Biopharmaceutical and pharmacokinetic attributes to drive nanoformulations of small molecule tyrosine kinase inhibitors.

Introduction

Cancer persists as the leading contributor to global healthcare burden, with nearly 2 million new patients and 600,000 fatalities predicted in 2023 in the USA alone. Chemotherapy, radiation therapy, surgery, hormone therapy, immunotherapy and targeted therapies are the common treatment options. Among them, chemotherapy is most widely applied due to its ease of administration. However, most conventional chemotherapeutic agents still cannot effectively distinguish between rapidly dividing non-pathological (bone marrow) cells and malignant cells, causing significant toxic effects.

In 2001, the United States Food and Drug Administration (FDA) approved imatinib (IM) to be used in chronic myelogenous leukemia (CML) with Philadelphia chromosome [ 1 ], introducing a new category of chemotherapeutic drugs with higher targetability to cancer cells called small- molecule tyrosine kinase inhibitors (smTKIs) that minimizes damage to healthy tissues, reducing adverse effects. These smTKIs specifically target the family of tyrosine kinase receptors like epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) and disrupt intracellular signaling cascades involved in tumor progression. These receptors are overexpressed in several cancer types [ 2 ]. Thus, smTKIs confer a targeted approach compared to conventional chemotherapeutic agents, which primarily work by disrupting DNA and cell division, leading to non-specific cytotoxicity. For instance, IM is a competitive pyridine-based inhibitor binds to the ATP-binding site of tyrosine kinase enzymes, like platelet-derived growth factor receptors (PDGFR), BCR-ABL fusion protein, and stem-cell factor receptor (c-Kit). These kinases play a crucial role in transduction of signaling pathways that are necessary for cell division, proliferation and death. The targeted approach leads to apoptosis in CML, where IM significantly prolongs survival rates, setting a precedent for targeted therapies in oncology. The overall survival percentage with first-line IM therapy was 83.3%. This number is comparable to the CML-IV research, which found that 84% overall survival of patients received IM-based regimens [ 3 ]. This brought a remarkable advancement in cancer chemotherapeutics as long-term follow-up studies reinforced its clinical significance [ [3] , [4] ]. To date, about 50 smTKIs have been approved by FDA ( Fig. 1 A) for clinical use in cancer, while some of these molecules are indicated against multiple target diseases. Certain smTKIs like ruxolitinib are utilized in non-malignant diseases such as polycythemia vera and myelofibrosis. The latest molecule in this class to obtain approval is neratinib, indicated for lung malignancies [ 5 ]. More number of smTKIs and their combinations continue to be investigated against varied clinical conditions [ [6] , [7] ] even as the identification of receptor mutations that can surmount specific resistances against these drugs also gains interest [ 8 ]. It is evident that these molecules represent a rapidly expanding class of anticancer drugs that have high potential in the treatment of various malignancies.

Conversely, many of smTKIs exhibit high protein binding and metabolism, limiting their effectiveness, which results in dose-dependent adverse effects [ 10 ]. High protein binding can reduce free concentration of the drug in the bloodstream, potentially lowering its efficacy. IM is recognized for its significant binding to plasma proteins, notably albumin and alpha-1-acid glycoprotein. This high protein binding characteristic of IM can restrict the amount of free drug available to produce therapeutic effects, potentially requiring higher doses to achieve the desired clinical outcomes [ 11 ]. Studies have shown that variations in protein binding among patients can lead to differences in drug efficacy and side effects. High protein binding can limit the availability of free drug, impacting efficacy, necessitating careful dose management and monitoring to ensure therapeutic benefits [ 12 ]. In case of metabolism, erlotinib (ETB) is metabolized predominantly by the CYP3A4 enzyme. Co-administration of ETB with strong CYP3A4 inhibitors, such as ketoconazole, can significantly increase its plasma levels, leading to enhanced toxicity, therefore, should be avoided, as it can lead to increased ETB concentrations and a higher risk of adverse effects. Conversely, the co-administration of ETB with CYP3A4 inducers can decrease ETB exposure and potentially reduce its therapeutic efficacy [ 13 ].

Most of these agents are quinazoline derivatives, possessing pH-dependent solubility profiles and suffer from solubility-limiting bioavailability. Nilotinib exhibits poor aqueous solubility, resulting in variable absorption and bioavailability. Its solubility decreases as the pH increases, as it is more soluble in the acidic environment of stomach (pH 1–2) compared to the higher pH of the gastrointestinal tract (pH 5–7). This solubility issue is further complicated by the need to take nilotinib on an empty stomach to avoid unpredictable food-drug interactions that can increase its bioavailability. If nilotinib is taken with food, it may precipitate rapidly in the gastrointestinal tract, leading to poor bioavailability. Various approaches have been explored to improve the solubility and bioavailability of nilotinib, such as formulating it as salts with inorganic counterions or maintaining it in a highly energetic amorphous state. However, these methods may not always provide sufficient solubility enhancement to achieve optimal bioavailability. Managing these patients often requires alternative dosing strategies, such as amorphous solid dispersion, to enhance drug absorption [ 14 ].

High inter- and intra-patient variability, with marked food effects, is also observed in the drugs of this class. These high fluctuations in the blood levels of smTKIs have often been attributed to both toxicity and sub-optimal efficacy [ 15 ]. Additionally, smTKIs are prescribed over extended period of time, raising concerns about patient compliance. The variability in blood levels of smTKIs is a significant challenge in their clinical use, which can result from a complex interplay of factors, including poor aqueous solubility, issues with permeability, membrane transport, and enzymatic metabolism. Additionally, food and drug-drug interactions can play a significant role in affecting the bioavailability of smTKIs. The impact of these factors on the bioavailability of smTKIs can lead to significant variations in plasma levels and exposure, which can affect treatment outcomes [16] , [17] . Clinicians often recommend an intermittent cessation of therapy or dose reduction to manage the complications and improve quality of patients’ life [18] , [19] , [20] , [21] . It is thus noteworthy that even after development of such a large pool of “targeted” small molecules, application of therapeutic drug monitoring (TDM)and precision medicine practices involving genetic screening are being contemplated to achieve the desired clinical efficacy of these compounds [22] , [23] , [24] , [25] . Some of these challenges are addressed by TDM and precision medicine in treating CML with IM. TDM has been effectively used to adjust doses based on plasma levels, improving clinical outcomes. Personalized dosing considers patient-specific factors like age, weight, liver function and genetic polymorphisms affecting drug metabolism. However, TDM and precision medicine practices can be costly due to the need for specialized testing, frequent monitoring, and advanced technologies and equipment. Access to TDM and genetic testing facilities may be limited, particularly in rural or underserved areas. Regular monitoring and dose adjustments require coordination between patients and healthcare providers, which can be challenging to maintain consistently [26] . Simplifying treatment regimens, such as using sustained-release formulations, can also enhance patient adherence and improve therapeutic results. These strategies help to manage the variability in drug levels and ensure that patients benefit most from their treatment [27] . Thus, there exist critical needs to develop delivery systems that modify the pharmacokinetics of smTKIs, reduce dependence of pharmacokinetics on host factors, and ultimately improve therapeutic outcomes.

Complex formulations, especially nanomedicines, have evolved greatly in last decade [28] , [29] . Fundamentally, these formulations allow for encapsulation of drugs, improving their solubility and stability. They can also provide a mechanism for temporal and spatial control over drug release, causing a reduction of off-target distribution, while a controlled release rate minimizes fluctuations in plasma concentration and modifies the metabolism kinetics of the drugs. In addition, nanoformulations are increasingly proving their applicability in precision medicine because of their ability to overcome systemic, tissue and cell-level barriers to drug delivery [30] , all of which show high heterogeneity across patients [ [31] , [32] , [33] ]. These nanoparticles (NPs) target diseased cells or tissues specifically based on their physical and chemical properties or by specific stimuli at pathological sites, minimizing unwanted effects [ [34] , [35] ]. A case study on NP delivery of gefitinib (GFT), an EGFR inhibitor used in non-small cell lung cancer (NSCLC), demonstrated that NPs could enhance drug delivery to tumor cells while reducing systemic toxicity. This innovative approach allows for better control over the drug release and distribution, potentially overcoming solubility and metabolism challenges. This method not only improves drug delivery efficiency but also enhances drug cytotoxicity and impedes the advancement of prostate cancer, showcasing its potential for targeted and effective cancer therapy [ 36 ]. Antibody-drug conjugates (ADCs) have also been explored to deliver tyrosine kinase inhibitors (TKIs). For instance, a conjugate of dasatinib (DAS) with a HER2-targeting antibody showed improved delivery and efficacy in HER2-positive breast cancer models, highlighting the potential for targeted therapies to improve treatment outcomes [37] . Polymeric micelles for the delivery of ETB have been shown to significantly improve pharmacokinetics of the drug, leading to better tumor accumulation and reduced systemic toxicity. This approach helps address solubility issues and allows for more controlled drug release [38] . Thus, there is a huge interest in development of complex formulations for various difficult-to-deliver drugs [ [39] , [40] , [41] ]. Several such formulations have already been established in market to provide superior therapeutic outcomes over conventional formulations. A popular nanomedicine called Doxil®, a liposomal doxorubicin (DOX), is used to treat many different cancers, including ovarian cancer and multiple myeloma. The liposomal formulation alleviates the toxicity of anti-cancer drug to healthy tissues and increases drug exposure. Abraxane™, albumin-bound paclitaxel (PTX)-based NPs, modifies drug pharmacokinetics and enhances drug concentration at target site compared to traditional PTX formulation. Emerging delivery systems, such as NPs, ADCs and polymeric micelles, offer promising solutions to improve the delivery and efficacy of smTKIs while reducing systemic toxicity. These innovative approaches have the potential to address the solubility issues, enhance tumor accumulation, and allow for more controlled drug release. However, there is an urgent need for further research and development of these novel delivery systems to optimize their performance and clinical applicability. The past commercial experience of complex nanoformulations of cytotoxic drugs provides a strong rationale for pursuing these innovations in order to enhance the clinical applicability of smTKIs.

Since a large number of smTKIs are being approved for clinical use and it is imminent that their complex formulations will be extensively investigated. The objective of this review is to provide a critical analysis of the biopharmaceutical and pharmacokinetic properties of smTKIs approved for clinical use, followed by examination of complex formulations of them developed in the past few years (2017 onwards). Investigations that have reported in vivo evaluation of pharmacokinetic and pharmacodynamic performance of complex formulations have been considered in the analysis ( Fig. 1 B). Furthermore, it offers a comprehensive review of the current state of research on innovative delivery systems for smTKIs, highlighting their potential benefits, limitations and future directions for the field.

Structure of the receptor tyrosine kinase (RTK)

RTKs are located on cellular surfaces and structurally do not vary much from receptor to receptor. Their primary components are a single transmembrane helix, an extracellular region with a ligand-binding area, a tyrosine kinase domain in cytoplasm, and regulatory domains with carboxy (C-) terminal at juxta membrane [ 42 ]. Tyrosine kinases are found in monomer form on the plasma membrane. Ligand binding, mediated by receptor crosslinking, results in conformational alterations that activate and phosphorylate the receptor. In phosphorylated form, RTK act as a docking site for adaptor proteins or directly phosphorylate signaling molecules which bind to phosphorylated receptors or phosphotyrosine-binding (PTB) domains. Docked adaptor proteins phosphorylate additional downstream molecules to continue signal transduction.

Different RTK members contain distinctive binding structures determining varying drug recognition. RTK complex formation and ligand recognition can both take distinct forms. For example, the VEGF subfamily possesses seven exterior motifs that recognize ligands, resulting in receptor dimerization. Fig. 2 A shows the monomer structure of EGFR and dimer structure of VEGFR (vascular endothelial growth factor receptor). Given that the VEGF ligand is dimeric in this case, a tetrameric complex containing two monomeric polypeptides that resemble VEGFR is recruited. The contact between a single EGFR polypeptide and an epidermal growth factor (EGF) molecule leads to the dimerization of EGFR and the formation of a receptor-ligand tetramer complex. In many higher eukaryotes, the insulin receptor (INSR) is a conserved gene family that belongs to the insulin-like growth factor receptor (IGFR) subfamily. A single polypeptide that underwent post-translational cleavage to generate a soluble extracellular domain, which is connected to the membrane-spanning polypeptide by a disulfide bond, is the source of the α2β2 complex, that permits the binding of ligands, activation, and subsequent initial phase of intracellular signaling pathways, resulting in cellular responses like growth, differentiation and survival. The RTK is presented as a pre-assembled, disulfide-linked heterotetramer, which makes this subfamily unique. Cells that produce both the INSR and IGFR gene products can express mixed or hybrid tetramers. Fibroblast growth factor receptors (FGFR) based signal transduction is maximized by the presence of heparan sulfate proteoglycans (HSPGs) as essential co-factors [ 43 ].

