent advances Nanomedicine 2014 9 487 499 10.2217/nnm.13.212 24746192

314. Isazadeh H. Oruji F. Shabani S. Behroozi J. Nasiri H. Isazadeh A. Akbari M. Advances in siRNA delivery approaches in cancer therapy: Challenges and opportunities Mol. Biol. Rep. 2023 50 9529 9543 10.1007/s11033-023-08749-y 37741808

315. Karthika C. Sureshkumar R. P-glycoprotein efflux transporters and its resistance its inhibitors and therapeutic aspects Biomarkers and Bioanalysis Overview IntechOpen London, UK 2020

316. Karthika C. Sureshkumar R. Zehravi M. Akter R. Ali F. Ramproshad S. Mondal B. Tagde P. Ahmed Z. Khan F.S. Multidrug resistance of cancer cells and the vital role of P-glycoprotein Life 2022 12 897 10.3390/life12060897 35743927 PMC9227591

317. Callaghan R. Luk F. Bebawy M. Inhibition of the multidrug resistance P-glycoprotein: Time for a change of strategy? Drug Metab. Dispos. 2014 42 623 631 10.1124/dmd.113.056176 24492893 PMC3965902

318. Zhou X. Chen L. Nie W. Wang W. Qin M. Mo X. Wang H. He C. Dual-Responsive Mesoporous Silica Nanoparticles Mediated Codelivery of Doxorubicin and Bcl-2 SiRNA for Targeted Treatment of Breast Cancer J. Phys. Chem. C 2016 120 22375 22387 10.1021/acs.jpcc.6b06759

319. Meng H. Xue M. Xia T. Ji Z. Tarn D.Y. Zink J.I. Nel A.E. Use of Size and a Copolymer Design Feature to Improve the Biodistribution and the Enhanced Permeability and Retention Effect of Doxorubicin-Loaded Mesoporous Silica Nanoparticles in a Murine Xenograft Tumor Model ACS Nano 2011 5 4131 4144 10.1021/nn200809t 21524062 PMC3905975

320. Kumar P. Salve R. Paknikar K.M. Gajbhiye V. Nucleolin Aptamer Conjugated MSNPs-PLR-PEG Multifunctional Nanoconstructs for Targeted Co-Delivery of Anticancer Drug and SiRNA to Counter Drug Resistance in TNBC Int. J. Biol. Macromol. 2022 229 600 614 10.1016/j.ijbiomac.2022.12.266 36586658

321. Nagaraj K. Senthil Murugan K. Thangamuniyandi P. Electron Transfer Reaction of Ion pairs: 1. Surfactant Cobalt(III) Complexes by Fe(CN)6 4- in Microheterogeneous Media Z. Phys. Chem. 2015 229 327 349 10.1515/zpch-2014-0581

322. Waghray D. Zhang Q. Inhibit or Evade Multidrug Resistance P-Glycoprotein in Cancer Treatment J. Med. Chem. 2017 61 5108 5121 10.1021/acs.jmedchem.7b01457 29251920 PMC6281405

323. Ullah M.F. Cancer Multidrug Resistance (MDR): A Major Impediment to Effective Chemotherapy Asian Pac. J. Cancer Prev. APJCP 2008 9 1 6 18439063

324. Duan C. Yu M. Xu J. Li B.-Y. Zhao Y. Kankala R.K. Overcoming Cancer Multi-Drug Resistance (MDR): Reasons, Mechanisms, Nanotherapeutic Solutions, and Challenges Biomed. Pharmacother. 2023 162 114643 10.1016/j.biopha.2023.114643 37031496

325. Ashfaq U.A. Riaz M. Yasmeen E. Yousaf M.Z. Recent advances in nanoparticle-based targeted drug-delivery systems against cancer and role of tumor microenvironment Crit. Rev. Ther. Drug Carr. Syst. 2017 34 317 353 10.1615/CritRevTherDrugCarrierSyst.2017017845 29199588

326. Lage H. An Overview of Cancer Multidrug Resistance: A Still Unsolved Problem Cell. Mol. Life Sci. 2008 65 3145 3167 10.1007/s00018-008-8111-5 18581055 PMC11131739

327. Masood F. Polymeric Nanoparticles for Targeted Drug Delivery System for Cancer Therapy Mater. Sci. Eng. C 2016 60 569 578 10.1016/j.msec.2015.11.067 26706565

328. Robey R.W. Pluchino K.M. Hall M.D. Fojo A.T. Bates S.E. Gottesman M.M. Revisiting the role of efflux pumps in multidrug-resistant cancer Nat. Rev. Cancer 2018 18 452 10.1038/s41568-018-0005-8 29643473 PMC6622180

329. Wilczewska A.Z. Niemirowicz K. Markiewicz K.H. Car H. Nanoparticles as Drug Delivery Systems Pharmacol. Rep. 2012 64 1020 1037 10.1016/S1734-1140(12)70901-5 23238461

330. Maimaitijiang A. He D. Li D. Li W. Su Z. Li J. Progress in Research of Nanotherapeutics for Overcoming Multidrug Resistance in Cancer Int. J. Mol. Sci. 2024 25 9973 10.3390/ijms25189973 39337463 PMC11432649

