Sophorolipids as anticancer agents: progress and challenges.

Introduction

Cancer is one of the world’s major health challenges which caused 10 million deaths in 2022 [ 1 ]. This is a multifaceted disease, with numerous genetic and epigenetic modifications that lead to increased cell division, local invasion of tissue, metastasis, immune response evasion, and suppression of growth inhibitors. Cancer remains a worldwide persistent disease with many factors such as demography, unhealthy lifestyles, toxic substances, environmental factors, pollutants, and carcinogen exposure continue to cause the disease. Its prevalence is linked to oxidative stress, genetic and somatic mutations, ionizing radiation, toxic chemicals, and biologic agents [ 2 ]. These factors influence various processes of the cellular machinery that controls cell proliferation, cell reproduction and cell death. Increased expression of oncoproteins and inactivation of tumor suppressor proteins contributes to disruption of apoptotic mechanisms and leads to enhance aberrant microtubule and mitotic problems [ 3 ]. In addition, biological agents such as viruses- Human papillomavirus, Herpesvirus, Hepatitis B and C; and bacteria- Helicobacter pylori and Salmonella are related with specific cancer types [ 4 ]. Human papillomaviruses regulate the expression of E6 and E7 oncogenes; while H. pylori releases toxins affecting tissue stability and integrity, resulting in chronic inflammations [ 5 ]. It is evident that the progression of tumor growth and cancer malignancies are associated with increased levels of pro-inflammatory markers such as cyclooxygenase-2 (COX-2) [ 6 ]. Additionally, several reactive oxygen species (ROS) molecules including H 2 O 2 , NO, O 2 ·− and OH · are capable of attacking important cellular structures like membranes, lipids, proteins and DNA and also, skewing tumor microenvironment to evade the immune system and enhance tumor growth.

Despite achieving significant improvement in precision medicine, radiotherapy, and immunotherapy for the treatment of cancer; gaps remain mainly in low- and middle-income countries [ 7 ]. According to the International Agency for Research on Cancer estimates, new cancer cases will exceed 26 million by 2030 [ 8 ]. Current cancer therapy strategies normally adopt chemotherapy, radiation and surgery which are associated with several side effects and complications, capable of harming the normal cells and cause nausea, immunosuppression, cardiotoxicity, neurotoxicity etc. [ 9 ]. Physiological and genetic differences, and heterogeneity of cancer cells are the major problems for effective treatment. The genetic heterogeneity of tumors results in a distinct genetic profile within each tumor, which impacts cancer therapy significantly by enhancing diverse subclonal populations. For example, in glioblastomas, wild type EGFR is present in 7% of cells, EGFRvIII mutant (deletion of exons 2–7) in 19%, and wild type EGFR and EGFRvIII in 1–2% of cells, complicating targeted therapies. Furthermore, variations in protein expression, such as CD antigens (CD34/CD38, CD24/CD44, CD133, CD271), are observed in different cancers such as leukemia, breast, colon, and melanoma, highlighting the need for personalized approaches to combat different mutations and prevent recurrences [ 10 ]. Another study in refractory multiple myeloma reported alteration in NF-κB and RAS/MAPK pathways in 45–65% of patients contributing to drug resistance mechanisms, which complicate treatment [ 11 ]. Hence, combination drug therapies specifically for the type and stage of cancer are tailored according to molecular target or action mode. Although this targeted therapy based personalized medicines improved cancer treatment immensely, it came with side effects that affect the quality of life such as alopecia, anorexia and fatigue [ 12 , 13 ]. Natural bioactive compounds particularly sourced from medicinal plants such as vinblastine, vincristine, topotecan, podophyllotoxin and paclitaxel showed promising anticancer effects by interrupting cellular metabolism, inducing apoptosis or inhibiting tumor growth [ 14 ]. Other bioactive compounds such berberine, curcumin, paclitaxel, quercetin, matrine and resveratrol have been reported to induce anticancer effects by rescuing miRNA expression on various cancer cells [ 15 ]. However, there are serious challenges in the extraction and stabilization of these compounds being resource intensive and yield dependent.