Activation of RTK

Tyrosine kinases have different pathways of activation in normal physiological conditions compared to an oncogenic conditions.

Activation in normal physiological conditions

When ligands bind to RTKs' extracellular regions, resulting induction of dimerization or oligomerization of the receptor, leading to conformational changes that enable the receptor to release trans-autophosphorylation and cis-autoinhibition of the kinase domains. This structural rearrangement allows the kinase domains to assume an active configuration, leading to downstream signaling and cellular responses specific to the ligand-receptor interaction. The autophosphorylation of these receptors triggers downstream signaling with Src homology 2 or PTB domains. By binding to particular residues, these domains collaborate with subsequent mediators to propagate important cellular signaling pathways [ 43 ].

Oncogenic activation of RTK

The oncogenic state can arise through three primary mechanisms of activation: overexpression or amplification of the gene, gain-of-function mutations, and autocrine activation. These pathways cause abnormal cellular reactions and signaling, which may aid in the onset and spread of cancer. Gain-of-function mutations in RTKs result in aberrant downstream signal transduction that cannot be accounted for by the regular "checks and balances" that occur in case of physiological signaling. It is particularly interesting to identify and characterize "driver mutations," which are described as modifications that might provide cells a selective growth advantage [ 44 ]. RTKs have been suspected of being overexpressed in several human cancers, which include EGFR in lung, glioblastoma multiforme (GBM), oesophageal and thyroid cancers, HER2/ErbB2 in breast and bladder cancer, and MET in gastric and lung cancer. Overexpression causes a local rise in receptor concentration, which elevates RTK signaling and overpowers the opposing regulatory effects. In addition to transcriptional and translational increase, oncogenic viruses and disruption of normal regulatory mechanismscan also induce RTK overexpression. Gene amplification is primarily responsible for the occurrence of RTK overexpression [ 43 ].

In order to communicate amongst cells, secretory cells produce "messengers" in the form of growth factors and cytokines, which are transported to distant target cells. Constitutive autocrine activation may cause clonal growth and tumor development, and autocrine activation of several RTKs, including TGF-EGFR, HGF-MET and SCF-KIT autocrine loops, has been well-studied in different types of malignancies. The RTK autocrine loop may promote tumor growth by collaborating with other autocrine growth pathways [ 45 ]. Fig. 2 B illustrates the activation of RTK in normal condition (B.1), gain-of-function mutation (B.2), overexpression (B.3) and autocrine activation (B.4).

Types of RTK

EGFR

EGFR has received extensive research, particularly in regard to lung cancer, and it is appropriately broad to include many RTK oncogenic changes. The alterations that activate EGFR in NSCLC have received the greatest attention in studies. The tyrosine kinase domain gene's exons 18, 19, 20 and 21 are the most often affected by these mutations [ [43] , [46] ]. These modifications disrupt the active-inactive balance of the receptor by independently activating EGFR without ligand binding and promoting increased kinase activity. Mutations in the extracellular domain (ECD) of EGFR are found in lung, brain, and colon tumors. Amplification of EGFR is a frequent consequence of mutation and occurs in breast, lung, ovarian and prostate cancers. Overexpression of EGFR leads to an increase in surface abundance which promotes receptor dimerization and subsequent kinase activation [ [47] , [48] ]. For epithelial cells to develop and proliferate, they require the EGFR, ErbB2, ErbB3, and ErbB4 members of the EGFR-related (ErbB) family. Examples are cetuximab (CTX), GFT, ETB, afatinib (AFA), osimertinib (OSI) and dacomitinib [ [49] , [50] , [51] ].

Vascular endothelial growth factor receptor (VEGFR)

VEGF ligands, such as VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor, have structural similarities to the three different types of VEGFRs, namely VEGFR1, VEGFR2 and VEGFR3 (also known as PIGF). Neuropilins are co-receptors that engage in ligand binding. Normal VEGFR activation results in biological activities such as angiogenesis, lymph angiogenesis, endothelial cell migration, fatty acid absorption, and so on. It has been found that lung, breast, colorectal, prostate and stomach cancer express VEGFRs and their ligands. The most frequent cause of abnormal VEGFR activation is overexpression. The MAPK pathway was activated as a result of increased expression of VEGFR1 and VEGF as exhibited in pancreatic cancer cells, hastening their growth. The presence of seven extracellular immunoglobulin-like domains that can recognize ligands and promote VEGFR dimerization is what makes the VEGF system unique. In this scenario, the dimeric version of the VEGF ligand promotes the recruitment of two monomeric polypeptides that resemble VEGFR to create a tetrameric complex. Examples are axitinib (AXT), pazopanib, sunitinib, sorafenib (SFN), vandetanib and cabozantinib [ 52 ].

Fibroblast growth factor receptor (FGFR)

Four distinct genes—FGFR1, FGFR2, FGFR3, and FGFR4—encode seven different types of FGFRs. Each gene has two different isoforms produced by alternative splicing, with the exception of FGFR4. However, there are more than twenty FGFs that may be divided into seven families. FGFR1 (49%) is the most often found genetically altered FGFR in malignancies, others are FGFR3, FGFR2 and FGFR4. Breast, brain, lung, head and squamous cell carcinomas all have mutations in all four FGFR receptors [ [42] , [43] ]. It has frequently been demonstrated that the formation of cancer-causing gene fusions involves FGFR2 and FGFR3. Examples of smTKIs targeting these subfamilies are erdafitinib and rogaratinib [ [46] , [47] ].

Platelet-derived growth factor receptor (PDGFR)

A pair of receptors called PDGFR-α and PDGFR-β respond to platelet-derived growth factors (PDGFs). Five distinct PDGFs, including PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC and PDGF-DD, stimulate these receptors. However, PDGFR-α mutations, particularly in exon 18, are often observed in gastrointestinal stromal tumors (GISTs). PDGFR gene fusions are frequent in myeloproliferative neoplasms, including acute myeloid leukemia, lymphoblastic leukemia, and hematological tumors. PDGFR-α only fuses with 5 intracellular proteins and 1 RTK, compared to 29 additional intracellular proteins of PDGFR-β. Examples of FDA-approved PDGFR are IM mesylate, sunitinib malate and regorafenib [ [46] , [47] , [53] ].

Insulin receptor

Insulin receptor (IR) is a conserved group of genes that belongs to the subfamily of the IGFR receptor, which can be found in many higher eukaryotes. This subfamily is distinctive in that the TK is displayed as a pre-assembled disulfide-linked heterotetramer. Mixed or hybrid tetramers can be expressed by cells that express both the INSR and IGF-1R gene products. The IGF-1R, IRA, IRB, IGF-1R/IR (hybrid), and IGF-2R molecules are all members of the IR family. Among these, ligands like IGF-1 and IGF-2 specifically activate IGF-1R. IGF-2R is a nonsignaling receptor that removes IGF2 from the surface of the cell. In cancers including colon, pancreatic, lung, and breast cancer, IGF-1R is reported to be overexpressed [ 53 ]. In animal studies with transgenic mice, activation of Akt, Erk1/Erk2 and STAT3, IGF-1R overexpression promotes the formation of breast tumors. In addition, it improves the migratory capability of mammary tumors with an increment in the proliferative genetic signature and decreases the latency period of tumors, and also protects cells from stressors in the tumor microenvironment and cell death [ 47 ].

Hepatocyte growth factor receptor

The MET gene encodes hepatocyte growth factor (HGF), a ligand of the hepatocyte growth factor receptor (HGFR). Malignancies of breast, lung, ovaries, colon, cervix, kidney, and blood have been shown to overexpress C-Met. HGF overexpression was found in NSCLC, and resulted in lymph node invasion by RhoA overexpression. According to a meta-analysis, breast cancer with high levels of c-Met overexpression had a larger tumor, distant metastases, and a higher histologic grade. Lung cancer is where MET-ATXN7L1 gene fusions have primarily been found, for example, savolitinib and crizotinib (CZT) [ 47 ]. Fig. 3 depicts the overview of several pathways followed by RTK along with their downstream signaling pathway.

Important biopharmaceutical and pharmacokinetic properties for complex formulation development

Molecular weight, permeability and solubility

As per the Lipinski Rule, drugs with a molecular weight (MW)< 500 daltons (D), lipophilicity not >5, and no >10 hydrogen bond acceptors or 5 donors have acceptable oral bioavailability. These guidelines are widely accepted in the pharmaceutical industry as a useful tool for predicting a drug's potential for oral bioavailability. The average MW of the 54 FDA-approved smTKIs is 540 D, ranging from 42 D for alectinib to 1221 D for gilteritinib (see supplementary Table S1). The drugs having MW of >500 D as found to be capmatinib, tofacitinib, DAS, selpercatinib, bosutinib, ponatinib, pralsetinib, sunitinib, encorafenib, tepotinib, selumetinib (SEL), ceritinib, entrectinib, nilotinib, brigatinib, dabrafenib (DAB), cabozantinib, SFN, infigratinib, neratinib, trametinib, mobocertinib, AFA, lapatinib (LPT), cobimetinib, and gilteritinib. Thus, out of the 54 smTKIs 32 violated Lipinski's rule with MW over 500 D, indicating the need for formulation intervention. The majority of the smTKIs approvaled by FDA have log P values under 5, except for vandetanib, entrectinib, ceritinib, cobimetinib, brigatinib, nilotinib, sunitinib, tofacitinib and alectinib (Table S1). It has also been recognized over the years that molecules with high log P are candidates for high metabolism (first-pass metabolism) at the liver when their orally administered. The median value of log P is 3.7.

The variable bioavailability of smTKIs can lead to plasma drug concentrations that are either ineffectively low or toxically high. Since smTKIs are prepared using combinatorial chemistry, they possess structures with low intrinsic solubility. Many biopharmaceutical concerns with smTKIs are related to their structure and function, and it has been noticed that their high specificity and poor absorption into the systemic circulation are related [54] , [55] .The advancement in molecular modeling enables structural activity relationship studies of inhibitory molecules with their target proteins. Highly lipophilic groups such as aromatic amines, heterocyclic aromatics, (substituted) phenyl and biaryl constructs are important for receptor binding. Drug development may also involve adding a hydrophilic group to the structure to enhance the drug's overall aqueous solubility. But this strategy may not be useful as hydrophobicity of the structure is necessary for its inhibitory action. This is the reason why the aqueous solubility of smTKIs remains low ( Fig. 4 ). The majority of smTKIs structure consists of a nitrogen-containing core combined with secondary amines, which causes their aqueous solubility to be pH-dependent. The few exceptions are vemurafenib, regorafenib and trametinib, which have a nearly pH-independent solubility. Most smTKIs contain an ionizable group, which facilitates their conversion into a salt form. Thus, most of the commercially available stable polymorphs of smTKIs are in the form of salt, which helps to enhance their solubility. However, for many drugs, the salt form alone is insufficient to significantly increase their solubility to meet the requirements for classification as BCS I. The solubility of smTKIs also depends on the solvate, hydrate and solventless crystalline form of the drug, but all these solid-state modifications have mostly been used to obtain stability via GIT. Moreover, solid state modification cannot overcome the metabolism (first pass) concerns. The drug's limited therapeutic window reflects severe side effects and decreased activity [ [54] , [55] ]. However, certain inherent limitations in considering additional factors that impact the disposition of drugs, including metabolism, distribution, and elimination, were later identified. To address the BCS limitation, Benet and his colleagues developed the Biopharmaceutics Drug Disposition Classification System (BDDCS), specifically designed to overcome the limitations of the BCS classification by incorporating essential aspects such as metabolism, distribution, elimination, and to predict metabolizing enzymes and drug-drug interactions into its framework [56] , [57] . Since most smTKIs are taken orally, it is necessary to classify them into BDDCS, which can provide valuable insights into their oral absorption, metabolism and potential drug-drug interactions. BDDCS primarily focuses on rate and not on the extent of permeability (as stated in BCS), the extent of metabolism and solubility. High permeability drugs exhibit extensive metabolism as it is reabsorbed from the kidney tubules, leading to higher exposure to metabolizing enzymes in the liver and other tissues, affecting the pharmacokinetics of drugs [57] . Oral smTKIs classified under BDDCS classes 1 and 2 can undergo extensive metabolism ( Table 2 ). Complex oral formulation strategies need to be developed to overcome the drug metabolism for BDDCS class 1, as well as solubility and drug metabolism for BDDCS class 2 smTKIs. Combining metabolic enzyme inhibitory agents with smTKIs can enhance oral bioavailability [58] . Thus, it is evident that >18% of present smTKIs can be benefited

Absorption pharmacokinetics

All the FDA-approved smTKIs, as of 2022, are administered orally as tablets or capsule dosage forms. Their larger molecular counterparts, such as monoclonal antibodies, are administered intravenously. The dose of smTKIs vary from 2 mg/d for trametinib on the lowest side to the highest dose recommended for vemurafenib (1,920 mg/d). The median dose of smTKIs is 160 mg/d ( Table 1 ). Some smTKIs needs repeated dosing in a single day like zanubrutinib, tucatinib, vemurafenib, SFN, SEL, pexidartinib, acalabrutinib, alectinib, AXT, binimetinib, CZT, DAB, erdafitinib and nilotinib need to be administered two times a day while neratinib needs to be administered thrice a day. Thus, from dose point of view, several smTKIs are good candidates for complex formulations.