331. Joshi D.C. Sharma A. Prasad S. Singh K. Kumar M. Sherawat K. Tuli H.S. Gupta M. Novel therapeutic agents in clinical trials: Emerging approaches in cancer therapy Discov. Oncol. 2024 15 342 10.1007/s12672-024-01195-7 39127974 PMC11317456

332. Zhang X. Xing H. Zhao Y. Ma Z. Pharmaceutical dispersion techniques for dissolution and bioavailability enhancement of poorly water-soluble drugs Pharmaceutics 2018 10 74 10.3390/pharmaceutics10030074 29937483 PMC6161168

333. Halder J. Pradhan D. Kar B. Ghosh G. Rath G. Nanotherapeutics approaches to overcome P-glycoprotein-mediated multi-drug resistance in cancer Nanomed. Nanotechnol. Biol. Med. 2022 40 102494 10.1016/j.nano.2021.102494 34775061

334. Chen T. Wu W. Xiao H. Chen Y. Chen M. Li J. Intelligent Drug Delivery System Based on Mesoporous Silica Nanoparticles Coated with an Ultra-PH-Sensitive Gatekeeper and Poly(Ethylene Glycol) ACS Macro Lett. 2015 5 55 58 10.1021/acsmacrolett.5b00765 35668579

335. Tang J. Wang Y. Wang D. Wang Y. Xu Z. Racette K. Liu F. Key structure of brij for overcoming multidrug resistance in cancer Biomacromolecules 2013 14 424 430 10.1021/bm301661w 23311629 PMC3574583

336. Kumbhar P.S. Nadaf S. Manjappa A.S. Jha N.K. Shinde S.S. Chopade S.S. Shete A.S. Disouza J.I. Sambamoorthy U. Kumar S.A. D-ɑ-Tocopheryl Polyethylene Glycol Succinate: A Review of Multifarious Applications in Nanomedicines Open Nano 2022 6 100036 10.1016/j.onano.2022.100036

337. Zastre J. Effect of Amphiphilic Diblock Copolymers on P-glycoprotein Substrate Permeability in Caco-2 Cells Ph.D. Thesis University of British Columbia Vancouver, BC, Canada 2004

338. Sawangrat K. Effects of Pharmaceutical Excipients on the Intestinal Transport and Absorption of Breast Cancer Resistance Protein Substrates Ph.D. Thesis Kyoto Pharmaceutical University Kyoto, Japan 2019

339. Wu Y.S. Ngai S.C. Goh B.H. Chan K.G. Lee L.H. Chuah L.H. Anticancer activities of surfactin and potential application of nanotechnology assisted surfactin delivery Front. Pharmacol. 2017 8 761 10.3389/fphar.2017.00761 29123482 PMC5662584

340. Woodcock D.M. Linsenmeyer M.E. Chojnowski G. Kriegler A.B. Nink V. Webster L.K. Sawyer W.H. Reversal of multidrug resistance by surfactants Br. J. Cancer 1992 66 62 68 10.1038/bjc.1992.217 1637678 PMC1977900

341. Sutton D. Nasongkla N. Blanco E. Gao J. Functionalized micellar systems for cancer targeted drug delivery Pharm. Res. 2007 24 1029 1046 10.1007/s11095-006-9223-y 17385025

342. Assaraf Y.G. Brozovic A. Gonçalves A.C. Jurkovicova D. Linē A. Machuqueiro M. Saponara S. Sarmento-Ribeiro A.B. Xavier C.P.R. Vasconcelos M.H. The Multi-Factorial Nature of Clinical Multidrug Resistance in Cancer Drug Resist. Updates Rev. Comment. Antimicrob. Anticancer. Chemother. 2019 46 100645 10.1016/j.drup.2019.100645 31585396

343. Saneja A. Khare V. Alam N. Dubey R.D. Gupta P.N. Advances in P-glycoprotein-based approaches for delivering anticancer drugs: Pharmacokinetic perspective and clinical relevance Expert Opin. Drug Deliv. 2014 11 121 138 10.1517/17425247.2014.865014 24295039

344. Singh M.S. Lamprecht A. Cargoing P-gp inhibitors via nanoparticle sensitizes tumor cells against doxorubicin Int. J. Pharm. 2015 478 745 752 10.1016/j.ijpharm.2014.11.064 25437111

345. Liu J. Cabral H. Mi P. Nanocarriers address intracellular barriers for efficient drug delivery, overcoming drug resistance, subcellular targeting and controlled release Adv. Drug Deliv. Rev. 2024 207 115239 10.1016/j.addr.2024.115239 38437916

346. Sharom F.J. Complex interplay between the P-glycoprotein multidrug efflux pump and the membrane: Its role in modulating protein function Front. Oncol. 2014 4 41 10.3389/fonc.2014.00041 24624364 PMC3939933

347. Sabir F. Qindeel M. Zeeshan M. Ul Ain Q. Rahdar A. Barani M. González E. Aboudzadeh M.A. Onco-receptors targeting in lung cancer via application of surface-modified and hybrid nanoparticles: A cross-disciplinary review Processes 2021 9 621 10.3390/pr9040621