More recently, sophorolipids (SLs), a class of glycolipid type of natural surfactants synthesized from yeasts such as Candida bombicola have been explored for anticancer activity due to its advantageous features such as low toxicity, lipophilicity, and pro-apoptotic activity [ 16 ]. SLs exhibit significant anticancer effects on several cancer types by inducing apoptosis through the activation of caspase pathways, necrosis as well as inhibition of cell proliferation [ 17 , 18 ]. These compounds can be produced sustainably through fermentation technology. The high efficiency, natural origin, biodegradability, and low toxicity of the molecules minimize the negative consequences that traditional chemotherapeutic agents pose. In spite of promising in vitro and in vivo studies indicating their ability to cause anticancer effects, SLs face significant research gaps in clinical translation. Most studies commonly employ preclinical models, and current understanding of the underlying molecular mechanisms by which these agents work to fight cancer is limited. Moreover, optimizing their stability, biocompatibility, and delivery in physiologic conditions, and assessing safety profile comprehensively pose further challenges for their use in clinical settings. Focused research addressing these gaps could provide ways for SLs to emerge as promising bio-based therapeutics in cancer therapy. This review emphasizes SLs’ multifaceted mechanisms as a novel and safer therapeutic option in cancer treatment, outlining their mechanisms, advancements, and challenges. The recent advances in the integration of SLs and nanotechnology for enhancing drug delivery in cancer therapy are also reviewed.

Sophorolipids and their pharmaceutical applications

SLs are a unique group of biosurfactants produced by non-pathogenic yeast such as Starmerella bombicola , C. bombicola , C. apicola , C. batistae , C. stellate , C. floricola and Wickerhamiella domercqiae and are characterized by the presence of a sophorose disaccharide moiety covalently attached to a fatty acid, at the C-1 position [ 19 , 20 ]. It may undergo acetylation at the C6ʹ and C6ʺ positions and the structural isoforms called lactonic (LSL) and acidic (ASL) SLs are formed (Fig. 1 ) [ 21 ]. The amphiphilic characteristics of SLs efficiently lower the surface and interfacial tensions, and this enlarges the spectrum of their utilization in the biomedical, industrial, cosmetic and food industries. These glycolipids are distinguished by their critical micelle concentration (CMC), which ranges between 10–200 mg/L. This CMC range is similar to or lower than other biosurfactants, including rhamnolipids (1.6–400 mg/L), surfactin (7.5–10 μM), and iturin (25–40 μM) [ 22 , 23 ]. Besides, SLs exhibit less surface activity in comparison to some biosurfactants, since their limiting surface tension ranges between 35–40 mN/m, while 71–32 mN/m for rhamnolipids and 27 mN/m for surfactin [ 23 , 24 ]. These physicochemical properties highlight the emergence of SLs as promising candidates for various biomedical applications. The commercial production of SLs is economically viable and sustainable, leveraging low-cost substrates such as waste oils, thus making it a plausible substitute for synthetic surfactants [ 16 ]. Besides, their biodegradability, non-toxicity, and stability at extreme environmental conditions made it more preferable over other biosurfactants for various applications (Fig. 2 ). Their commercial values are also supported by the fact that they are produced by non-pathogenic microbes unlike many other antibiotics, and ensure large scale production. Synthetic biology and metabolic engineering rely tremendously on gene editing technique such as CRISPR–Cas9 for maximum output. The CRISPR–Cas9 mediated engineering of Starmerella bombicola increased ASL production to 99.5 g/L for diverse applications including cancer therapy [ 25 ].