Absorption of smTKIs from their dosage form depends on various factors such as physicochemical properties (solubility, polymorphism, pKa, pH, lipophilicity), dosage form characteristics and patient-related factors. Table S1 demonstrates that most of the smTKIs show pH-dependent solubility. The solubility of smTKIs is reduced by using drugs that alter the stomach pH [60] . LPT significantly increases exposure when administered in the fed state compared to the fasting state. Studies have shown that LPT exposure is ∼4 times higher when taken with food [61] . On the other hand, the bioavailability of SFN decreases with food [62] . Systemic clearance (metabolism in the GI tract and liver, as well as excretion), solubility, stability, permeability, efflux/uptake transporters and small bowel dissolution rate all play a significant role in overall oral exposures. To determine whether the clearance is fast, moderate or slow, as compared to liver blood flow. Clearance values are typically classified as rapid if they go over 70% of liver blood flow [63] . In preclinical species (rats), about 26% of these drugs were quickly eliminated. Acalabrutinib, the smTKIs with the lowest T max value, is prescribed at a higher dose because of its quick metabolism. A smTKIs with the highest T max value is sunitinib.

Distribution properties of smTKIs

Distribution involves the movement of a drug from the bloodstream to various tissues and organs, allowing it to reach its target sites of action. Factors influencing drug distribution include blood flow to different organs, drug properties (lipophilicity and molecular size), and drug transporters. Log P (pH independent) and log D (pH dependent) are used to measure the lipophilicity of drugs. Since smTKIs are pH dependent and contain an ionizable moiety at a particular pH, log D is considered a more comprehensive and accurate lipophilicity descriptor than Log P, providing a more realistic representation of how an ionizable compound behaves in biological systems [64] , [65] . Drug protein binding is another factor that affects the distribution. From Table 1 , most of the smTKIs exhibit high protein binding results in low volume of distribution (V d ) and longer half-life (T ½ ). V ss is a theoretical parameter used to represent how extensively a drug is distributed throughout the body. While it lacks physiological significance, it provides a general understanding of drug distribution. In a study involving 54 smTKIs, these drugs were found in various tissues, such as the liver, kidney, lung, gastrointestinal tract, and glandular tissues. However, most of them had limited penetration into the central nervous system. The apparent volume of distribution at steady state (V d,ss /F) values ranged from 48 to 10,000 l. Reviewing the plasma protein binding (PPB) levels across rats in all 54 smTKIs ( Table 1 ) revealed that about 29% of these drugs had ∼99% protein binding, and only ∼8% of them exhibited < 70% binding. PPB was as low as 40% for a drug such as tofacitinib.

Metabolism

Bioavailability measures the fraction of an administered drug dose that reaches system circulation in an unchanged form. Extensive research on the clinical pharmacokinetics of AFA shows that it has 95% bioavailability and is minimally metabolized in the human body, primarily eliminated unchanged through feces. Only a small portion of the drug is eliminated through urine. The low metabolism of AFA may be due to the formation of covalent bonds with the plasma proteins via a chemical reaction called Michael addition, which bypasses enzymatic catalysis [66] . However, the metabolism of smTKIs can be influenced by various factors such as liver function, age and disease conditions (cirrhosis). Adjustment of smTKIs dosage is necessary for these individuals. After exploring the metabolic pathways and enzymes involved in the clearance of these smTKIs, around CYP3A4 cleared 76% of kinase inhibitors. In addition, CYP2D6, CYP1A1, CYP2C8, UGT1A19, CYP2C9, UGT, SULT1A1 CYP1A2, CYP2C19, CYP2C8, CYP3A5, and UGT1A3, CYP3A4, and UGT1A4, as well as hydrolytic enzymes, play a role in metabolizing 24 % of these drugs. Though not much data, first-pass metabolism (FPM) is a serious concern, and changing route of administration may be the only effective way.

Complex formulations for improving the therapeutic efficacy of smTKIs

Various complex formulations have been approved in the last decades for drugs such as DOX, IM, DAS and others. This complex formulation can be one among micelles, NPs, liposomes, nanosponges, nanocrystals, nanocapsules and CNTs. These systems provide benefits, such as targeted drug delivery, improved drug stability, prolonged circulation, and improved therapeutic outcomes, as shown schematically in Fig. 5 . Examples include polymeric micelles with drug-loaded cores, NPs with enhanced permeability and retention (EPR), liposomes with extended circulation times, nanosponges for drug sequestration and delivery, nanocrystals for solubility enhancement, polymeric nanocapsules with liquid/solid cores, and functionalized CNTs for targeted therapy. The section briefly describes the various complex nanoformulations close to realizing clinical translation and their properties in correlation with various smTKIs and their route of administration, as shown in Fig. 6 .

Micelles

These are systems of amphiphilic nature with a hydrophobic core and hydrophilic outer layer in a spherical shape. The hydrophobic core carries drugs of the same nature while the hydrophilic surface makes it easy to deliver the payload. Such amphiphilic carriers are formed by using di- or tri-block, graft and ionic copolymers. Due to their nano-size (<100 nm), polymeric micelles can successfully enter tissue without being detected by the mononuclear phagocyte system (MPS), giving them enough time to accumulate at the target region. Moreover, the presence of polymers in polymeric micelles has been demonstrated to make them biodegradable. Further to these benefits, polymeric micelles exhibit a regulated drug release profile, an improved drug loading capacity, and environmental protection for the encapsulated pharmaceuticals. Although there are drawbacks to polymeric micelles, such as low stability in the gastrointestinal environment, numerous methods have been documented to increase the stability of the polymeric micelle. In order for the polymer to maintain the drug in the gastrointestinal environment, crystallized polycaprolactone is primarily utilised to improve the stability of polymeric micelles [67] . The physical stability of the drug-loaded polymeric micelles can also be increased by increasing the intensity of the cohesive force that persists between the drugs and the polymeric core [68] . Multiple parameters, including pH, enzymes, and bile salts, need to be taken into account when determining the stability of polymeric micelles in the GI environment. Therefore, to address the stability issues with polymeric micelles, a mix of various solutions may be used. USFDA has approved estrogen-based polymeric micelles formulations for marketed use, namely Estrasorb® [69] . Genexol-PM is another PEG-based di-block copolymer-based micelles of PTX approved for the treatment of metastatic breast cancer in South Korea.

NPs (polymeric or lipidic)

These are nanoparticulate systems made of various polymers (PLGA, PLA, chitosan, alginate etc.) or inorganic material between the range of 10–1,000 nm [69] . In pharmaceutical research, particularly in the area of oncology, NPs have drawn a lot of interest. The extensive focus on NPs in cancer therapies has been greatly influenced by the EPR effect; because of this effect, NPs can gather preferentially in tumor masses, as well as inflammatory and infectious locations. It occurs because tumors have aberrant and leaky vasculature, which enables NPs to extravasate and build up in the tumor microenvironment. According to reports, the majority of peripheral human tumors have effective blood vessel endothelial pore size in the range of 200 to 600 nm in diameter. Passive targeting of NPs to tumors may be achievable, depending on the size of the leaky vasculature. For administration of cancer drugs, the EPR effect has various benefits, including enhanced accumulation, prolonged retention and selective targeting [70] . By attaching certain ligands or antibodies to their surface, NPs can be generated to actively target tumor cells. More precise delivery of drugs to tumor cells is made possible while minimizing systemic side effects thanks to this active targeting and the passive accumulation caused by the EPR effect [71] , [72] , [73] . In 2005, FDA approved Abraxane®, a nanoparticle-bound albumin formulation of PTX, to diagnose breast cancer, pancreatic cancer and NSCLC. Ontak® is another inorganic NP approved by FDA.

Liposomes

The fundamental composition of liposome is consists of an aqueous core encircled by one or more lipid bilayers. Amphiphilic molecules, which have both hydrophilic and hydrophobic areas, join together to form lipid bilayers. Multiple types of liposomes can be identified depending on the size, content and structure of the individual particles. Liposomes can be classified into unilamellar, multilamellar, as well as small unilamellar (SUVs) and large unilamellar vesicles (LUVs). Main drawback of liposomes is their low T 1/2 due to the activation of the MPS. Several strategies have been used to improve the liposomes' circulation half-lives. One method is to add a negatively charged lipid called phosphatidylinositol to the liposomal formulation, which stabilizes the liposomes in vivo . This changes the surface charge composition of liposomes. Stealth liposomes are another approach to counter the high blood clearance of liposomes [74] . A biocompatible polymer that could elude immune detection was grafted onto liposomes. A biocompatible polymer is one like that, such as polyethylene glycol (PEG). When PEG-lipid conjugates are present, a hydrophilic, sterically stabilized aqueous shell forms, making the liposomes immune system elusive. An example of such a stealth liposome is Doxil® [75] , it is a FDA-approved marketed product containing DOX in its core and coated with PEG. Another marketed liposomal formulation includes a liposomal formulation of daunorubicin and cytarabine called vyxeos®. Thermodox, a heat-sensitive liposomal construct of DOX, received USFDA fast track designation.

Nanosponges

Nanosponges are extremely small, sponge-like particles that are often made of biocompatible polymers such as cyclodextrins, PEG and polyvinyl alcohol (PVA). These particles can absorb and sequester a variety of compounds, including poisons and therapeutic substances, due to their porosity shape. Anticancer drugs can be added to nanosponges either physically encapsulated within the porous structure or chemically conjugated to the surface. Nanosponges are appealing for cancer treatment due to their special characteristics, such as great stability, extended blood circulation times, and immune system evasion. Additionally, targeting ligands or antibodies can be functionalized on nanosponges to enable targeted therapy and precise drug administration by allowing them to recognize and bind to cancer cells. Preclinical studies have shown that nanosponges have the potential to limit tumor growth, reduce drug resistance and enhance therapeutic outcomes, even if the concept of using them to treat cancer is still in its infancy. To completely comprehend their safety, effectiveness and potential for inclusion in cancer therapy regimens, however, more investigation and clinical trials are required. Cyclodextrin, DNAzyme and ethycellulose-based nanosponges have extensively been used in cancer research for delivering drugs like ETB, PTX, camptothecin, DOX and withaferin A [76] .

Nanocrystals

High manufacturing cost, platform instability, loading issues and hurdles in scale-up are some of the common problems related to NPs, liposomes or solid lipid NPs (SLNs). Contrarily, drug nanocrystals can be injected intravenously without the use of any carrier materials for encapsulation and/or solubilization, albeit most of the time surfactants or polymers are required for stabilizing pure drug crystals in order to minimize aggregations. Drug crystals with a particle size of a few hundred nanometers are known as nanocrystals. These nanocarriers are preferred for drugs with poor solubility, and most of the smTKIs are BCS class II drugs. It can increase pharmacokinetics properties and decrease fed-fasted variability of drug substances. Panzem® [77] is an example of 2-methoxyestradiol drug nanocrystal which completed its phase II study for safety and effectiveness in relapsed multiple myeloma and phase I study for advanced solid tumor indication. Paxceed™ [78] is another example of PTX drug nanocrystal under investigation.

Nanocapsules

Polymeric nanocapsule consisting of a liquid/solid core coated with a polymeric shell. Due to their core-shell microstructure, polymeric nanocapsules have gained increased attention in recent years for use in drug delivery applications. The solid/oil core of nanocapsules can significantly improve drug-loading efficiency as compared to polymeric nanospheres. Moreover, smart compounds that may interact with certain proteins can functionalize the polymeric shell, providing targeted drug delivery. Since an amount of anti-cancer drugs have hydrophobic qualities, different nanocapsule delivery techniques have been developed to get around this restriction and boost the effectiveness of anti-cancer therapy. The choice of polymers and formulation techniques is primarily determined by the properties of the pharmaceutical ingredient and the intended application. Polymeric nanocapsules have the potential to increase the bioavailability of medications and allow for sustained and targeted distribution when utilized as drug delivery vehicles. Additionally, they can successfully reduce the negative interactions between the drug and the tissue milieu around it. The drug is shielded against biologically-induced efficacy loss or degradation by being enclosed in polymeric nanocapsules. Additionally, this strategy can lessen the negative effects the drug has on healthy tissues. The majority of studies have concentrated on creating and describing polymeric nanocapsules filled with bioactive materials. The storage and sterilization procedures for these drug-loaded polymeric nanocapsules, however, must also be taken into consideration and call for additional study and development [79] . DOX, 5-fluorouracil, camptothecin and gemcitabine are some anti-cancer drugs that have been investigated as nanocapsule formulations.