348. Jain A.N.K.I.T. SK J. P-gp inhibitors: A potential tool to overcome drug resistance in cancer chemotherapy Nanomedicine Tissue Engineering Apple Academic Press Palm Bay, FL, USA 2021 9780429162206

349. Jonsson Ö. Behnam-Motlagh P. Persson M. Henriksson R. Grankvist K. Increase in doxorubicin cytotoxicity by carvedilol inhibition of P-glycoprotein activity Biochem. Pharmacol. 1999 58 1801 1806 10.1016/S0006-2952(99)00262-2 10571255

350. Ward R.A. Fawell S. Floc’h N. Flemington V. McKerrecher D. Smith P.D. Challenges and opportunities in cancer drug resistance Chem. Rev. 2020 121 3297 3351 10.1021/acs.chemrev.0c00383 32692162

351. Wu S. Fu L. Tyrosine kinase inhibitors enhanced the efficacy of conventional chemotherapeutic agent in multidrug resistant cancer cells Mol. Cancer 2018 17 25 10.1186/s12943-018-0775-3 29455646 PMC5817862

352. Vaghari-Tabari M. Hassanpour P. Sadeghsoltani F. Malakoti F. Alemi F. Qujeq D. Asemi Z. Yousefi B. CRISPR/Cas9 gene editing: A new approach for overcoming drug resistance in cancer Cell. Mol. Biol. Lett. 2022 27 49 10.1186/s11658-022-00348-2 35715750 PMC9204876

353. Bukowski K. Kciuk M. Kontek R. Mechanisms of multidrug resistance in cancer chemotherapy Int. J. Mol. Sci. 2020 21 3233 10.3390/ijms21093233 32370233 PMC7247559

354. Khaleel S.A. Al-Abd A.M. Ali A.A. Abdel-Naim A.B. Didox and resveratrol sensitize colorectal cancer cells to doxorubicin via activating apoptosis and ameliorating P-glycoprotein activity Sci. Rep. 2016 6 36855 10.1038/srep36855 27841296 PMC5107943

355. Gottesman M.M. Lavi O. Hall M.D. Gillet J.P. Toward a better understanding of the complexity of cancer drug resistance Annu. Rev. Pharmacol. Toxicol. 2016 56 85 102 10.1146/annurev-pharmtox-010715-103111 26514196

356. Pollard J. Rajabi-Siahboomi A. Badhan R.K. Mohammed A.R. Perrie Y. High-throughput screening of excipients with a biological effect: A kinetic study on the effects of surfactants on efflux-mediated transport J. Pharm. Pharmacol. 2019 71 889 897 10.1111/jphp.13072 30784086

357. Patel D. Sethi N. Patel P. Shah S. Patel K. Exploring the potential of P-glycoprotein inhibitors in the targeted delivery of anti-cancer drugs: A comprehensive review Eur. J. Pharm. Biopharm. 2024 198 114267 10.1016/j.ejpb.2024.114267 38514020

358. Bansal T. Akhtar N. Jaggi M. Khar R.K. Talegaonkar S. Novel formulation approaches for optimising delivery of anticancer drugs based on P-glycoprotein modulation Drug Discov. Today 2009 14 1067 1074 10.1016/j.drudis.2009.07.010 19647803

359. Hanke U. May K. Rozehnal V. Nagel S. Siegmund W. Weitschies W. Commonly Used Nonionic Surfactants Interact Differently with the Human Efflux Transporters ABCB1 (P-Glycoprotein) and ABCC2 (MRP2) Eur. J. Pharm. Biopharm. 2010 76 260 268 10.1016/j.ejpb.2010.06.008 20600890

360. Singh M.S. Nanocarrier System for Overcoming Multidrug Resistance in Cancer Ph.D. Thesis Universitäts-und Landesbibliothek Bonn Bonn, Germany 2015

361. Dong X. Mumper R.J. Nanomedicinal strategies to treat multidrug-resistant tumors: Current progress Nanomedicine 2010 5 597 615 10.2217/nnm.10.35 20528455 PMC2925023

362. Radhakrishnan A. Shanmukhan N.K. Samuel L.C. Pharmacogenomics influence on MDR1-associated cancer resistance and innovative drug delivery approaches: Advancing precision oncology Med. Oncol. 2025 42 67 10.1007/s12032-025-02611-w 39913003

363. Bu H. Gao Y. Li Y. Overcoming Multidrug Resistance (MDR) in Cancer by Nanotechnology Sci. China Chem. 2010 53 2226 2232 10.1007/s11426-010-4142-5

364. Sharifi-Azad M. Zenjanab M.K. Shahpouri M. Adili-Aghdam M.A. Fathi M. Jahanban-Esfahlan R. Codelivery of methotrexate and silibinin by niosome nanoparticles for enhanced chemotherapy of CT26 colon cancer cells Biomed. Mater. 2024 19 55015 10.1088/1748-605X/ad5d9b 38953496