SLs exhibit a broad spectrum of biological activities including antimicrobial, virucidal, immunomodulating as well as anticancer activities [ 21 , 26 ]. SLs have been reported to exhibit antibacterial activity against both Gram positive and Gram negative bacteria Bacillus subtilis and Escherichia coli , generating ROS [ 27 ]. ASLs showed antibacterial activities towards infective strains of Enterococcus faecalis and Pseudomonas aeruginosa resulting in the reduction of colony forming units at a concentration of 5 mg/mL [ 28 ]. Furthermore, LSLs showed antifungal activities against pathogenic Candida albicans via disruption of cellular membrane [ 26 ]. The antimicrobial activity of SLs is mainly ascribed to their surfactant properties that cause disruption of microbial membranes, increase permeability, and result in cell lysis and leakage of intracellular materials [ 29 ]. Due to their natural antimicrobial properties, non-toxic nature and enormous compatibility with skin, SLs could find applications in skincare formulations [ 30 ]. It is also an active ingredient in antimicrobial formulations for wound healing, as it efficiently inhibits pathogens in combination with antibiotics such as cefotaxime, kanamycin [ 28 , 31 ]. Similarly, they illustrate antifungal activities by inhibiting fungal growth and biofilm formation of Candida albicans by generating ROS that cause oxidative stress, necrosis, and apoptosis [ 32 , 33 ]. The virucidal activity of SLs is linked to their interruption with the viral envelope. The structural features, acetyl groups in SLs, make them more hydrophilic and promote antiviral activity [ 21 , 34 ]. Molecular structure plays a highly significant role for the development of antiviral activity. For example, ASLs with shorter fatty acid chain length or diacetylate ethyl ester SLs had stronger virucidal activity than LSLs. Previous research work has shown that derivatives of SLs such as amino acid conjugates and ethyl ester of leucine-conjugated SLs have great virucidal activity, specifically against Moraxella sp., S. anguinis and M. imperial [ 35 , 36 ]. SLs possess activity against several viral pathogens, such as HIV, influenza virus and herpes virus, and have a potential application as antiviral agents in formulations that could minimize viral infection [ 37 ]. However, the currently available knowledge regarding the antiviral activities of SLs remains scanty. Although SLs are believed to disrupt lipid envelopes of herpes viruses and retroviruses, in-depth mechanistic studies are lacking, and thus important molecular interactions between SLs and viral components are partially described [ 38 ]. Although SLs are thought to be nontoxic, their safety and toxicity is a concern because SLs are derived from various microorganisms that may contain elements of toxicity for application in pharmaceutical and food industries. Furthermore, the dearth of use in vivo toxicity and efficacy studies of SLs generally impedes the deployment of SLs as antiviral agents. In addition, our limited knowledge of their pharmacokinetics, bioavailability and long-term safety limits future therapeutic endeavors.

Besides, SLs have significant immunomodulatory properties that could further expand their therapeutic applications. Animal model experiments, for example, using Sprague–Dawley rats, proved that SLs could potentially modulate inflammatory responses. SLs suppress pro-inflammatory cytokines, such as IL-1β and TNF-α, but up-regulate anti-inflammatory cytokines like TGF-β1. This balance could reverse or reduce inflammation and also prevent over-immunized reactions caused by exaggerated immune responses, such as septic shock, thus, the mortality index due to inflammation decreased dramatically with SL treatment [ 39 ]. SLs exhibit anti-inflammatory properties by modulating specific signaling pathways that regulate inflammatory genes and cytokine expression. These glycolipids suppress nuclear factor kappa B (NF-κB) signaling that downregulate tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6) and nitric oxide (NO) production thereby reducing inflammation in RAW264.7 cells [ 40 ]. In addition, it also decreases the expression of immunoglobulin E (IgE) by suppressing of TLR-2, signal transducer and activator of transcription 3 (STAT3) and interleukin 6 (IL-6) in U266 cells [ 41 ]. Since SLs interfere with the immune response in a manner that is relatively nontoxic, their potential utility lies in therapeutic contexts where regulated responses to inflammation are crucial.

In addition to these applications, SLs have also been studied for disruption of biofilm formation. In a study conducted by Díaz De Rienzo et al. [ 42 ] it was reported that SLs effectively disrupted the biofilms produced by B. subtilis BBK006 and Staphylococcus aureus ATCC 9144 individually as well as mixed culture of these bacteria. This indicates their potential use as promising agents in biomedical applications especially as adjuvants in antimicrobial therapies against pathogens and biofilm associated infections. Biofilm disruption across various environments by SLs evidences their tremendous potential as a key to biofilms associated challenges. SLs downregulate the expression of hypha specific genes of Candida albicans and inhibit biofilm formation [ 32 ]. Disruption of biofilms of several bacteria including Bacillus subtilis and S. aureus by SLs through elimination of cellular element and the release of intracellular contents have been reported [ 43 ]. The combination of SLs with other biosurfactants such as rhamnolipid, further enhanced their biofilm disruption activity. This may be useful for medical and industrial purposes as it prevents biofilm development on environmental and material surfaces, decreasing their hydrophobicity. Furthermore, the broad spectrum efficacy in preventing adhesion of mixed species biofilms makes these molecules, widely applicable [ 38 , 43 ]. SLs interfere with the expression of genes critical for biofilm persistence and disrupt the microbial membrane integrity by leakage and cell lysis. Thus, SLs are broadly applicable to biofilm related issues in medicine, industry, as well as ecology.