Carbon nanotubes (CNTs)

The cylindrical group of carbon allotropes known as fullerenes includes CNTs with special physicochemical characteristics that make surface modification simple. The development of polyvalent CNTs as cancer therapeutic tools is moving very quickly. The most promising strategy is the targeted administration of medications, which is intended to aim the therapeutic treatment specifically for tumors. Based on their capacity to penetrate biological barriers, functionalized CNTs have demonstrated considerable potential as innovative delivery systems. Various in vitro and in vivo studies demonstrated that a wide variety of chemically functionalized CNTs are compatible with the biological environment, highlighting how the degree and type of functionalization, both crucial factors that need to be precisely controlled, could modulate the material's behavior when used in living organisms. DOX, PTX, gemcitabine and camptothecin have been investigated as CNT formulations and have shown better profiles than the conventional therapies of the same drugs [80] , [81] .

Recent advances in complex formulation of smTKIs

The following section describes and analyses the recent advancements in complex formulations of the smTKIs, especially appraising and discussing in detail the in vivo improvements in pharmacokinetics of the smTKIs from complex formulations. The key components and results of these systems are summarized in Table 3 .

Afatinib (AFA)

AFA, an irreversible TKI, exerts its pharmacological activity by inhibiting certain tyrosine kinases, particularly in the ErbB family, including EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4). It is highly soluble over the physiological pH range of 1–7.5 with T max of 2–5 h, minimal FPM, and covalent protein binding with T 1/2 of 37 h after repeated dosing. AFA's BCS Classification is unknown because of its high solubility and susceptibility to efflux transport by intestinal P-glycoprotein (Pgp). Based on its characteristics, it can be categorized into BCS class 1 or 3 drug [123] . The above parameters suggest that AFA is more appropriate for oral administration, with caution regarding the concomitant use of Pgp inhibitors or inducers. FDA approved AFA, an aniline-quinazoline derivative, in the year of 2013 for metastatic NSCLC treatment as a first-line drug. Jinli et al. prepared transferrin-containing, redox-sensitive ligand-polymer hybrid NPs loaded with AFA (Tf-SS-Afa-LPNs) in the year 2019. Nano-precipitation technique was employed to fabricate Tf-SS-Afa-LPNs using PLGA as a polymeric material. The optimized Tf-SS-Afa-LPNs showed an average size of 104 nm and surface charge of −21 mV with an entrapment efficiency of 90 %. The condition of tumor site was simulated by studying the in vitro release of the drug in presence of NSCLC (GSH), which showed an enhancement in release profile in the absence of GSH. In in vitro studies, the AFA -LPNs showed higher efficiency than free AFA on PC-9 cells. The in vivo study was conducted by intravenous administration of the formulation and free drug in Sprague-Dawley rats at a dose of 2.5 mg/kg of body weight. The obtained results demonstrated NPs site-specific release and improved pharmacokinetics than pure drug. AUC of Tf-SS-Afa-LPNs was ∼867 mg/l·h, which was larger than free AFA (404.73 mg/l·h, P < 0.05). Tf-SS-Afa-LPNs showed a peak plasma concentration (C max ) of 25 l/kg/h and a plasma T 1/2 of 43 h The final formulation exhibited appreciable anti-tumor efficacy and reduced volume of tumor cells compared to free AFA from 920 ± 1 mm 3 to 211 ± 1 mm 3 after 28 d of treatment as compared to pure drug [84] .

To enhance drug loading efficiency and enable effective tracking of NSCLC cells, Ming-Hsien et al. [124] have developed near infrared-persistent luminescence nanomaterials (NIR PLNs) using a silica shell-assisted synthetic route to achieve uniform dispersion and utilized in the nano vehicle. NPs were prepared initially as mesoporous silica NPs (MSNPs) and further modified with ZnGa2O4:Cr 3+ to form PLNs for the loading of AFA. The surface of PLNs was further modified by a specific sequence of aptamer named MAGE-A3 by utilizing the Michael addition reaction. The optimized formulation showed an excitation band of PLN at around 265 nm, which revealed that doping Sn 4+ is advantageous for increasing the efficiency and stability of PLNs. The surface-functionalized AFA-loaded PLN showed a significant tumor accumulation in lung cancer cells. The in vitro cell viability and cytotoxicity were carried out in CL1–5 lung cancer, Beas2B normal lung, and A549 cell lines, which showed that surface-modified AFA-loaded PLNs were effective against metastatic CL1–5 cancer cells. The drug was administered subcutaneously at a concentration of 10 µg/ml injecting orthotopically to cancer-induced left lung of mouse for in vivo study. The surface-modified AFA-loaded PLN could act as a highly sensitive sensor and a therapeutic agent for inhibiting lung cancer metastasis.

Dehui et al. [85] developed lipid-polymer hybrid NPs (LPH NPs) loaded with AFA and cisplatin (CPT) to treat nasopharyngeal carcinoma (NPC) using PLGA, 1,2-distearoyl-sn‑glycero-3-phosphoethanolamine-N-amino(polyethylene glycol) (DSPE-PEG) and 1,2-dilauroyl-sn‑glycero-3-phosphocholine (DLPC). The anti-tumor efficacy of drug-loaded NPs was tested using NPC xenograft model at a 5 mg kg -1 dose given intravenously. After evaluation, compared to free drug complex, particulate formulations were more effective in increasing cell apoptosis, decreasing cell viability and inhibiting cell migration and cell cycle. In CPT monotherapy, cell viability was 85.1 %, reduced to 39.5 % in CPT+AFA (1:1 w/w) combination therapy. The AFA+CPT-loaded NPs showed a significant delay in tumor growth with no cytotoxicity as compared to AFA/CPT-loaded LPH NPs and thus displayed a higher potential to treat NPC.

In another study, Xiaoyan et al. [86] prepared AFA-loaded immuno-liposomes (immuno-LPs) by incorporating CTX to enhance the circulation time and selectivity. CTX was conjugated with drug-loaded LPs to prepare “immune LPs” and provide selectivity towards tumor cells. Transmembrane ammonium sulfate gradients were used to develop AFA-LPs using hydrogenated soybean phospholipids (HSPCs), cholesterol and DSPE-PEG 2000 at a ratio of 60:36:4, with (DSPE-PEG 2000− Maleimide) and solution of ammonium sulfate. Further, these sulfhydryl-containing LPs reacted with thiolated antibodies to form immuno-LPs and mAb. After evaluation, the internalization rate into A549 and H1975 cells of immuno-LPs was greater than normal liposomes and free drug. The in vivo study was carried out by intravenous administration at a dose of 4 mg/kg body weight in male Sprague–Dawley rats, which resulted in an increased AUC (92 h·µg/ml) with prolonged T 1/2 (9.5 h). The results showed that compared to free AFA and liposomes, immuno-LPs enhanced the tumor efficacy selectivity and reduced side effects in NSCLC xenograft model.

To enhance the efficacy of AFA in treating NSCLC, researchers have explored combination therapy and site-specific targeted delivery approaches. One such approach involves the use of liposomes and lipid polymer hybrid NPs (LPHNPs). These NPs can be tailored to improve drug stability, drug uptake by cancer cells, and prolong drug release at the tumor site. By utilizing these delivery systems, the researchers aim to achieve a more efficient and targeted delivery of AFA to the tumor cells in NSCLC.

However, despite the success of these delivery systems, the issue of patient compliance may arise. Taking AFA through intravenous administration can be inconvenient and may have certain drawbacks. An alternative approach to address this issue is to develop a dry powder inhalation formulation of AFA, which is cost-effective and allows direct deposition of the drug particles in the respiratory tract, enabling efficient drug absorption by the target cells in the lungs while minimizing systemic exposure. This approach bypasses the need for intravenous administration and offers a more patient-friendly and convenient option for administering AFA. Vanza et al. prepared AFA dimaleate loaded liposomes, later lyophilized with trehalose to form dry powder inhalation. A cellular uptake study showed that liposomes were internalized and exhibited lower IC 50 value than plain drug.

Apatinib (APA)

APA is a smTKIs used to treat advanced or metastatic gastric cancer that specifically targets and inhibits VEGFR-2. APA shows a non-linear dose proportionality in relative bioavailability model using a sigmoidal E max curve. Dosing of APA in certain patient groups requires adjustments [125] , indicating that precision nanomedicines can improve therapeutic outcomes.

APA was encapsulated in PLGA and Poloxamer 407 NPs (APA/p NPs) by Zhang et al. [87] to enhance the effectiveness in treating melanoma. B16 cells were employed to investigate in vitro efficacy. On tumor B16 cells, APA/p NPs had a greater level of cytotoxicity than the free drug solution. The cytotoxic impact was stronger on B16 cells as the drug concentration had been increased. The viability of B16 cells significantly decreased when exposed to APA/p NPs containing 40 mg APA, resulting in a minimal number of surviving cells after 48 h Furthermore, ∼0.1 ml B16 cell solution was injected into male C57BL/6 mice to develop a melanoma mouse model for testing in vivo effectiveness of the NPs. The investigation was accomplished by comparing with normal saline, blank NPs, APA (2, 4 and 6 mg/kg) and APA/p NPs (6 mg/kg -1 ). The drug was administered over a 10-s period after the tumor was pierced. The saline-injected blank control group witnessed the quickest tumor development, on Day12, the tumor volume had increased up to 4,690 mm 3, and the weight of tumor get doubled in control and PLGA groups than the APA group. The tumor weight and development in the APA/p NPs group were the lowest. The inhibition of tumor growth in melanoma mice treated with APA/p NPs was considerably greater than the other treatment groups, APA/p NPs were capable of efficiently eradicating tumor cells in vivo . As seen from Fig. 7 , APA/p NPs were prepared for the effective treatment of melanoma.

Lecithin, cholesterol and PEG-DSPE polymer were used to develop an APA-containing PEG-modified liposome (APA-Lipo/PEG) by Hu et al. [88] . To improve aqueous solubility, hydrophilic PEG was extended out at the liposomal surface, while the water-insoluble APA was enclosed in the hydrophobic domains. APA-Lipo/PEG therapy for 48 h caused 4.6%, 8.3%, 6.7%, 15.9%, 40.6% and 44.9% of Annexin V + cells in the CT26 cell line, according to cell apoptosis assay, rendering APA-Lipo/PEG therapy effective in vitro . CT26 cells-injected female BALB/c mice were investigated to confirm the in vivo efficacy of the liposomal formulation. A subcutaneous and peritoneal model was developed, and three distinct treatment groups, normal saline (NS), PEG-modified liposome (Lipo/PEG), and APA-Lipo/PEG were employed. The APA-Lipo/PEG group received an oral dosage of 50 mg/kg. The mice body weight of the APA-Lipo/PEG group in the peritoneal model was lower than that of the NS and Lipo/PEG group and the quantity of tumor nodules and tumor weight were both considerably decreased with APA-Lipo/PEG therapy, which demonstrated a notable decrease in tumor volume and tumor weight in the subcutaneous model. As a result, the findings showed that APA-Lipo/PEG had remarkable in vivo anti-tumor activity against mouse colorectal cancer.

When delivering APA to human colonic cancer, Song et al. [89] produced cRGD and PEG-modified liposomes (cRGD-Lipo-PEG) as a targeted delivery method. The results of an in vitro apoptosis study on HCT116 cells treated for 24 h with free APA, APA-loaded cRGD-Lipo-PEG and LipoPEG revealed significant apoptosis in the liposome-treated groups. For Lipo-PEG/APA and cRGD-Lipo-PEG/APA, early apoptotic ratios were around 7% and 14%, respectively, whereas late apoptotic ratios were 4.5% and 28%. HCT116 cells were implanted in female BALB/c nude mice for an in vivo study. A group of control and treated with free APA and cRGD-Lipo-PEG/APA was there, where the APA was given at a dose of 50 mg/kg. With a tumor mass of 0.18 ± 0.08 g and tumor volume of 272.5 ± 168.11 mm 3 , cRGD-Lipo-PEG/APA was shown to be more effective against tumor than free APA and the PBS-treated control groups. The results show a significantly stronger impact of cRGD-Lipo-PEG/APA (82.1%) than free APA, which only had a statistically significant impact of 26.3% on the rate of reduction of tumor mass.