365. Liu X. Fang R. Feng R. Li Q. Su M. Hou C. Zhuang K. Dai Y. Lei N. Jiang Y. Cage-modified hypocrellin against multidrug-resistant Candida spp. with unprecedented activity in light-triggered combinational photodynamic therapy Drug Resist. Updates 2022 65 100887 10.1016/j.drup.2022.100887 36370664

366. Agustina R.E.N.I. Setyaningsih D.E.W.I. Solid dispersion as a potential approach to improve dissolution and bioavailability of curcumin from Turmeric ( Curcuma longa L.) Int. J. App. Pharm. 2023 15 37 47 10.22159/ijap.2023v15i5.48295

367. Xu R. Design, Synthesis and Evaluation of Innovative Carriers for Delivery of MR Contrast Agents and Nucleic Acids Ph.D. Thesis University of Utah Salt Lake City, UT, USA 2009

368. Nerurkar M.M. Burton P.S. Borchardt R.T. The use of surfactants to enhance the permeability of peptides through Caco-2 cells by inhibition of an apically polarized efflux system Pharm. Res. 1996 13 528 534 10.1023/A:1016033702220 8710741

369. Gomaa S.E. Abbas H.A. Mohamed F.A. Ali M.A. Ibrahim T.M. Abdel Halim A.S. Alghamdi M.A. Mansour B. Chaudhary A.A. Elkelish A. The anti-staphylococcal fusidic acid as an efflux pump inhibitor combined with fluconazole against vaginal candidiasis in mouse model BMC Microbiol. 2024 24 54 10.1186/s12866-024-03181-z 38341568 PMC10858509

370. MacEwan S.R. Chilkoti A. From composition to cure: A systems engineering approach to anticancer drug carriers Angew. Chem. Int. Ed. 2017 56 6712 6733 10.1002/anie.201610819 PMC6372097 28028871

371. Warsi M.H. Development and optimization of vitamin E TPGS based PLGA nanoparticles for improved and safe ocular delivery of ketorolac J. Drug Deliv. Sci. Technol. 2021 61 102121 10.1016/j.jddst.2020.102121

372. Kontogiannis O. Selianitis D. Perinelli D.R. Bonacucina G. Pippa N. Gazouli M. Pispas S. Non-ionic surfactant effects on innate pluronic 188 behavior: Interactions, and physicochemical and biocompatibility studies Int. J. Mol. Sci. 2022 23 13814 10.3390/ijms232213814 36430294 PMC9697813

373. Rasul A. Imran Khan M. Ur Rehman M. Abbas G. Aslam N. Ahmad S. Abbas K. Akhtar Shah P. Iqbal M. Ahmed Al Subari A.M. In vitro characterization and release studies of combined nonionic surfactant-based vesicles for the prolonged delivery of an immunosuppressant model drug Int. J. Nanomed. 2020 15 7937 7949 10.2147/IJN.S268846 PMC7569247 33116510

374. Manaargadoo-Catin M. Ali-Cherif A. Pougnas J.L. Perrin C. Hemolysis by surfactants—A review Adv. Colloid Interface Sci. 2016 228 1 16 10.1016/j.cis.2015.10.011 26687805

375. Wen C. Hu H. Zhang W. Liu X. Jiang X. Wang L. Assessing cyp2c8-mediated pharmaceutical excipient-drug interaction potential: A case study of tween 80 and Cremophor El− 5 Pharmaceutics 2021 13 1492 10.3390/pharmaceutics13091492 34575568 PMC8467590

376. Abdulbaqi I.M. Assi R.A. Yaghmur A. Darwis Y. Mohtar N. Parumasivam T. Saqallah F.G. Wahab H.A. Pulmonary delivery of anticancer drugs via lipid-based nanocarriers for the treatment of lung cancer: An update Pharmaceuticals 2021 14 725 10.3390/ph14080725 34451824 PMC8400724

377. Win K.Y. Feng S.S. In vitro and in vivo studies on vitamin E TPGS-emulsified poly (D, L-lactic-co-glycolic acid) nanoparticles for paclitaxel formulation Biomaterials 2006 27 2285 2291 10.1016/j.biomaterials.2005.11.008 16313953

378. Nielsen C.K. Kjems J. Mygind T. Snabe T. Meyer R.L. Effects of Tween 80 on growth and biofilm formation in laboratory media Front. Microbiol. 2016 7 1878 10.3389/fmicb.2016.01878 27920774 PMC5118432

379. Ten Tije A.J. Verweij J. Loos W.J. Sparreboom A. Pharmacological effects of formulation vehicles: Implications for cancer chemotherapy Clin. Pharmacokinet. 2003 42 665 685 10.2165/00003088-200342070-00005 12844327

380. Jash A. Ubeyitogullari A. Rizvi S.S.H. Liposomes for Oral Delivery of Protein and Peptide-Based Therapeutics: Challenges, Formulation Strategies, and Advances J. Mater. Chem. B 2021 9 4773 4792 10.1039/D1TB00126D 34027542

381. Pokhrel D.R. Sah M.K. Gautam B. Basak H.K. Bhattarai A. Chatterjee A. A recent overview of surfactant–drug interactions and their importance RSC Adv. 2023 13 17685 17704 10.1039/D3RA02883F 37312992 PMC10258811