Anticancer mechanisms of sophorolipids

SLs have gained attention recently as potential anticancer agents. Most anticancer effects of SLs have been attributed to their cytotoxicity against cancer cells through induction of apoptosis and inhibition of cancer cell proliferation. SLs are shown to be cytotoxic selectively against a number of cancer cell lines and the cytotoxic effect has been demonstrated to be structure, degree of saturation, and carbon chain length dependent. The assessment of in vitro anticancer effects of diacetylated LSLs (C16:0–C18:3) derived from S. bombicola revealed higher cytotoxic potential of the molecules with longer carbon chains (C18:1) [ 44 ]. Another study demonstrates that diacetylated LSLs are superior to monoacetylated LSLs in cytotoxicity against human esophageal cancer lines (KYSE 109 and KYSE 450). Degree of saturation within the fatty acid moiety also affects cytotoxic activity. The cyotoxic activity of monounsaturated SLs against cancer cells was found to be higher than diunsaturated SLs; whereas saturated SLs, in general, showed the weakest cytotoxicity [ 45 , 46 ]. Furthermore, diacetylated LSLs (C18:0 and C18:1) exhibited high cytotoxic effect against breast cancer cells (MDA-MB-231) increasing the intracellular ROS and inhibited the cancer cell migration without affecting normal cell viability [ 47 ]. Moreover, cetyl alcohol SLs with different degree of acetylation that consist of non-hydroxylated tail with the sophorose head, inhibited the survival of human cervical cancer cells by enhancing caspase-3, -8 and -9 activity [ 17 ]. SLs have been demonstrated to cause apoptosis in a variety of cancer cells including esophageal, pancreatic, cervical, breast, brain, liver and colon cancers by modulating metabolic pathways vital for tumor growth and survival [ 16 , 17 , 45 , 48 – 50 ]. SL induced cancer cell death mechanism is associated with the destruction of the mitochondrial function (Fig. 3 ). It was observed that the binding of SLs to cancer cell membrane receptors increase the expression of Bax and APAF1 and decrease Bcl-2 and Bcl-x [ 51 ]. This shift in the Bcl-2 family proteins favours mitochondrial outer membrane permeabilization (MOMP) and triggers the release of cytochrome c in the cytosol. The release of cytochrome c further activates apoptotic protease activating factor 1 (APAF-1) followed by caspase-9 and caspase-3 which cause programmed cell death through DNA fragmentation, nuclear condensation and cell disruption.

Besides, SLs exert anticancer effects by inducing oxidative stress via the production of ROS and disrupt the redox homeostasis in cancer cells. They enhance intracellular oxidative stress through mitochondrial pathways with subsequent down regulation of antioxidant defense systems. SLs can impair mitochondrial membrane potential causing leakage of electrons, and superoxide (O 2 −· ) generation followed by the production of other ROS such as H₂O₂ and OH · . ROS overload damages cellular components such as lipids, proteins and DNA and triggers apoptotic pathways [ 52 ]. Higher ROS level brings about the activation of pro-apoptotic signaling pathways including JNK and p38 MAPK and leads to mitochondrial dysfunction and the release of apoptotic signals [ 53 ]. Down regulation of antioxidant enzymes such as superoxide dismutase (SOD) and catalase, may further increase the extent of oxidative stress. ROS accumulation in breast cancer cells induces apoptosis through activation of the MAPK/ERK and JNK pathways [ 54 ]. Similarly, in leukemia cells, SLs can be implicated to ROS mediated activation of caspase-3 and -9, the core mediators of the intrinsic apoptotic pathway [ 55 ]. By targeting these specific markers and pathways, SLs selectively exploit the vulnerability of cancer cells to oxidative stress while sparing normal cells with robust antioxidant defenses. In addition to ROS generation, SLs cause an accumulation of intracellular Ca 2 ⁺, which distorts calcium balance [ 33 ]. The high calcium overload makes the mitochondrial membrane to become even more permeabilized and apoptotic factors released. The opening of the mitochondrial calcium uniporter (MCU) and influx of Ca 2 ⁺ into the mitochondria, further initiates and amplifies the apoptotic signaling cascade through calcium-calpain pathway based activation of caspases (caspase-3, caspase-6, and caspase-7) [ 56 ]. For instance, SLs mediated increase intracellular ROS level induce endoplasmic reticulum stress and cause apoptosis of Human cervical cancer cells through DNA fragmentation [ 44 ]. Similarly, it induces apoptosis of human liver cancer cells through increased cytoplasmic Ca 2+ concentration and DNA fragmentation [ 48 ]. Moreover, the impaired DNA repair mechanisms in cancer cells make them more susceptible to apoptosis induced by SLs, as compared to normal cells with intact repair systems [ 17 ].