Although APA is approved to treat metastatic gastric cancer, ongoing research and clinical trials are exploring its potential use in other types of cancer, such as metastatic breast cancer, melanoma, metastatic colorectal cancer, and hepatocellular carcinoma (HCC). VEGFR-2 plays a crucial role in facilitating angiogenesis, a vital process for the growth and metastasis of various types of cancer. By inhibiting VEGFR-2, APA can block angiogenesis in various cancers, leading to tumor regression or inhibition of further development.

Axitinib (AXT)

AXT, a potent VEGFR inhibitor (molecular weight 386 g mol -1 , log P 4.2, IC 50 0.10 nM), rapidly soluble with T 1/2 of 2.5 h and 58% mean absolute bioavailability. AXT's pharmacokinetic properties are ideal for preparing control release drug delivery system, which can reduce the dosing frequency (b.i.d). AXT shows substantial inter- and intra-patient variation in C max was observed (0.02–11.2 ng/ml/mg), which depends upon glucuronidation activity, while another study has reported C max in metastatic renal cell carcinoma (mRCC) between 12.4–40.2 ng/ml [126] . Precision nanomedicines can therefore improve the therapeutic efficacy.

AXT, used as second-line therapeutic agent for mRCC, inhibits VEGFR as reported in a clinical trial study conducted in 2016 [127] . Choi et al. [90] have developed AXT-loaded hybrid liposomal NPs coated with polypeptide (P-LNP/AXT) by utilizing a thin-film hydration technique, and the optimized formulation exhibited higher drug loading of 95% with narrow size distribution (∼150 nm). Compared with free AXT and LNP/AXT, P-LNP/AXT had majorly inhibited tumor growth when the drug was injected intravenously at 1 mg/kg dose into mice. P-LNP/AXT demonstrated limited internalization by the mouse macrophage cell line RAW 264.7, implying their potential ability to evade the reticuloendothelial system. Furthermore, an upregulation in the levels of poly (ADP-ribose) polymerase and caspase-3, as well as a downregulation in the level of platelet/endothelial cell adhesion molecule 1 (PECAM1, CD31), were observed in tumor tissues, indicating the occurrence of apoptosis.

Choi et al. [91] developed MSNPs -loaded with celastrol (CST) and AXT within the PEGylated lipid bilayer. The complex formulation showed significant ( P < 0.05) mitochondrial-based apoptosis and cancer angiogenesis. Exposure of neuroblastoma (SH-SY5Y), squamous carcinoma (SCC7) and breast cancer (BT474) cell lines to the complex formulation resulted in a reduction in the expression of hypoxia-inducible factor (HIF)−1α, which might be a crucial factor for inhibiting tumor growth. Western blotting revealed that the NPs had a superior anticancer impact in many cancer cells. In complex formulation, both drugs synergistically controlled VEGFR. In tumor xenograft model, mice treated with the complex formulation exhibited 64% tumor inhibition. Immune-histochemistry revealed overexpression of poly (ADP-ribose) polymerase, caspase-3, and downregulation of Ki-67 and CD31 expression, indicating tumor apoptosis via mitochondrial and anti-angiogenic actions. As seen in Fig. 8 A, the CST-AXT loaded PEGylated MSNs were prepared. The optimized formulation possesses reduction in tumor volume ( Fig. 8 B), and body weight ( Fig. 8 C). Histopathological changes in nude mice after treatment with AXT/CST-loaded combination NPs (D1), immunoreactivities of caspase-3 and poly (ADP-ribose) polymerase (PARP) (D2) and CD-31 and Ki-67 (D3) in tumor masses of nude mice showed tumor apoptosis via mitochondrial and anti-angiogenic activity.

Cabozantinib

Cabozantinib is a potent multiple TKI BCS class II drug (IC 50 : 0.04 nM, practically insoluble in water) with an extended T 1/2 of ∼99 h Due to its multiple tyrosine kinase inhibitory properties, cabozantinib can simultaneously target several signaling pathways (MET, VEGFR2, RET and AXL) involved in cancer cell growth and angiogenesis. This sustained inhibition of relevant kinases and extensive protein binding (>99%) is facilitated by its extended T 1/2 , allowing for less frequent dosing schedules [128] . Furthermore, the therapeutic window for cabozantinib has been expected to be 540–620 ng/ml, which is considerably narrow, illustrating a drug with high efficacy but also high toxicity [129] . USFDA-approved cabozantinib to treat differentiated thyroid cancer, by inhibiting the tyrosine kinase activity of c-MET (mesenchymal-epithelial transition factor), VEGFR, MER (MerTK or Mer tyrosine kinase), KIT proto-oncogene, RET (rearranged during transfection) and AXL RTK.

Kiranj et al. [92] developed cabozantinib PLGA-COOH polymeric NPs coated with bovine serum albumin (BSA) for murine PTEN/p53-deficient prostate tumors. The in vitro study of the NPs showed that activated neutrophils internalized the BSA-coated NPs to a greater extent than the uncoated NPs. In vivo experiments were conducted on p53 mice using intravenous administration of BSA-coated NPs for 12 h daily, 3 d consecutivly. Study findings suggested that as compared to control group, the cabozantinib-loaded BSA-coated NPs treated group showed enhanced neutrophils up to 4-fold within tumor microenvironment. Targeted intratumoral delivery of NPs mediated by neutrophils was demonstrated by the depletion of Ly6 G and neutrophils, eliminating dye-loaded BSA-NP accumulation within tumors to normal levels. Figs. 9 A and B represents the methods opted for the preparation of dye-loaded BSA-coated PLGA NPs and the mechanism of uptake of NPs. The cellular uptake of BSA-NP, cabozantinib-NPs, cabozantinib-BSA-NPs, and cabozitinib-BSA-NPs-Ly6 G antibody in various organs such as liver, kidney, spleen and lungs showed that BSA coating significantly increased NPs internalization by ∼6 fold compared to uncoated NPs ( Figs. 9 C–9F). Due to its multiple kinase activity, it is tested in various cancers such as prostate, HCC and RCC. Additional research is required to explore the potential of cabozantinib in clinical treatment for various cancers.

Crizotinib (CZT)

CZT, a BCS class II drug, exhibits poor bioavailability (< 45%) and non-linear pharmacokinetics due to metabolism and is administered orally twice daily at a dose of 250 mg. It exhibits pH-dependent solubility (poor at higher pH) and a primary mode of elimination through feces with an extended T 1/2 of 42 h [130] . Bioavailability of CZT is 30%−60%, and high-fat meals reduce the AUC and C max by ∼14% [131] . Improving the pharmacokinetic properties of CZT is a compelling objective of formulation advances. CZT is a receptor d'origine nantais (RON) and HGFR (c-Met) inhibitor of RTK. CZT, along with alectinib, is used in the treatment of naive anaplastic lymphoma kinase-positive advanced NSCLC patient [132] .

Zhong et al. [120] have formulated polymeric NPs for the effective delivery of CZT and SFN using a double-emulsion solvent evaporation method to treat lung cancer. The NPs were prepared at ratios of 2:1, 1:1 and 1:2 (SFN/CZT). Biodegradable triblock poly(ethylene glycol)-poly(ε-caprolactone)-poly(ethylene glycol) (PEG-PCL-PEG, PECE) polymeric NPs were prepared, and in vitro and in vivo studies were performed to investigate the effectiveness of NPs on lung cancer. Poly dispersive index (PDI) of the NPs (2:1, 1:1 and 1:2) was found 0.16, 0.11 and 0.21, respectively. SFN and CZT polymeric NPs exhibited sustained release with varying release rates over 72 h During this timeframe, the NPs released 63% of SFN and 50% of CZT. In A549 and 4T1 cells, the NPs exhibited significant apoptosis than free drugs. As compared to free drug, the intravenous administration of NPs at a dose of 10 mg/kg (SFN) and 5 mg/kg (CZT), a ratio of 2:1 (SFN/CZT) and concentration of 8.50 mg/ml to nude mice with 4T1 cancer cell xenograft model showed considerable reduction in tumor progression, improved survival rate with reduced liver toxicity, hypertension and visual disturbance.

Wang et al. [121] have evaluated the safety and efficacy of polydopamine-polylactide-TPGS NPs loaded with CZT (CZT-pD-PT NPs) for the treatment of NSCLC. The optimized NPs demonstrated a sustained-release profile as compared to free CZT with enhanced cellular absorption. The optimized NPs showed approximately zeta potential of −23.7 mV, encapsulation efficiency of 84% and drug loading of 3%. In vivo studies finding suggest that as compared to free CZT and CZT NPs, the CZT-pD-PT NPs possess enhanced cellular apoptosis of cancer cells. Furthermore, the optimized formulation was evaluated against various markers such as ALT, ALP, DBIL and AST, and the result suggests that no significant effect was observed with CZT/pD-PT NPs. The study finding suggests that CZT/pD-PT NPs could be an effective strategy to modify and improve the chemotherapeutic property of CZT for NSCLC with minimum hepatotoxicity.

Khaled et al. [122] developed CZT and DAS-loaded micellar NPs for the treatment of glioblastoma multiforme. The CZT and DAS were encapsulated using poly (styrene-co-maleic acid) (SMA). The water solubility of SMA-CZT and SMA-DAS micelles was found to be 53.7 and 27.2 mg/ml, respectively. The average size and PDI of SMA-CZT were 121 nm and 0.251 and of SMA-DAS were 89 nm and 0.251. Cell viability assay performed on GBM cell lines showed 0.2 mM of free or micellar DAS and 4 mM of free or micellar CZT were capable of reducing the cell count by 60%. In vivo studies were conducted in female C57BL/6 mice, and the data revealed a decrease in tumor growth due to both free and micellar forms of drug, as well as the drug combination.

Dabrafenib (DAB)

DAB, commercialized as a mesylate salt, is classified as BCS class II drug (log P 2.9) and pH-dependent solubility where it is insoluble at pH 4–8. It exhibits high PPB (99%), with T max of 2 h and T 1/2 of 8 h Oral immediate-release tablets are more suitable for DAB than control-release tablets as it shows pH-dependent solubility (practically insoluble above pH 4) [133] . Though the bioavailability of oral DAB is 95 %, DAB exposure (C max and AUC) becomes non-linear function of dose after repeat twice daily dosing, attributed to induction of its own metabolism [134] . DAB has been used in combination with trametinib for the treatment of positive melanoma.

Pham et al. [93] developed DAB loaded human serum albumin (HSA) nanosystems conjugated with transmembrane protein CD47 for chemo-immunomodulation. CD47 was conjugated with DAB-loaded-HSA using cis-aconityl-PEG-maleimide (CA), an acid-labile linker ( Fig. 10 A). The resulting formulation demonstrated specificity for melanoma via targeting glycoprotein60 on cancer cell surface as well as release of drug in acidic tumor microenvironment pH compared to normal physiological pH. The optimized CD47-CA@D@HSA possesses an average size of ∼220 nm. In comparison to free DAB, CD47-conjugated nanosystems showed increased extent of internalization, accumulation, cytotoxicity and apoptosis by B16 F10 cells. The in vivo studies showed that CD47-CA@D@HSA treatment increased the migration of cytotoxic T cells and tumor-associated macrophages towards the tumors, including DAB, D@HSA, CD47-CA@D@HSA, PD-1, and CD47-CA@D@HSA + PD-1, where the doses of DAB, PD-1 and CD47 were 10, 5 and 2.5 mg/kg, respectively and the mice were treated with various intravenous injections except PD-1 (intraperitoneally). As seen from Fig. 10 B, CD47-CA@D@HSA showed a reduction in tumor progression. Combination therapy using CD47-CA@D@HSA and PD-1 showed significantly enhanced antitumor activity compared to CD47-CA@D@HSA, D@HSA and free drug (Fig. 10C&10E) and no significant histopathological findings were observed in the major organs ( Fig. 10 D).