382. Elmowafy E.M. Tiboni M. Soliman M.E. Biocompatibility, biodegradation and biomedical applications of poly (lactic acid)/poly (lactic-co-glycolic acid) micro and nanoparticles J. Pharm. Investig. 2019 49 347 380 10.1007/s40005-019-00439-x

383. Ashique S. Garg A. Hussain A. Farid A. Kumar P. Taghizadeh-Hesary F. Nanodelivery systems: An efficient and target-specific approach for drug-resistant cancers Cancer Med. 2023 12 18797 18825 10.1002/cam4.6502 37668041 PMC10557914

384. Bhusare N. Gade A. Kumar M.S. Using nanotechnology to progress the utilization of marine natural products in combating multidrug resistance in cancer: A prospective strategy J. Biochem. Mol. Toxicol. 2024 38 e23732 10.1002/jbt.23732 38769657

385. Kirtane A.R. Kalscheuer S.M. Panyam J. Exploiting Nanotechnology to Overcome Tumor Drug Resistance: Challenges and Opportunities Adv. Drug Deliv. Rev. 2013 65 1731 1747 10.1016/j.addr.2013.09.001 24036273 PMC3849460

386. Davodabadi F. Sajjadi S.F. Sarhadi M. Mirghasemi S. Hezaveh M.N. Khosravi S. Andani M.K. Cordani M. Basiri M. Ghavami S. Cancer Chemotherapy Resistance: Mechanisms and Recent Breakthrough in Targeted Drug Delivery Eur. J. Pharmacol. 2023 958 176013 10.1016/j.ejphar.2023.176013 37633322

387. Bhalani D.V. Nutan B. Kumar A. Singh Chandel A.K. Bioavailability enhancement techniques for poorly aqueous soluble drugs and therapeutics Biomedicines 2022 10 2055 10.3390/biomedicines10092055 36140156 PMC9495787

388. Kibria G. Hatakeyama H. Harashima H. Cancer multidrug resistance: Mechanisms involved and strategies for circumvention using a drug delivery system Arch. Pharmacal Res. 2014 37 4 15 10.1007/s12272-013-0276-2 24272889

389. Kazi M. Lipid-Based Nano-Delivery for Oral Administration of Poorly Water Soluble Drugs (PWSDs): Design Adv. Technol. Deliv. Ther. 2017 3 31

390. Sita V.G. Vavia P. Bromocriptine nanoemulsion-loaded transdermal gel: Optimization using factorial design, in vitro and in vivo evaluation AAPS PharmSciTech. 2020 21 80 10.1208/s12249-020-1620-8 31975311

391. Sharifi E. Bigham A. Yousefiasl S. Trovato M. Ghomi M. Esmaeili Y. Samadi P. Zarrabi A. Ashrafizadeh M. Sharifi S. Mesoporous bioactive glasses in cancer diagnosis and therapy: Stimuli-responsive, toxicity, immunogenicity, and clinical translation Adv. Sci. 2022 9 2102678 10.1002/advs.202102678 PMC8805580 34796680

392. Pei J. Yan Y. Jayaraman S. Rajagopal P. Natarajan P.M. Umapathy V.R. Gopathy S. Roy J.R. Sadagopan J.C. Thalamati D. A review on advancements in the application of starch-based nanomaterials in biomedicine: Precision drug delivery and cancer therapy Int. J. Biol. Macromol. 2024 265 130746 10.1016/j.ijbiomac.2024.130746 38467219

393. Karsa D.R. Porter M.R. Biodegradability of Surfactants Springer Science & Business Media Dordrecht, The Netherlands 2012

394. Scott M.J. Jones M.N. The biodegradation of surfactants in the environment Biochim. Biophys. Acta BBA Biomembr. 2000 1508 235 251 10.1016/S0304-4157(00)00013-7 11090828

395. Ann-Kathrin B. Bippus L. Oraby A. Noll P. Zibek S. Albrecht S. Environmental Impacts of Biosurfactants from a Life Cycle Perspective: A Systematic Literature Review Adv. Biochem. Eng. Biotechnol. 2022 235 269 10.1007/10_2021_194 35318488

396. Moammeri A. Chegeni M.M. Sahrayi H. Ghafelehbashi R. Memarzadeh F. Mansouri A. Akbarzadeh I. Abtahi M.S. Hejabi F. Ren Q. Current advances in niosomes applications for drug delivery and cancer treatment Mater. Today Bio. 2023 23 100837 10.1016/j.mtbio.2023.100837 PMC10632535 37953758

397. Sharma R.K. Dey G. Banerjee P. Maity J.P. Lu C.M. Siddique J.A. Wang S.C. Chatterjee N. Das K. Chen C.Y. New aspects of lipopeptide-incorporated nanoparticle synthesis and recent advancements in biomedical and environmental sciences: A review J. Mater. Chem. B 2023 11 10 32 10.1039/D2TB01564A 36484467

398. Matteis V.D. Cascione M. Rizzello L. Liatsi-Douvitsa E. Apriceno A. Rinaldi R. Green Synthesis of Nanoparticles and Their Application in Cancer Therapy Green Synthesis of Nanoparticles: Applications and Prospects Springer Singapore 2020 163 197 10.1007/978-981-15-5179-6_8