In a recent study, a critical chemotherapeutic agent for acute lymphoblastic leukemia (aLL) treatment, l -asparaginase, has been shown to mediate IP3R dependent ER Ca 2 ⁺ release, leading to a deleterious increase in [Ca 2 ⁺]cyt and cell death through Ca 2 ⁺ regulated caspase pathway. During the process mitochondrial permeability transition pores (mPTPs) are formed in an IP3R dependent manner in the cells. ER-to-mitochondria Ca 2 ⁺ transfer induced by l -asparaginase leads to elevated mitochondrial ROS. The elevated cytoplasmic Ca 2 ⁺ through mPTPs leads to apoptosis of aLL cells via Ca 2 ⁺ dependent caspase activation pathways [ 57 ]. This mechanism of Ca 2 ⁺ mediated induction of apoptosis of cancer cells by L-asparaginase may find implication in pharmaceutical developments. Furthermore, the amphiphilic nature of SLs also interferes with cell membrane integrity and disrupts the membrane fluidity and permeability, resulting in ionic imbalance, leakage of intracellular content, and ultimately the cell lysis [ 18 ]. SLs also cause membrane disruption and release of damage-associated molecular patterns (DAMPs) that trigger secondary apoptotic signals that reduce cancer cell defenses. Thus, SLs inhibit the multiplication of human cervical cancer cells by blocking cell cycle at G1/S phase, probably due to upregulation of p21, a cell cycle inhibitor and preventing cyclin-CDK interactions which are important for cell cycle progression [ 17 ]. Perturbation of the PI3K/AKT may also add to anti-proliferation by checking and limiting cancer cell growth as well as their survival rate. Altogether, SLs exhibit cell death-inducing capacities against diverse cancers via mitochondrial disruption, intracellular ROS production, unbalance intracellular Ca 2+ , membrane destabilization, and muted survival signaling. These mechanisms are interlinked and enhance apoptotic cell death and decrease proliferation of cells, and therefore SLs can be regarded as potential anticancer agents.

Sophorolipids in nanotechnology for enhancing drug delivery in cancer therapy

Nanotechnology is a burgeoning field with a highly valuable impact on drug and gene delivery systems. It enhances early diagnosis through quality imaging, and improves localized drug targeting of diseases, causing minimal harm to the body. These advantages are primarily because of its nano-size, enhancing bioavailability, altering drug pharmacokinetic profiles, and inducing targeted cell apoptosis (Fig. 4 ). In oncology, nanotechnology provides potential prospects in drug delivery systems, gene therapy, biomarker identification, and molecular imaging [ 58 ]. For example, several nanocarrier based drugs including Doxil and Abraxane contribute to specific targeting of cancer tissues; similarly, mRNA vaccines demonstrate advanced immunotherapies causing minimum toxicity [ 59 , 60 ]. Even though these NPs display high specificity and low side effects in off-target tissues, challenges with its stability may perplex therapeutic effects. Therefore, biosurfactants such as SLs, are often employed to stabilize NPs, offering a sustainable and eco-friendly approach to nanomaterial synthesis [ 61 ].

SLs exhibit ideal properties for enhancing the application of NPs in cancer therapy due to their low eco-toxicity, biodegradability, and structural diversity. These attributes make SLs more preferable to synthetic surfactants. For example, microbial-derived SL-coated NPs developed by Liu et al. [ 62 ] demonstrated enhanced bioavailability and inhibited breast cancer metastasis. The SL coatings improved mucin affinity, enhancing NPs stability, cellular uptake, and prevented aggregation in the gastrointestinal tract. SLs are capable of being modulated in order to achieve maximum drug release within the gastrointestinal tract. The encapsulation of SLs into PEGylated poly (lactic- co -glycolic acid) (PLGA) nanoparticles enhances stability and improves targeted release of drugs. This method could significantly inhibit the colon cancer growth in murine models [ 50 ]. Further, SLs functionalized liposome loaded with piperine also maintained stability with modulated drug release kinetics as they are potentially useful for pharmaceuticals and nutraceutical applications [ 63 ]. Moreover, nanostructures of SLs such as micelles improve the solubility of hydrophobic drugs, like curcumin and enhance bioavailability of the drugs in the gastrointestinal milieu of the rat [ 64 ].