Nguyen et al. [94] have prepared NPs composed of a cationic amphiphilic block co-polymer called poly-b-caprolactone-polyethyleneimine (PCL-PEI) to deliver miR-200c and DAB simultaneously (miR-PCL-PEI/Dab NPs), in which DAB was entrapped within the hydrophobic core of PCL and the miR-200c was adsorbed on the cationic layer of PEI by means of electrostatic interactions. The miR-PCL-PEI/Dab NPs were further coated with Y2510924, a CXCR-4-targeting peptide conjugated with redox-sensitive polymer. The polymer was synthesized by cross-linking of poly- l -glutamic acid-thiol (PGA) with orthopyridyl disulfide (OPSS)-PEG-NHS to form a CXCR-4-targeted system for the simultaneous delivery of DAB and miR-200c (miR-PCL-PEI/Dab-PGA-pep). The in vivo results showed immunogenic cell death, and the PD-L1 expression gets suppressed due to treatment with CXCR-4 targeted NPs. To investigate in vivo biodistribution of the complex formulation Cy5.5-NHS was loaded onto the NPs following the same method as of Dab's loading. Mice with MC-38 tumors were intravenously injected with miR-PCL-PEI/Dab and miR-PCL-PEI/Dab-PGA-pep NPs that were labeled with Cy5.5.

Dasatinib (DAS)

Oral absorption of DAS occurs rapidly with T max of 0.25–1.5 h and T 1/2 of 3–4 h Initially, DAS was administered twice daily, but due to tolerability issues, the approved dosage was optimized to 100 mg once daily, resulting in improved tolerability and lower discontinuation rates [135] . DAS inhibits receptors including c-KIT, BCR-ABL, SRC family, PDGFR-β and EPHA2, used for the effective treatment and management of Philadelphia chromosome-positive (pH+) CML. DAS exhibits high variation in exposure among patients, risking some toxicity while others obtain suboptimal efficacy [136] . Dose reduction has been implemented in CML patients. DAS within patient and between variation (40%–80%) has been observed for C max and AUC [137] , [138] , [139] , [140] . The oral bioavailability also around 15%−50% [141] , [142] , influenced by gastric pH (pK a = 3.1, 6.8 and 10.8) as the drug precipitates in the small intestine [143] . These biopharmaceutical limitations can be overcome by developing complex formulations of DAS.

Bahman et al. [95] have formulated DAS encapsulated in SMA to produce SMA-DAS NPs (SMA@D NPs). The optimized NPs showed a zeta potential of 0.0035 mV, average size of 198 nm, PDI of 0.17 and loading capacity of 11.5%. Both free drug and SMA-drug exhibited significant cytotoxicity against 4T1 cells, which was higher compared to MCF-7 and MDA-MB-231 with IC50 values of approximately 0.014 µM and 0.083 µM, respectively. In vivo biodistribution studies showed that spleen, kidney and lung exhibited a higher accumulation of DAS after receiving SMA-DAS treatment (< 50%) to free DAS injection (> 50%). DAS showed positive outcome when used as a single agent or neoadjuvant to treat triple-negative breast cancer (TNBC) [95] , [144] .

Utilizing CPT and DAS derivatives, Yang et al. [96] have synthesized carrier-free amphiphilic drug-drug conjugate (ADDC), which get self-assembled and led to the formation of reduction-responsive NPs (CP-DDA NPs). DAS had been modified by succinic anhydride, and subsequently connected to CPT derivative by ester bonds. CP-DDA NPs had a size of 119 nm and PDI of 0.046. The in vitro release rates of CPT were 22.49% and 5.24% at pH 6.0 and 7.4, and 32.18% and 92.93% at pH 7.4+GSH and pH 6.0+GSH, respectively. The release of DAS reached 67.72 % in 24 h while being in a pH 6.0+GSH (10 mM) surroundings, and it increased to 81.97% in <50 h At pH 7.4 +GSH (2 uM), the DAS release rate was <30% in 48 h In contrast, even after 144 h, the amount of DAS released at pH 7.4 and 6.0 in the absence of GSH was below 25%. The use of CPT-DAS NPs led to a significant reduction in tumor progression, while also minimizing the toxic effects of CPT on healthy cells, particularly those located in the kidneys, nerves and the inner ear.

Erlotinib (ETB)

ETB belongs to BCS class II drug. It exhibits extensive FPM with T max of 2–4 h and T 1/2 of 10–36 h It showed 60% bioavailability, which improved with food up to 100% [145] , [146] , [147] . The drug has high potency with IC 50 values quite lower compared to other drugs in the series; however, incidences of adverse reactions are also higher (a narrow therapeutic index). Moreover, it requires 7–10 d to attain steady-state plasma concentration and is sensitive to gastrointestinal pH for effective absorption [148] , [149] . ETB is a well-known TKI for the treatment of advanced or metastatic pancreatic or NSCLC therapy.

Tan et al. [97] developed a pH-sensitive and redox-responsive NP containing ETB using poly (acrylic acid)-cystamine-oleic acid (PAA-ss-OA). They prepared ETB-loaded PAA-ss-OA-modified lipid NPs using an emulsification solvent evaporation technique (PAA-ETB-NPs). The particle size of the NP formulation was found to be 170 nm and zeta potential of −32 mV. The drug loading capacity and encapsulation efficiency were 2.6% and 85%, respectively. In vitro cytotoxicity studies revealed that ETB-NPs were more effective than ETB solution. Treatment with PAA-ETB-NPs significantly inhibited tumor growth in mice compared to ETB-NPs and ETB solution. In vivo , a xenograft nude mouse model with human lung cancer cells was used to evaluate the inhibition effect of ETB-NPs where PAA-ETB-NPs reduced tumor growth more than ETB-NPs ( P < 0.05), ETB solution ( P < 0.01) and saline control ( P < 0.001).

Shen et al. [98] prepared ETB-albumin NPs co-modified with hyaluronic acid (HA) and HSA (ERT-HSA-HA NPs) by using precipitation method for NSCLC treatment. The drug loading and encapsulation efficiency of ERT-HSA-HA NPs were 5.65% and 81.2%, respectively. The in vitro release study of ETB from the NPs revealed no initial burst release effects. The optimized NPs exhibited significant anti-proliferative activity on A549 cells. In vivo studies showed that mice treated with ERT-HSA-HA NPs intravenously (dose = 10 mg/kg) demonstrated reduced tumor growth with no recurrence.

Wan et al. [99] prepared a PLA-based nano-platform (NP-EB) to target TNBC. Knowing EGFR inhibition resistance is due to Notch-EGFR, to counter this, a gamma-secretase inhibitor (GSI) called DAPT was incorporated into the core of the NPs to inhibit Notch signaling activation, resulting in the formation of NP-EB/DART, containing both ETB and DAPT. A new peptide called CF was developed to achieve tumor-specific targeting by combining two distinct peptides, CREKA (a tumor-homing peptide) and F3 (a cell-penetrating peptide), linked together using a pH-sensitive hydrazone bond. Then, CF peptide was attached to the surface of NP-EB/DART, resulting in CF-NP-EB/DART, where these NPs when reached the tumor site, the unique acidic environment of the tumor triggers the breakdown of the pH-sensitive linkage exposing F3 peptide facilitating the internalization of NPs. The CF-NP-EB/DART NPs exhibited a narrow particle size distribution with a PDI of 0.179, zeta potential of 24.3 mV, entrapment efficacy of 42%, drug loading of 0.8%, and an XPS assay value of 0.56%. In vitro studies were conducted using human adenocarcinoma cells (MCF-7) and normal human dermal fibroblast cells (NHDF) to evaluate the cytotoxic effects of the nanoparticle formulation (5 mg/kg), demonstrated that the nanoparticle formulation exhibited higher cytotoxicity towards MCF-7 cells than NHDF cells.

Ibrutinib (IBR)

IBR is a Bruton's TKI (BTK) used for the treatment of mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) and B-cell malignancies. The drug is practically insoluble in water, rendering absolute oral bioavailability of the drug between 4%−15% depending upon food administration. IBR bioavailability is reduced because of extensive fast oxidative transformation by hepatic cytochrome P450 [150] , [151] , [152] . It is currently undergoing clinical investigations against patients suffering from multiple hematologic malignancies as well. In 2013, IBR approvaled by FDA under the brand Imbruvica® for mitigating MCL, CLL, Waldenstrom macroglobulinemia, lymphoma and graft-versus-host disease. IBR is considered a BCS-Class II drug as it is low soluble and highly permeable. IBR is insoluble in aqueous solvents and exhibits a maximum solubility of 13 µg/ml at pH 8.0. IBR exhibits poor bioavailability, limiting to 3.9% upon oral administration and high FPM as the solubility of drug is a pre-determined factor for drug dissolution, absorption and distribution either for onsite action or to enter into the systemic circulation. A maximum daily dose of IBR up to 420 mg is given orally for patients with CLL and up to 560 mg for MCL to exhibit better therapeutic benefits [153] . Though IBR has shown potential effects against MCL and CLL, its application in cancer has been limited because of adverse effects such as atrial fibrillation, diarrhea, bleeding and infection upon continuous use. A clinical study in patients (9%−23%), reveals that off-target effects of IBR could be the major reason for various adverse effects associated with the drug [154] , [155] , [156] . In a clinical study conducted on patients with CLL, IBR showed a T max of 2 h and T 1/2 of 6–9 h The AUC increased gradually with the increase in dose at a range of 420–840 mg/d [157] . Investigational studies are currently underway to enhance the bioavailability and reduce its adverse effects while aiming to enhance its therapeutic efficacy in clinical setting.

Abdullah et al. [100] prepared IBR-loaded PLGA NPs using the nanoprecipitation technique to improve oral bioavailability. IBR suspensions at 10 mg kg -1 or an equivalent dose of IBR-loaded NPs were orally administered in a Wister albino rat. Study findings suggested enhancement of oral bioavailability of IBR-loaded NPs by around 4-fold as compared to free IBR solution. The C max of the NPs and free IBR-solution was approximately 574 ng/ml and 146 ng/ml ( P < 0.01), respectively. The results revealed that PLGA NPs could improve IBR's bioavailability and therapeutic effectiveness.

Nagarjun et al. [101] prepared IBR nanosuspension employing precipitation ultrasonication technique to enhance the oral bioavailability of IBR with reduced fast-fed state variability. Pluronic F127 was used as a stabilizer and the nanosuspension formulation exhibited mean particle sizes between 278 and 453 nm and PDIs between 0.055 to 0.198, respectively. DSC and powder XRD proved that the active ingredient transformed from a crystal to an amorphous state. The nanosuspension resulted in a 21-fold enhancement in the solubility of IBR. IBR solution possesses C max of 49 ng/ml and AUC (0-t) 138 ng/ml ( P < 0.01) in fasting states, whereas IBR loaded nanosuspension showed improvement in C max (∼3.5 folds) and AUC 0-t (∼5.8 folds) in the same states. In case of both the fed and fasted stages, no distinct variation in the pharmacokinetics of nanosuspension was found. These findings suggested that nanosuspension could be an effective method for the enhancement of solubility as well as absorption with reduced variability.

Imatinib (IM)

IM is a protein smTKI and blocks the Bcr-Abl tyrosine kinase, approved for the treatment of CML in 2001. It was the first ever smTKI to get approval from FDA. It is a selective inhibitor of PDGFR-α and PDGFR-β. IM marketed by Novartis under the brand Gleevec™ as. a methane sulfonate salt, which is available as a capsule equivalent to 100 mg IM-free base [158] . IM is extremely hydrophobic in nature, and conversion into the salt form enhanced its bioavailability. IM-free base in water is practically insoluble (0.001 g/100 ml), whereas its mesylate form in water shows higher solubility at a pH < 5.5 [159] . IM mesylate falls under the BCS Class-I due to its high solubility. Upon oral administration, IM mesylate exhibits a T 1/2 of 18 h and T max of 2–4 h, showing around 97% bioavailability. The AUC increases with the dose range of 25–1,000 mg. The drug shows around 95% human plasma binding particularly to α1- acid glycoprotein and albumin. Similar to other smTKI-inhibitors, IM also has side effects such as diarrhea and nausea. Periorbital hypertrophy, edema and myelosuppression are the most frequently reported adverse effects associated with this drug [160] , [161] . IM therapy is reported to be associated with high variability in exposures, and poor compliance [162] , [163] . Moreover, IM concentrations > 1,000 ng/ml are needed for event-free survival, but just 1.6 times higher concentrations are correlated with diarrhea and edema [164] , [165] . This indicates a need for formulation interventions.

Chen et al. [82] developed DOX and IM co-loaded pH-sensitive liposomes functionalized with folate (FPL-DOX/IM) and cleavable TPGS analog where alpha tocopheryl acid succinate (VES) was chemically coupled to PEG through an acid-labile hydrazone linker. The co-loaded liposomal formulation was stable in blood circulation even after 24 h The formulation possessed a diameter of 100 nm. Co-loaded liposomes reduced ABC transporter function and enhanced chemotherapeutic sensitivity, thus helping to overcome the chemoresistance associated with DOX. In vivo studies conducted for pharmacokinetics assessment in female Kunming mice via intravenous administration at a IM dose of 45 mg/kg and DOX dose of 3 mg kg -1 showed that after 24 h, the drug level of DOX and IM (∼0.8 and ∼7.2 µg/ml, respectively) was maintained. Anti-tumor efficacy study conducted in MCF-7/ADR xenografted BALB/c nude mice concluded that co-delivery of IM and DOX increased their therapeutic efficacy. Further, functionalized liposomal construct provided acid sensitivity and long circulation time with less systemic toxicity.