399. Molchanov V.S. Philippova O.E. Stimuli-responsive systems based on polymer-like wormlike micelles of ionic surfactants and their modern applications Polym. Sci. Ser. C 2023 65 113 127 10.1134/S1811238223700340

400. Alrbyawi H. Poudel I. Annaji M. Arnold R.D. Tiwari A.K. Babu R.J. Recent advancements of stimuli-responsive targeted liposomal formulations for cancer drug delivery Pharm. Nanotechnol. 2022 10 3 23 10.2174/2211738510666220214102626 35156590

401. Abbasi K. Siddiqui K. Bano S. Iqbal S. Shaikh S.A. Future Trends and Innovation in Nano Drug Delivery for Cancer Therapy, Application of siRNA (Nanoparticle-Based RNA) Therapy, Ultrasound Linked Nano-Cancer Therapeutics, and Application of Exosomes-Based Cancer Therapy Nano Drug Delivery for Cancer Therapy: Principles and Practices Springer Nature Singapore 2024 197 251

402. Qiao Y. Wan J. Zhou L. Ma W. Yang Y. Luo W. Yu Z. Wang H. Stimuli-Responsive Nanotherapeutics for Precision Drug Delivery and Cancer Therapy Wiley Interdiscip. Rev. Nanomed. Nanobiotechnology 2018 11 e1527 10.1002/wnan.1527 29726115

403. Raza S.A. The Role of Biotechnology in Developing Targeted Drug Delivery Systems for Cancer Therapy Biomed. Thought 2024 1 86 100

404. You Y. Sun H. Cheng Z. Xu X. Li J. Advanced stimuli-responsive host-guest biomaterials for treating bacterial infections Polymer 2024 307 127312 10.1016/j.polymer.2024.127312

405. Ding H. Tan P. Fu S. Tian X. Zhang H. Ma X. Gu Z. Luo K. Preparation and application of pH-responsive drug delivery systems J. Control. Release 2022 348 206 238 10.1016/j.jconrel.2022.05.056 35660634

406. Verkhovskii R.A. Ivanov A.N. Lengert E.V. Tulyakova K.A. Shilyagina N.Y. Ermakov A.V. Current principles, challenges, and new metrics in pH-responsive drug delivery systems for systemic cancer therapy Pharmaceutics 2023 15 1566 10.3390/pharmaceutics15051566 37242807 PMC10222897

407. Malam Y. Lim E.J. Seifalian A.M. Current Trends in the Application of Nanoparticles in Drug Delivery Curr. Med. Chem. 2011 18 1067 1078 10.2174/092986711794940860 21254971

408. Ma W. Wang X. Zhang D. Mu X. Research progress of disulfide bond based tumor microenvironment targeted drug delivery system Int. J. Nanomed. 2024 19 7547 7566 10.2147/IJN.S471734 PMC11283832 39071505

409. Shende P. Deshpande G. Disulfide bond-responsive nanotherapeutic systems for the effective payload in cancer therapy Curr. Pharm. Des. 2020 26 5353 5361 10.2174/1381612826666200707131006 32634075

410. Fusciello M. Ylösmäki E. Cerullo V. Viral Nanoparticles: Cancer Vaccines and Immune Modulators Adv. Exp. Med. Biol. 2021 1295 317 325 10.1007/978-3-030-58174-9_14 33543466

411. Shim N. Cho H. Jeon S.I. Kim K. Recent developments in chemodrug-loaded nanomedicines and their application in combination cancer immunotherapy J. Pharm. Investig. 2024 54 13 36 10.1007/s40005-023-00646-7

412. Kandasamy G. Karuppasamy Y. Krishnan U.M. Emerging trends in nano-driven immunotherapy for treatment of cancer Vaccines 2023 11 458 10.3390/vaccines11020458 36851335 PMC9968063

413. Li H. Zhu Y. Wang X. Feng Y. Qian Y. Ma Q. Li X. Chen Y. Chen K. Joining forces: The combined application of therapeutic viruses and nanomaterials in cancer therapy Molecules 2023 28 7679 10.3390/molecules28227679 38005401 PMC10674375

414. Lin M. Qi X. Advances and challenges of stimuli-responsive nucleic acids delivery system in gene therapy Pharmaceutics 2023 15 1450 10.3390/pharmaceutics15051450 37242692 PMC10220631

415. Jin W. Al-Dulaymi M. Badea I. Badea S.C. Rehman J. El-Aneed A. Cellular Uptake and Distribution of Gemini Surfactant Nanoparticles Used as Gene Delivery Agents AAPS J. 2019 21 98 10.1208/s12248-019-0367-1 31388860

416. Abrahamse H. Hamblin M.R. New photosensitizers for photodynamic therapy Biochem. J. 2016 473 347 364 10.1042/BJ20150942 26862179 PMC4811612

417. Zhang J. Jiang C. Longo J.P.F. Azevedo R.B. Zhang H. Muehlmann L.A. An updated overview on the development of new photosensitizers for anticancer photodynamic therapy Acta Pharm. Sin. B 2018 8 137 146 10.1016/j.apsb.2017.09.003 29719775 PMC5925394