Furthermore, SLs are also suitable as coating agents for nano-systems, such as mesoporous carbon nanoparticle (MCNs). Hussain and Guo [ 65 ] demonstrated its prominent stability, biocompatibility, functionalization and emulsification efficiencies, required for ideal encapsulation. The integration SLs with PLGA nanocarriers enhanced intracellular drug delivery and accomplished 57% reduction of colon carcinoma in murine models [ 50 ]. SLs can form nanostructures like micelle and vesicle that was used to functionalize iron oxide NPs for embodiments in biomedical imaging and therapeutic applications, enhancing stability and biocompatibility [ 66 ]. Bacterial fluorescence analysis study recently reported that gram positive and gram negative bacteria can take up curcumin encapsulated acidic SLNPs. The fluorescence quenching coincided with the uptake, suggesting its possible diagnostic imaging and therapeutic efficacy [ 67 ]. Naz et al. [ 68 ], utilized a particular type of SLNPs (nanoceria encapsulated with LSL and ganetespib) for treating Non Small-Cell Lung Cancer (NSCLC). In the process, ganetespib synergistically increased the therapeutic efficacy of SLs through its Hsp90 inhibition mechanism, and the redox activity of nanoceria. SLs are also used as surface stabilizers in metal NPs. Dhar et al. [ 69 ] demonstrated that gold NPs stabilized with SLs and gellan gum showed increased efficacy in targeting human glioma cell lines. Such biocompatible, SL functionalized NPs achieved high cellular uptake and cytotoxic effects on glioma stem cells, underscoring their therapeutic value. Furthermore, NP based drug delivery systems can effectively counter drug resistant cancers through efflux transporters and apoptotic pathways. The expression of P-glycoprotein in cancer cells reduces intracellular drug concentration, causing to treatment failure. NPs can deliver drugs into cancer cells through endocytosis bypassing glycoprotein efflux [ 70 ]. Thus, the integration of multiple anticancer drugs into a carrier NP as combination therapy improves pharmacokinetics and therapeutic efficacy. For instance, co-delivery of COX 2 inhibitors and doxorubicin using NPs reversed multidrug resistance in breast cancer [ 71 ]. Similarly, miRNA-495 and doxorubicin conjugated with silica NPs down-regulated the expression of efflux transporters in lung cancer [ 72 ]. In addition, co-delivery of doxorubicin and resveratrol loaded NPs induced apoptosis in resistant breast cancer cells by down-regulating the expression of Bcl-2, NF-kB and efflux transporters [ 73 ]. These illustrate the potential of NPs based strategies to overcome drug resistant cancers. As part of combination therapy aimed at targeting both cancer cells and cancer stem cells, SLs conjugated Gellan Gum gold nanoparticle (SL-GG-AuNPs) induced significant cytotoxicity of the human glioma cell lines (LN-229) and human glioma stem cell line (HNGC-2). The cytotoxic effects on the cells were further enhanced through the induction of apoptosis when an anti cancer drug doxorubicin hydrochloride conjugated to the gold nanoparticles (DOX-SL-GG-AuNPs) was used [ 69 ]. However, very limited information on the impact of SLs on cancer stem cells and their mechanism of action is available. Despite existing challenges in in-vivo applications, continued advancements in nanotechnology, diagnostics, bio-imaging, and machine learning are positioning nanotechnology to drive personalized treatments, significantly advancing cancer management.