Wang et al. [83] developed realgar (As 4 S 4 ) nanocrystals with a consistent size of ∼40 nm by using a bottom-up method. The As 4 S 4 nanocrystals were stabilized using BSA, a frequently utilized carrier for nano-drug delivery due to its affordability, compatibility with living beings, and numerous functional groups ideal for loading and modifying drugs. An As4S4 and IM co-delivery system (As 4 S 4 /IMA) was formed in this study due to the efficient incorporation of IM into the hydrophobic areas of BSA. Folic acid (FA) was functionalized to BSA to enable its recognition of tumor cells as a target, and FA was then used as a ligand to stabilize As 4 S 4 nanocrystal (As/IMA@FA). A synergistic effect for the treatment of CML was meticulously achieved by carefully balancing the drug ratio within the co-delivery system. Healthy SD rats were used in a pharmacokinetics study, and 2 mg/kg of free IM was administered intravenously along with As/IMA@FA NPs. The outcomes showed that free IM had a T 1/2 of 8.8 h, was rapidly excreted from the body, and was almost undetectable after 10 h However, when given as As/IMA@FA NPs, which have an extended T 1/2 of 11.9 h, IM circulation was markedly prolonged. Additionally, compared to free IM, the apparent AUC of the NPs was significantly larger. Female BALB/c nude mice with K562 cell-induced tumors were injected with As/IMA NPs and As/IMA@FA NPs via the tail vein in order to examine the biodistribution and in vivo antitumor efficacy. The study showed that As/IMA@FA NPs improved drug uptake and extended circulation in the tumor. Additionally, the tumor-targeting effect was improved with the inclusion of FA modification, leading to greater tumor suppression for As/FA NPs. The As/IMA@FA NPs had the best results among these NPs, almost completely inhibiting tumor growth.

Lenvatinib (LFT)

LFT, an FDA-approved kinase inhibitor since 2015, effectively blocks the functions of various VEGF and FGF receptors, including VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), FGFR1, FGFR2, FGFR3 and FGFR4. It also inhibits PDGFR, KIT and RET. LFT is a potent drug but routine follow-ups have become important due to several adverse effects [166] , which indicate that complex formulations can improve therapeutic outcomes.

A conventional co-precipitation method by Zhang et al. [118] has been utilized to develop LFT-loaded sodium glycocholate and soy phospholipid mixed micelles (LFT-MMs). LFT-MMs demonstrated a significant improvement in solubility (500-fold), encapsulation efficiency (87.6%) and adequate stability (> 1 month at 4 °C). In vitro anti-tumor study revealed that compared to LFT and LFT mesylate, LFT-MMs demonstrated improved inhibitory action against differentiated thyroid cancer cells (BCPAP and FTC-133). Pharmacokinetic studies conducted in SD rats after oral administration showed that LFT-MMs had a relative bioavailability of 177% compared to LFT. AUC 0-∞ of LFT-MMs was found significantly higher (∼ 13,200 µg·h /l) compared to free LFT mesylate (∼ 7,500 µg·h /l).

Osimertinib (OSI)

OSI is a kinase inhibitor of EGFR, approved by FDA in 2015. It exhibits linear pharmacokinetics but has very low solubility [167] . The T 1/2 (6 h) and dose of 80 mg make it ideal for developing a controlled release formulation (presently administered once a day).

Chen et al. [119] linked SEL with PEG to synthesize PEG-SEL prodrug using reactive oxygen species (ROS)-responsive linker (PEG-S-SEL). Due to the amphiphilic character, PEG-S-SEL self-assemble in aqueous solution to form micelle and act as a delivery vehicle for OSI. In vivo study conducted in female athymic mice xenografted with PC-9/AR cells revealed that OSI+SEL NPs treated group significantly showed reduction in tumor weight than OSI NP or SEL NP treated groups. Furthermore, the OSI-SEL NPs exhibited significant tumor suppression and successfully induced apoptosis by inhibiting EGFR and MEK simultaneously in OSI-resistant NSCLC cells and decreased OSI-resistant tumor.

Pazopanib

Pazopanib approved by FDA in 2009 for the treatment of renal cell cancer that inhibits VEGFR-1, −2 and −3, PDGFR, FGFR-1 and - 3, interleukin-2 receptor inducible T-cell kinase and cytokine receptor (Kit). Additionally, it can be utilized in the management of colorectal cancer. Pazopanib exhibits complex pharmacokinetics with a high pH-dependency of solubility. The bioavailability of the drug is low (14 % to 39%), time-dependent and non-linear, with considerable interpatient variability. Total systemic exposure, as well as pazopanib trough level (≥ 20 mg/l), correlate with observed tumor shrinkage and progression-free survival as well as toxicity. Current 800 mg daily dose fails to provide the required minimum concentration (C min ) in 20% of patients, exposing them to suboptimal treatment [168] , [169] . Therefore, several aspects of pazopanib therapy can benefit from complex formulation approaches.

Lahoti et al. [102] formulated a colon-targeted liposomal drug delivery system for colorectal cancer of pazopanib by utilizing high-pressure homogenization process. HSPC, m-PEG DSPE-2000 (phospholipid) and cholesterol were used for the preparation of drug-loaded liposomes. The optimized formulation depicted particle size of ∼109 nm with PDI values of 0.998 at homogenization pressures of 1000 psi, 1500 psi and 2000 psi, and cycles of 9, 6 and 6, respectively. In vivo studies were conducted in wistar rats, and carcinogenesis was induced by 1,2-dimethylhydrazine. The liposomal formulation was given as an oral dose of 30 mg/kg, and the control was treated with distilled water. After 30 d pazopanib-loaded liposomes exhibited lesser tumor weight and volume (∼0.4 g and ∼125 mm 3, respectively) as compared to the control group. This process was also deemed to be scalable in industrial setup, which makes it an attractive option for the treatment of colorectal cancer.

Sorafenib (SFN)

Numerous intracellular (cCRAF, mutant BRAF, and BRAF) and cell surface (KIT, FLT-3, RET, FLT-3, RET/PTC, VEGFR-1, 2, 3, and PDGFR-ß) kinase receptors have been demonstrated to be inhibited by SFN which is FDA-approved for hepatocellular and RCC in 2007 and 2005, respectively. SFN pharmacotherapy is limited by high variability, low therapeutic index, ∼40% bioavailability and dose reduction approach has shown to benefit many clinical outcomes [170] , [171] , [172] . These limitations provide a driving force for developing complex formulations of SFN.

Mahmoud et al. [103] employed alginate polymer to microencapsulate SFN absorbed on the CNTs (CNTs-SFN-MC). MTT assay demonstrated that the drug-loaded CNTs were 2-fold cytotoxic to HepG2 cells compared to free SFN. Additionally, the in vivo experiments on male Wistar rats showed an AUC value of ∼681 µg·h/ml and a T 1/2 of 18.43 h There was a considerable reduction in the circulating ratio of Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3%) in N-nitrosodiethylamine (DENA) induced HCC rat model with CNTs-SFN-MCs group as compared to the DENA and SFN groups. Immunofluorescence analysis and western blot analysis of a few HCC-relevant biomarkers of control groups showed significant level of changes as compared to CNTs-SFN-MC. This research demonstrates that CNTs-SFN-MCs had higher anticancer activity both in a rat model of DENA-induced HCC and against HepG2 cells in vitro .

Clavreul et al. [104] prepared SFN-loaded lipid nanocapsules (LNCs) exhibiting a very high encapsulation efficiency (> 90%). SFN-loaded LNCs decreased the viability of human U87MG glioblastoma (GB) cells as well as decreased angiogenesis. In vivo studies conducted in female Swiss nude mice bearing an orthotopic U87MG human GB xenograft showed single dose of intratumoral injection of SFN-LNCs (3.5 µg) increased the blood perfusion to the tumor core as compared to control (HBSS) and free SFN treated group (∼62 ml/100 g/min, ∼50 ml/100 g/min, ∼49 ml/100 g/min, respectively) ( P < 0.05). SFN-LNCs were found to be more effective in inducing early tumor vascular normalization resulting from decreased vessel area than free SFN.

Mo et al. [105] formulated three liposomal formulations of SFN: a HA-coated liposome (HA-SFN-Lip), an uncoated liposome (SFN-Lip), and a PEGylated HA-coated SFN liposome (PEG-HA-SF-Lip). The cytotoxicity and cellular uptake of PEG-HA-SFN-Lip and HA-SFN-Lip were higher than those of SFN-Lip in MDA-MB-231 cells that overexpress CD44, but no overt changes were seen in MCF-7 cells with low CD44 expression. This shows that CD44 is involved in uptake of coated liposomes. In vivo study conducted in male Sprague Dawley rats exhibited that PEG-HA-SFN-Lip formulation exhibited almost higher AUC, enhanced T 1/2 , and decreased clearance compared to free SFN solution and uncoated liposomal formulation. PEG-HA-SFN-Lip also recorded the highest tumor growth inhibition in the MDA-MB-231 tumor xenograft female NCr athymic nude mice model. It also displayed high plasma stability and hemocompatibility.

Li et al. [106] developed SFN-loaded TPGS-NPs by utilizing dendritic poly(amidoamine)-poly(γ-benzyl- l -Glutamate)-b- d -α-tocopheryl PEG1000 succinate (NP-TPGS-SFB) to improve the shorter T 1/2 of SFN. SFN released in response to acid was accomplished by TPGS-SFN—NPs. As compared to free SFN, PEG-conjugated NPs (NP-PEG-SFB) demonstrated noticeably greater cellular absorption in HepG2 human liver cells. The MTT assay proved that NP-PEG-SFB and free SFN both exhibited reduced cytotoxicity than NP-TPGS-SFB. Additionally, NP-TPGS-SFB considerably reduced tumor growth by ∼87 mm 3 compared to 360 mm 3 of saline, 228 mm 3 of free SFB and 181 mm 3 of NP-PEG-SFB in mice receiving HepG2 xenografts.

Sheng et al . [107] developed SFN NPs by utilizing the nanoprecipitation method. SFN was combined with a copolymer composed of racemic polylactic acid and PEG monomethyl ether to prepare nanoformulation. In vivo study conducted in tumor-bearing mice showed that SFN—NPs possessed substantially greater SFN concentration in tumor tissues (∼2,800 ng/ml) than free SFN (∼870 ng/ml). In vivo , retention time of the formulation was considerably longer than SFN alone. SFN—NPs were found more efficient at inhibiting tumor growth (∼70%) than SFN alone (∼50%). Park et al . [108] developed SFN—NPs using supercritical fluid and fat. Formulation variables HPMC, PVP K30 and poloxamer were optimized. In vivo PK profile study performed in beagle dogs showed improvement in blood levels, greater absorption than the reference (Nexavar®), AUC 0–48 was 35,560 ng·h /ml, C max was 4,316 ng/ml, and T max was 3.71 h This work demonstrated the value of systematic formulation design for determining how formulation factors affect the properties of the poorly soluble drug NPs.

Nevertheless, because certain molecules have low oral bioavailability, it becomes necessary to administer them in high doses, which can result in dose-limiting toxicity, particularly when given daily over an extended period of time. An oral complex delivery system for SFN tosylate has shown almost twice the increase in bioavailability, resulting in a better toxicity profile. The formulation contained albumin as carrier and was prepared using a scale-up-ready high-pressure homogenization process, which had a size of ∼300 nm and surface charge of −55 mV. In the orthotopic murine hepatic tumor model, significantly improved tumor regression was observed at half the clinical dose of 400 mg. The complex formulation showed higher selective distribution in liver tissue [173] .

Lapatinib (LPT)

The intracellular tyrosine kinase domains of the human epidermal receptor type 2 and the EGFR are targeted by the 4-anilinoquinazoline kinase inhibitor, named LPT which was approved by FDA in 2007 for the effective treatment of metastatic breast cancer.

Pavithra et al. [109] formulated LPT nanosponges (LPT NSs) by employe PVA as the stabilizer and Eudragit RS100 as the polymer. LPT NSs was found to be more soluble than free LPT. In vivo pharmacokinetic investigation conducted on female Wister rats (22mg/kg dose given via oral route) recorded a significant improvement in LPT NSs compared to the free LPT with C max , T max , AUC 0-t and elimination T 1/2 . Hence, it has been demonstrated that LPT NSs possesses higher bioavailability and could be helpful in reducing the oral dosage of LPT.