418. Castillo R.R. Colilla M. Vallet-Regí M. Advances in mesoporous silica-based nanocarriers for co-delivery and combination therapy against cancer Expert Opin. Drug Deliv. 2017 14 229 243 10.1080/17425247.2016.1211637 27402029

419. Kumar M. Jinturkar K. Yadav M.R. Misra A. Gemini amphiphiles: A novel class of nonviral gene delivery vectors Crit. Rev. Ther. Drug Carr. Syst. 2010 27 237 278 10.1615/CritRevTherDrugCarrierSyst.v27.i3.20 20540688

420. Wu K. He M. Mao B. Xing Y. Wei S. Jiang D. Wang S. Alkuhali A.A. Guo J. Gan Z. Enhanced delivery of CRISPR/Cas9 system based on biomimetic nanoparticles for hepatitis B virus therapy J. Control. Release 2024 374 293 311 10.1016/j.jconrel.2024.08.019 39151831

421. Veselov V.V. Nosyrev A.E. Jicsinszky L. Alyautdin R.N. Cravotto G. Targeted delivery methods for anticancer drugs Cancers 2022 14 622 10.3390/cancers14030622 35158888 PMC8833699

422. Danhier F. Feron O. Préat V. To exploit the tumor microenvironment: Passive and active tumor targeting of nanocarriers for anti-cancer drug delivery J. Control. Release 2010 148 135 146 10.1016/j.jconrel.2010.08.027 20797419

423. Kutova O.M. Guryev E.L. Sokolova E.A. Alzeibak R. Balalaeva I.V. Targeted delivery to tumors: Multidirectional strategies to improve treatment efficiency Cancers 2019 11 68 10.3390/cancers11010068 30634580 PMC6356537

424. Pisani L. Algera A.G. Neto A.S. Paulus F. de Abreu M.G. Pelosi P. Dondorp A.M. Bellani G. Laffey J.G. Schultz M.J. Geoeconomic Variations in Epidemiology, Ventilation Management, and Outcomes in Invasively Ventilated Intensive Care Unit Patients without Acute Respiratory Distress Syndrome: A Pooled Analysis of Four Observational Studies Lancet Glob. Health 2022 10 e227 e235 10.1016/S2214-109X(21)00485-X 34914899 PMC8766316

425. Barua S. Mitragotri S. Challenges associated with penetration of nanoparticles across cell and tissue barriers: A review of current status and future prospects Nano Today 2014 9 223 243 10.1016/j.nantod.2014.04.008 25132862 PMC4129396

426. Setia A. Sahu R.K. Ray S. Widyowati R. Ekasari W. Saraf S. Advances in hybrid vesicular-based drug delivery systems: Improved biocompatibility, targeting, therapeutic efficacy and pharmacokinetics of anticancer drugs Curr. Drug Metab. 2022 23 757 780 10.2174/1389200223666220627110049 35761494

427. Lee J. Choi M.K. Song I.S. Recent advances in doxorubicin formulation to enhance pharmacokinetics and tumor targeting Pharmaceuticals 2023 16 802 10.3390/ph16060802 37375753 PMC10301446

428. Jahan R. Bodratti A.M. Tsianou M. Alexandridis P. Biosurfactants, Natural Alternatives to Synthetic Surfactants: Physicochemical Properties and Applications Adv. Colloid Interface Sci. 2020 275 102061 10.1016/j.cis.2019.102061 31767119

429. Bagade O. Sampathi S. Restoration and Sustenance of Nano Drug Delivery Systems: Potential, Challenges, and Limitations Biosystems, Biomedical & Drug Delivery Systems: Characterization, Restoration and Optimization Springer Nature Singapore 2024 105 139

430. Wang Z. Wang X. Xu W. Li Y. Lai R. Qiu X. Chen X. Chen Z. Mi B. Wu M. Translational challenges and prospective solutions in the implementation of biomimetic delivery systems Pharmaceutics 2023 15 2623 10.3390/pharmaceutics15112623 38004601 PMC10674763

431. Chen Y. Tang Y. Li Y. Rui Y. Zhang P. Enhancing the Efficacy of Active Pharmaceutical Ingredients in Medicinal Plants through Nanoformulations: A Promising Field Nanomaterials 2024 14 1598 10.3390/nano14191598 39404324 PMC11478102

432. Sar P. Ghosh A. Scarso A. Saha B. Surfactant for better tomorrow: Applied aspect of surfactant aggregates from laboratory to industry Res. Chem. Intermed. 2019 45 6021 6041 10.1007/s11164-019-04017-6

433. Shah A. Shahzad S. Munir A. Nadagouda M.N. Khan G.S. Shams D.F. Dionysiou D.D. Rana U.A. Micelles as soil and water decontamination agents Chem. Rev. 2016 116 6042 6074 10.1021/acs.chemrev.6b00132 27136750

434. Liang Q. Liu X. Zeng G. Liu Z. Tang L. Shao B. Zeng Z. Zhang W. Liu Y. Cheng M. Surfactant-Assisted Synthesis of Photocatalysts: Mechanism, Synthesis, Recent Advances and Environmental Application Chem. Eng. J. 2019 372 429 451 10.1016/j.cej.2019.04.168