Progress and challenges of sophorolipid applications in cancer therapy

SLs exhibit significant anticancer activity by inducing apoptosis and inhibiting proliferation of breast, lung, and liver cancer cell lines through mechanisms involving membrane disruption, oxidative stress, and modulation of mitochondrial pathways, thereby selectively targeting cancer cells. SLs enhance the efficacy of conventional chemotherapeutics via synergistic effects, potentially lowering of required doses and reducing chemotherapy-associated toxicity. Their diverse structure facilitates the delivery of hydrophobic drugs, improving solubility, bioavailability, and targeted delivery to the tumor cells while minimizing impact on healthy tissue. To further enhance targeted drug delivery and sustained release to tumor sites while reducing toxicity to the healthy cells, SLNPs and liposomes are being developed [ 74 ]. Biodegradable SLs derived from renewable microbial sources, present an eco-friendly and sustainable alternative to synthetic anticancer agents, with microbial fermentation offering a cost-effective scalable production method [ 75 , 76 ]. Nanotechnology advancements in SL research are focused on conjugating SLs with targeting ligands to further increase precision in tumor targeting and minimize side effects. Recently, in vivo studies have illustrated cytotoxic effects of SLs on cancer cells, that significant reduced tumor size in animal models with minimal side effects [ 50 ]. ASLs have been shown to selectively reduce viability of colon cancer cells in Apc min± mouse model without affecting the viability of the normal cells. In vitro and in vivo trials confirmed the induction apoptosis and necrosis of the cancer cells, inhibition of migration and colony formation of the cancer cells [ 77 ]. Diacetylated lactonic sophorolipids (DLSLs) showed effective cytotoxicity on human breast cancer cells by enhancing intracellular ROS and prevented cancer cell migration [ 47 ]. Furthermore, DLSLs have been reported to selectively induce apoptosis of the human cervical cancer cells with the activation of Caspase-3 and Caspase-12 probably through ER signaling pathways, and the cell cycle was arrested at G 0 and G 2 phase [ 44 ]. This provides the basis for clinical trials, however several factors including dosage standardizations, and efficacy and safety regularities remain crucial barriers.

There are several challenges associated with the use of SLs for cancer therapy in clinical settings due to their vulnerability to instability and alteration of functions under diverse physiological conditions. Their efficacy and bioavailability may be limited by their propensity to hydrolyze under varying pH conditions, enzymatic actions and their interaction with plasma proteins. To resolve these issues, current studies employ chemical modification such as methylation or acetylation to improve stability of the structures and also to decrease their vulnerability to hydrolysis. The production of SL variants with tailored properties such as lactonic or acidic forms also demonstrates the potential to amend SL stability profiles [ 77 ]. The encapsulation of SLs with liposomes, nanoparticles or hydrogels further protects them from harsh physiological conditions facilitating their controlled release [ 50 ]. In order to stabilize the products and enhance their functioning in the specific applications, such as improving drug efficacy in targeted delivery, several methods of handling SL formulations including encapsulation with nanocarrier as such PLGA nanoparticles, SL coated silver nanoparticles, SL conjugated Gellan Gum gold nanoparticles, SL micelles containing bioactive compound like curcumin and enzymatically and structurally modified SL have been adopted [ 78 ]. However, selective toxicity still presents another major challenge as it must possess selective affinity towards tumors while sparing other surrounding normal cells. For example, ASLs kill HT29 colorectal cancer cells, but not normal human colonic or lung cells [ 77 ]. Novel SL derivatives synthesized from cetyl alcohol have been reported to inhibit survival of human cervical cancer cells (HeLa), without affecting viability of normal human umbilical vein endothelial cells (HUVEC) [ 17 ]. SLs strongly inhibited viability of human liver cancer cells (H7402), while normal liver cells HL-7702 were unaffected, whereas Chang liver cells experienced slightly reduced viability [ 48 ]. These findings indicate that SLs may have a certain degree of specificity for cancer cells, and therefore may have a lower toxicity than regular chemotherapeutic drugs. Nevertheless, the underlying mechanisms by which this selectivity occurs are not completely understood, and in some cases, SL formulations have been reported to affect both cancerous and normal cells [ 79 ]. Consequently, further research is needed to clarify selective cytotoxicity of SLs, and also to develop optimized formulations for targeted cancer therapy. SLs face challenges in clinical trials due to production variability, where fermentation yields are highly varied with diverse congeners differing in fatty acid chain lengths and degree of acetylation, giving rise to inconsistent biological and physicochemical properties complicating standardization for clinical use. In preclinical assessments, inadequate characterization of SLs, the impurities, stability concern, and limited understanding of its pharmacokinetics lead to challenging efficacy and safety profiles, impeding unduly the comprehensive evaluation necessary for clinical validation [ 80 ]. Moreover, microbial contamination requires rigorous and expensive purification processes for safe production of the desired SLs. This may involve the utilization of advanced biotechnological techniques with standardized procedures to facilitate its clinical translation. Additional challenges related to the commercialization of SLs include the high cost of the products, strict operational conditions for the fermentation process as well as regulatory concerns [ 81 ]. Generally, the synthetic surfactants (USD 2/kg) have a lower production cost than SLs (USD 2–10/kg); however, still very much cost effective as compared to other biosurfactants such as rhamnolipids (USD1250/kg), surfactin (USD 20 K/g), iturin (USD 105 K/g), and fengycin (USD 106 K/g) [ 76 , 82 ]. Moreover, SLs still require preclinical and clinical trials, as well as pharmacological quality approval from the regulatory authorities, and these trials are costly and time-consuming. There are major ethical concerns regarding safety and efficacy assessment of SLs in preclinical studies, particularly for the welfare of the animals used in testing. The experimental animals should experience minimal harm by strictly following ethical principle of Replacement, Reduction and Refinement. In addition, the production of SLs from genetically modified microorganisms may also be another threat to biosafety and the environment. Furthermore, transparency in reporting is imperative primarily for commercial interests; and the equitable sharing of benefits of SL based achievements is needed to avoid disparities. Besides, large-scale synthesis of SLs for commercialization requires optimization of yeast fermentation to enhance production, quality, and reproducibility. Commercialization of SL-based products requires academic innovation, industrial resources and market expertise, leading to successful academia-industry collaborations. Fundamental research and process optimization come from academia, while industries provide large scale production and regulatory insights. Thus, the partnerships can promote application of SLs in various sectors including healthcare, cosmetic, environmental remediation etc.