Dehghankelishadi et al. [111] studied the in vitro and in vivo effectiveness of PTX-LPT loaded Pluronic micelles. MTT test performed to analyze the in vitro cellular uptake of the drug-loaded micelles demonstrates that drug-loaded micelles are more cytotoxic than free drugs. In vivo studies conducted on female BALB/c mice showed that in PTX-LPT loaded micelles group, the tumor growth rate appeared to be slower. In vivo imaging analyses showed that in liver, the highest concentration of the micellar system was observed. The commercial Intaxel® formulation was found less effective in vivo than micelles loaded with PTX-LPT.

LPT, a dual TKI, absorbs poorly from the gastrointestinal system due to its limited water solubility. Sara et al. [113] formulated a highly stable, LPT-loaded liposomal formulation and tested its therapeutic effectiveness on the 4T1 and TUBO cell lines. The results demonstrated that, in comparison to control groups, liposomal LPT dramatically increases autophagy and apoptosis while inhibiting cell growth. Additionally, it demonstrated potential advantages on the life of tumor-bearing female BALB/c mice by extending the time to end in the TUBO cell line from ∼24 d in the control group to 40 d and in 4T1 TNBC cell line and ∼30 to ∼40 d when combined with liposomal DOX. The results of biodistribution experiments exhibited that liposomal LPT tagged with I125 enhanced the drug accumulation in organs, notably in the tumor. More effectively than control group, liposomal LPT or oral Tykerb®, Caelyx® slowed the pace of tumor progression. The results revealed that more studies were necessary to completely understand the potential effects of liposomal LPT on autophagy, apoptosis and particularly immune system cells.

Bonde et al. [110] prepared LPT-loaded polymeric micelles (LP-PM), which showed greater cytotoxic properties in SKBr3 breast cancer cells and significantly inhibited the development of the tumor in vivo in a xenografted BALB/c mice model. After 28 d of treatment, the growth rate in the LP-PM group significantly slow down when contested against control group. The commercial oral formulation produced an inhibition in the range of 23%. There was a significant difference of around 45% between the inhibition found in animals treated with LS, marketed formulation and LP-PMs. The findings of this study suggest that LP-PMs have a larger potential for treating breast cancer effectively.

With some effectiveness, photodynamic treatment (PDT), administered by Gleolan®, has been investigated in the past to treat and prolong the life of malignant cancers. In a recent study, Fisher et al. [114] sought to ascertain anti-tumor PDT efficacy of liposomal LPT by combining it with ALA-protoporphyrin IX (PpIX). In vivo study was conducted in GSC30 Rag2−/ −SCID rat model at a dose of 0.125 mg/kg for 3 to 4 d following PDT. Study findings suggested that PDT with LPT treatment exhibited a mean survival time of approximately 29 d in U87 tumor cells. PDT in conjunction with LPT markedly boosted accumulation of PpIX and prominently decreased the LD50 of PpIX-initiated PDT as well as enhanced the amount of MRI-quantified glioma responses in U87 and GSC-30 cell lines.

Agarwal et al. [112] investigated the use of LPT in the form of nanocrystals coated with HA (LPT-HA-NCs) as a targeting agent for cancer cells that overexpress CD44, a cell surface receptor commonly found in TNBC. As seen from Fig. 11 A, LPT-HA-NCs were prepared using pluronic F127 as a stabilizer. In vivo study conducted in female BALB/c mice with breast tumors caused by 4T1 cells showed significant accumulation of LPT-HA-NCs in tumors over a long period of time, and the greatest distribution observed at 24 h LPT-HA-NCs produced higher tumor suppression and improved survival rates ( Fig. 11 B- 11 E) in animals, which displayed nearly 52%, 74.65% and 83.32% reduction in tumor burden than LPT-NCs, free LPT and control groups, respectively. The study also found that compared to the control group, which had 100% lung metastasis, free LPT had only 3% lung metastasis (0.33 nodules/lung), whereas LPT-NCs and LPT-HA-NCs had 0 lung metastasis since their lungs had no nodules at all, which further confirms excellent anti-tumor and metastasis activity of LPT-HA-NCs ( Fig. 11 F). Histopathological analysis displays undifferentiated cells with abundant nuclei, indicating their proliferating nature ( Fig. 11 G).

Gefitinib (GFT)

GFT is a selective TKI, specifically targeting the EGFR and inhibiting cell signaling. The overexpression of EGFR was predominantly observed in numerous solid tumors present in lungs, colon, breasts, brain and ovaries [174] , [175] , [176] . GFT inhibits the autophosphorylation of tyrosine connected to receptors by inhibiting the kinase activity of wild-type EGFR and certain activating variants. In 2003, GFT received FDA approval to treat locally advanced or metastatic NSCLC in patients following the failure of docetaxel and platinum-based chemotherapies [177] . The solubility of GFT is very poor in aqueous phases like water and other aqueous buffers [178] . A high oral dose of GFT (250 mg/d) is necessary to achieve the desired therapeutic effects due to its low solubility in water, FPM and high Pgp efflux. In rats, C max , T max and AUC of GFT were measured at 248.43 ng/ml, 1.25 h and 1,342.85 ng/ml/h, respectively, after oral administration. GFT exhibits low bioavailability (60%) due to its limited aqueous solubility when administered orally [179] , [180] , [181] . Furthermore, oral administration of GFT results in metabolic, gastrointestinal and nutritional disturbances [182] . In recent years, efforts to enhance the bioavailability and solubility of GFT by implying novel formulation strategies have gained interest.

Nayek et al. [115] employed Lipoid S PC-3 as a novel lipid and used different concentrations of lipid and poloxamer 407 to prepared GFT SLNs by a modified hot homogenization technique. The average particle size was recorded at 178 nm with a PDI of 0.27. The SLNs showed a > 92% entrapment efficiency and negative zeta potential (−25 mV). In vitro study analysis revealed a steady release (> 90%) over 72 h, followed by initial burst release (25%) of SLNs. The Higuchi model was found to be best fit the release profile. The in vitro cytotoxicity of SLN showed greater antitumor efficacy (cell viability > 65%) than the free drug. After intravenous administration of GFT SLN (20 mg/kg) in female albino Wister rats, differential distribution showed the highest drug concentrations in liver (∼29,000 ng) followed by kidneys (∼22,300 ng), and brain (∼7,100 ng) had the lowest drug concentrations .

GFT NP formulation using poly (e-caprolactone)-PEG-poly(e-caprolactone) polymer was formulated by solid dispersion method by Ni et al. [116] . The formulations were prepared with 9% loading and 92% entrapment efficacy while release profile showed absence of biphasic pattern. In vivo study conducted in A549 tumor cell bearing nude BALB/c mice, GFT NPs significantly increased antitumor efficacy (∼113 d median survival time) with reduced or no side effects, in comparison with free GFT (∼90 d of median survival time). Cell apoptotic rate increased in group treated with GFT NPs (∼65%) than free GFT (50%) and control (∼25%) due to the tumor growth without rapid angiogenesis. Also, the NPs group had significantly lower ki-67, CD31, and EGFR expression levels; thus, they can circumvent problems such as organ toxicity, treatment resistance, and illness recurrence in order to provide superior outcomes.

Lai et al. [117] have developed GFT and curcumin-loaded and polyglutamic acid (PGA) coated NPs (PGA-Gef/Cur NPs), which had a diameter of ∼550 nm, a GFT loading efficacy of 89.5% and curcumin loading efficacy of 100%. The reported NPs were internalized by SAS cells, which markedly decreased their viability. In vivo anti-tumor study conducted in SAS cell xenografted athymic BALB/c nude mice showed that the treatments of PLGA NPs, free Gef and Cur, and PGA-Gef/Cur NPs did not significantly change the appearance or body weight of mice. But as compared to the group receiving only Gef/Cur, the PGA-Gef/Cur NPs considerably reduced tumor growth. The findings have shown that in an in vivo xenograft animal model obtained using SAS cells, PGA-Gef/Cur NPs exhibited better anti-cancer effects than free GFT and curcumin.

Conclusions and future perspectives

smTKIs target specific kinases intracellularly. Although these drugs should selectively inhibit abnormal kinase activity in cancer cells, they still have off-target effects on normal cells that express similar kinase activity leading to adverse or unwanted side effects [183] , [184] . Several smTKIs suffer from suboptimal biopharmaceutical and pharmacokinetic properties, limiting their therapeutic effectiveness and causing inter-patient variations. Therapeutic drug monitoring, dose adjustments and recently precision medicine are increasingly recommended by clinicians to improve therapeutic outcomes of smTKIs. On the other hand, complex formulations and nanomedicines can be employed to improve many of these shortcomings [185] . Though several nanoformulations of smTKIs have shown efficacy in animal models, their clinical translation will require careful development.

A detailed analysis of the biopharmaceutical and pharmacokinetic properties concludes that at least 10, 32 and 30 numbers of smTKIs have a narrow therapeutic index, low bioavailability and high dosing regimens, respectively. >80% of smTKIs are poorly water-soluble; however, a high number of smTKIs (around 44) have low IC 50 values. This clearly indicates that formulation innovations through complex formulations can improve the therapeutic activity of these drugs. Currently, almost all smTKIs are delivered orally, which also leads to high inter-patient and intra-patient variations. Complex formulations through the oral route can be feasible only for drugs that do not possess pH-dependent solubility, like vemurafenib, regorafenib, and trametinib, while drugs such as acalabrutinib, binimetinib, bosutinib, ceritinib, cobimetinib, CZT, DAB, encorafenib, ETB, GFT, larotrectinib, nilotinib and pazopanib will pose significant difficulty. Controlled-release oral formulations may be an attractive choice for delivering low T 1/2 smTKIs, such as acalabrutinib, AXT, binimetinib, bosutinib, encorafenib, ruxolitinib, and tofacitinib, which do not undergo extensive FPM. On the other hand, such formulations for larotrectinib, which undergoes extensive FPM, may not be very productive.

For many smTKIs, changing the route of administration can be a viable approach to improve therapeutic outcomes, especially for the ones with extensive FPM. For example, inhalation-targeted therapy using smTKIs will be a promising approach for treating lung cancer and can effectively target tumor cells. ETB, AFA, OSI, brigatinib, and lorlatinib may be delivered as inhalable formulations. DPI of smTKIs is an active research area, but the determination of IC 50 values specific to inhalation delivery will need to be performed. LPT, neratinib, and pyrotinib are medications approved for treating cancer, such as breast cancer. A breakthrough approach for targeting breast cancer is the development of in situ tough hydrogels. These hydrogels are designed to remain at the application site, slowly releasing medication over time to deliver treatment directly to the cancerous tissue. This approach offers a promising way to deliver targeted therapy to breast cancer patients, potentially improving treatment outcomes and minimizing side effects associated with traditional chemotherapy [186] . Intramuscular and parenteral routes of administration should be considered for smTKIs as patients tend to show compliance with the parenteral route if overall quality of life is improved. Moreover, many smTKIs are recommended to be taken for 21–30 d period, and present technologies in long-acting injectables can conveniently provide drug release rates for this time duration. Since a large number of smTKIs have low IC 50 values, this will enable their formulation as long-acting injectables.

The present studies concerning development of complex nanoformulations of smTKIs have shown an increase in pharmacokinetic parameters (AUC and C max ) and pharmacodynamic endpoints in terms of tumor regression volume and weight. Therefore, significant improvement in drug exposure is already established, which will overcome the suboptimal effectiveness of smTKIs. However, most of these studies have been performed at a dose of 10 mg/kg and administered intravenously. These studies have not yet emphasized the concentration fluctuation in plasma over an extended period of time that may establish their applicability in reducing plasma variation. Similarly, metabolism studies after conventional and nanoformulations should be performed and compared. Most of these studies have revealed increased bioavailability, distribution, tumor suppression and decreased off-target side effects. As several smTKIs become off-patent, it is predicted that complex formulations of these drugs will be more extensively investigated. However, such studies must take into account the physico-chemical and pharmacokinetic-pharmacodynamic properties of the drug molecule for more judicious development. As each smTKIs is approved for a specific cancer type, it should be noted that the heterogeneity of tumor microenvironment for each type of cancer will call for a specific approach to develop a targeted complex formulation of smTKIs. In addition, the manufacturing, sterilization, in vivo-in vitro correlation on release rate and quality control of complex formulations should be standardized within a regulatory framework to enable their clinical translation soon after in vivo efficacy is established.

Conflicts of interest

The authors declare that there are no conflicts of interest.

Footnotes

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.ajps.2024.100980 .

Supplementary materials

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