435. Venhuis S.H. Mehrvar M. Health Effects, Environmental Impacts, and Photochemical Degradation of Selected Surfactants in Water Int. J. Photoenergy 2004 6 115 125 10.1155/S1110662X04000157

436. Adhikari J. Synthesis, Characterization, and Antibacterial Evaluation of Metal Complexes of Surfactant Based Schiff Bases Ph.D. Thesis Institute of Science & Technology Sheffield, UK 2024

437. Halamoda-Kenzaoui B. Vandebriel R.J. Howarth A. Siccardi M. David C.A.W. Liptrott N.J. Santin M. Borgos S.E. Bremer-Hoffmann S. Caputo F. Methodological needs in the quality and safety characterisation of nanotechnology-based health products: Priorities for method development and standardisation J. Control. Release 2021 336 192 206 10.1016/j.jconrel.2021.06.016 34126169 PMC8390938

438. Moghaddam F.D. Dadgar D. Esmaeili Y. Babolmorad S. Ilkhani E. Rafiee M. Wang X.D. Makvandi P. Microfluidic platforms in diagnostic of ovarian cancer Environ. Res. 2023 237 117084 10.1016/j.envres.2023.117084 37683792

439. Serrano D.R. Luciano F.C. Anaya B.J. Ongoren B. Kara A. Molina G. Ramirez B.I. Sánchez-Guirales S.A. Simon J.A. Tomietto G. Artificial intelligence (AI) applications in drug discovery and drug delivery: Revolutionizing personalized medicine Pharmaceutics 2024 16 1328 10.3390/pharmaceutics16101328 39458657 PMC11510778

440. Khan M.S. Alshahrani M.Y. Wahab S. Gupta G. Kesharwani P. Evolution of artificial intelligence as a modern technology in advanced cancer therapy J. Drug Deliv. Sci. Technol. 2024 98 105892 10.1016/j.jddst.2024.105892

441. Dangeti A. Bynagari D.G. Vydani K. Revolutionizing Drug Formulation: Harnessing Artificial Intelligence and Machine Learning for Enhanced Stability, Formulation Optimization, and Accelerated Development Int. J. Pharm. Sci. Med. 2023 8 18 29 10.47760/ijpsm.2023.v08i08.003

442. Prajapati J.B. Paliwal H. Saikia S. Prajapati B.G. Prajapati D.N. Philip A.K. Faiyazuddin M. Impact of AI on drug delivery and pharmacokinetics: The present scenario and future prospects A Handbook of Artificial Intelligence in Drug Delivery Academic Press Cambridge, UK 2023 443 465

443. Petrarca C. Clemente E. Amato V. Pedata P. Sabbioni E. Bernardini G. Iavicoli I. Cortese S. Niu Q. Otsuki T. Engineered metal-based nanoparticles and innate immunity Clin. Mol. Allergy 2015 13 1 12 10.1186/s12948-015-0020-1 26180517 PMC4503298

444. Abbasi R. Shineh G. Mobaraki M. Doughty S. Tayebi L. Structural parameters of nanoparticles affecting their toxicity for biomedical applications: A review J. Nanoparticle Res. 2023 25 43 10.1007/s11051-023-05690-w 36875184 PMC9970140

445. Tripathy D.B. Biosurfactants: Green Frontiers in Water Remediation ACS EST Water 2024 4 4721 4740 10.1021/acsestwater.4c00604

446. Jiao J. Jiao X. Wang C. Wei L. Wang G. Deng Y. Song Y. The contribution of PEG molecular weights in PEGylated emulsions to the various phases in the accelerated blood clearance (ABC) phenomenon in rats AAPS PharmSciTech 2020 21 300 10.1208/s12249-020-01838-2 33140142

447. Mu L. Seow P.H. Application of TPGS in polymeric nanoparticulate drug delivery system Colloids Surf. B Biointerfaces 2006 47 90 97 10.1016/j.colsurfb.2005.08.016 16412619

448. Wen P. Ke W. Dirisala A. Toh K. Tanaka M. Li J. Stealth and pseudo-stealth nanocarriers Adv. Drug Deliv. Rev. 2023 198 114895 10.1016/j.addr.2023.114895 37211278

449. Illum L. Davis S.S. Müller R.H. Mak E. West P. The organ distribution and circulation time of intravenously injected colloidal carriers sterically stabilized with a blockcopolymer-poloxamine 908 Life Sci. 1987 40 367 374 10.1016/0024-3205(87)90138-X 3807638

450. Li J. Kataoka K. Chemo-physical strategies to advance the in vivo functionality of targeted nanomedicine: The next generation J. Am. Chem. Soc. 2020 143 538 559 10.1021/jacs.0c09029 33370092

451. Mokhtarzadeh A. Alibakhshi A. Yaghoobi H. Hashemi M. Hejazi M. Ramezani M. Recent advances on biocompatible and biodegradable nanoparticles as gene carriers Expert Opin. Biol. Ther. 2016 16 771 785 10.1517/14712598.2016.1169269 26998622