Conclusion

SLs offer several promising advantages over conventional therapies in terms of efficacy and side effect. SLNPs improve drug delivery by enhancing stability and biocompatibility of the products, and also facilitate precise targeting by enhancing permeability and retention effects. Besides, SLs cause minimal cytotoxic effect to the normal cells at therapeutic doses as compared to many synthetic drugs as well as surfactants which can cause sensitivity or long-term ecological damage and chronic irritation. SLs exhibit desirable characteristics of novel anticancer agents based on their multiple mechanisms such as induction of apoptosis through caspase activation, modulation of Bcl-family proteins, disruption of the mitochondrial membrane, and cell cycle arrest through the production of intracellular ROS and calcium management. This uniqueness further increases the anticancer efficiency of SLs when used in nanotechnology, enhancing the targeting, bioavailability, and diagnostic precision. Such spectral transformations are implicated in combating cancer and therein putting forward SLs as the possible future therapies for cancer management. However, challenges concerning its large scale production, stability under physiological conditions, and selective cytotoxicity to different tumors have become significant issues for clinical applications. Regulatory challenges for SL based therapies include the need for precise chemical characterization and robust production processes, which are critical to safety and efficacy. Pathogenicity of the SL producing microorganisms and variations in SL structures must be carefully evaluated. Addressing these issues requires standardized purification methods, as well as advanced safety assessments through in vitro and in vivo models. In addition, the overcoming of regulatory barriers requires adequate preclinical and clinical investigation to determine safety, effectiveness and applicability. Future research should be directed in developing advanced delivery systems using nanostructures, including liposomes, polymeric nanoparticles, and micelles for the improvement in stability and solubility, protection from degradation and controlled release of SLs and drugs for cancer therapy. Chemical modifications, such as polymer conjugation and functionalization, can improve stability characteristics, or offer tumor specificity for optimization. Further amplification of therapeutic efficacy by encapsulation with biocompatible excipients and co-delivery of synergistic drugs is currently being explored. Specific targeting of tumors can be achieved through ligand based approaches reducing systemic toxicity. Together with computational modeling and clinical validation, these approaches may contribute to translation of SL based therapies to effective cancer treatments. Addressing these features will play an important role in moving forward SLs from just preclinical evidence to clinical translation that may be a sustainable and effective solution to traditional chemotherapy.

Author contributions

SSB: formal analysis, illustrations, writing—original draft preparation, review & editing. KK: formal analysis, illustrations, writing—original draft preparation, review & editing. AR: formal analysis, illustrations, writing—original draft preparation, review & editing; AB: formal analysis, illustrations, writing—original draft preparation, review & editing; VS: formal analysis, illustrations, writing—original draft preparation, review & editing. AD: conceptualization, supervision, writing—original draft preparation, review & editing. All authors reviewed the manuscript.

Funding

No funding was received for this work.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

Footnotes

Publisher's Note

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Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.