Resistance mechanisms of non-small cell lung cancer and improvement of treatment effects through nanotechnology: a narrative review

Introduction

Lung cancer remains the leading cause of cancer-related deaths globally, resulting in over 1.7 million deaths annually (1). Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and includes histological subtypes such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (2). Most patients present with advanced-stage disease, and the 5-year survival rate is only around 15% (3). The global age-standardized incidence and mortality rates for lung cancer are 22.4 and 18.0 per 100,000 people, respectively (4). While early-stage NSCLC can be treated with surgery, platinum-based chemotherapy has remained the mainstay of treatment for advanced NSCLC (5). However, limited efficacy and resistance are major obstacles.

The emergence of targeted therapies inhibiting growth factor receptor (GFR), anaplastic lymphoma kinase (ALK), ROS Proto-Oncogene 1 (ROS1), B-raf proto-oncogene (BRAF), and other driver alterations has improved clinical outcomes for NSCLC patients harboring these mutations (6). For example, ositinib [epidermal growth factor receptor (EGFR) inhibitor] has shown superior efficacy than standard EGFR tyrosine kinase inhibitor (TKI) in first-line treatment of advanced NSCLC with positive EGFR mutations (7). Additionally, immune checkpoint inhibitors (ICIs) blocking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death-ligand 1 (PD-L1) have shown durable antitumor activity in subsets of NSCLC (8). However, intrinsic and acquired resistance frequently occur, limiting the effectiveness of targeted therapies and ICIs (9,10). A comprehensive understanding of resistance mechanisms and innovative treatment strategies to overcome resistance is crucial for further improving the survival of NSCLC patients.

Nanotechnology-based drug delivery systems offer opportunities to improve the therapeutic efficacy of chemotherapy by modifying the pharmacokinetics and biodistribution of drugs (11). High polymer nanoparticles, liposomes, dendrimers, and inorganic platforms have been widely used as nano-carriers for various chemotherapeutic agents, demonstrating improved drug accumulation in tumors while reducing systemic exposure and toxicity (12). For example, polymer nanoparticles and liposomes combine to form polymer lipid hybrid nanoparticles (PLHNPs), which have positive properties such as high biocompatibility and stability, and effective drug loading (13). Furthermore, targeting moieties conjugated to nano-carriers provide active tumor-targeting capabilities (14). Nano-formulation aids in overcoming pharmacokinetic resistance barriers, including poor solubility, instability, low bioavailability, and rapid clearance (15,16). Nano-drug delivery also presents opportunities for simultaneous delivery of multiple drugs to attack resistance at multiple levels (17).

This article reviews the molecular mechanisms of resistance in NSCLC and highlights how nanotechnology-based delivery strategies can help overcome these barriers to improve treatment effectiveness. The article also discusses approaches to modulate tumor immunity using nanotechnology-based immunotherapy and the clinical translation of nanotechnology-based methods in the treatment of NSCLC. Rational design of combination nanomedicine strategies that address multiple resistance mechanisms simultaneously is explored. In-depth understanding of the drug resistance mechanism and the innovative treatment strategies to overcome the drug resistance barriers are of crucial importance for further improving the survival rate of NSCLC patients, promoting drug research and development, and monitoring the progress of the disease, etc. We present this article in accordance with the Narrative Review reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1078/rc).

Methods

Databases [PubMed, Cochrane Library, Google Scholar, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang databases] were searched for the literature on resistance mechanisms of NSCLC and the treatment of nanospheres. The relevant literatures are screened out according to the criteria in Table 1.

Resistance mechanisms in NSCLC

Chemoresistance in NSCLC can be categorized into two major types: intrinsic resistance and acquired resistance (18). Intrinsic resistance refers to the inherent tumor characteristics that lack response to the initial drug therapy, while acquired resistance develops during the treatment and leads to recurrence after an initial response. Below, we summarize the key molecular mechanisms of intrinsic and acquired resistance to standard chemotherapy, targeted therapy, and immunotherapy in NSCLC.

Resistance to conventional chemotherapy

Platinum-based drugs such as cisplatin and carboplatin in combination with microtubule-targeting agents (e.g., paclitaxel, docetaxel) or antimetabolites (e.g., gemcitabine, pemetrexed) remain the frontline treatment for advanced NSCLC (5). However, the rapid development of resistance hinders clinical efficacy. The main mechanism involves increased drug efflux mediated by upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (ABCB1), multidrug resistance-associated protein 1 (ABCC1), and breast cancer resistance protein (ABCG2) (19). These transport proteins reduce intracellular drug concentrations below effective levels. Cancer stem cells (CSCs) also exhibit high expression of ABC transporters, driving intrinsic resistance (20).

Other resistance mechanisms include decreased drug uptake, increased drug metabolism/inactivation, DNA repair, and evasion of apoptosis (21). Repair of platinum-DNA adducts mediated by nucleotide excision repair (NER) and mismatch repair (MMR) pathways can promote cancer cell survival (22). Downregulation of copper transporter CTR1/2 limits the uptake of platinum agents (23). Increased synthesis of glutathione and enhanced activity of glutathione S-transferase (GST) facilitate detoxification and efflux of platinum drugs (24). Alterations in pro-apoptotic and anti-apoptotic B-cell lymphoma-2 (Bcl-2) proteins inhibit cell death pathways (25). Epithelial-mesenchymal transition (EMT) leads to a CSC-like phenotype associated with increased invasiveness, stemness, and chemoresistance (26). Overall, multiple mechanisms contribute to intrinsic and acquired resistance to cytotoxic chemotherapy in NSCLC.

Resistance to EGFR inhibitors

EGFR is widely expressed in various tissues and cell membranes and is located on chromosome 7, region 7p12. It belongs to the receptor tyrosine kinase family of EGFRs. EGFR mutation is an independent prognostic factor for NSCLC and is closely related to the overall survival of patients. EGFR TKIs such as gefitinib, erlotinib, and afatinib are standard treatment for NSCLC patients with activating EGFR mutations (27). However, most patients develop acquired resistance within 10–16 months, primarily due to the gatekeeper mutation EGFR T790M (28) or bypass signaling induced by mesenchymal-epithelial transition (MET) factor amplification (29). The third-generation EGFR inhibitor osimertinib can overcome T790M-related resistance and is the most widely used third-generation EGFR TKI. Among patients with advanced NSCLC who have not been treated in the past and have EGFR mutations, patients receiving ositinib treatment have a longer overall survival than those receiving EGFR-TKI in the control group (30). Meanwhile, the application of osimertinib can improve the survival rate of NSCLC patients with brain metastasis (31). However, mechanisms leading to reduced sensitivity to osimertinib include the C797S mutation, loss of T790M, and activation of downstream HER2/HER3/MET pathways (32), with the C797S mutation being the major mechanism of acquired resistance to osimertinib, directly preventing its covalent binding to the EGFR kinase domain (33). Amplification of other oncogenes such as Kirsten rat sarcoma viral oncogene homolog (KRAS), BRAF, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) can also induce resistance by driving parallel signaling pathways (34). Phenotypic conversion to a small cell lung cancer (SCLC) morphology represents another mechanism of resistance (35). Combination therapy with multiple drugs is another viable approach to overcome resistance to third-generation EGFR inhibitors (36).

Resistance to ALK inhibitors

ALK belongs to the insulin receptor superfamily and is located in the p23.2-p23.1 region of chromosome 2. ALK rearrangement occurs in 3–7% of NSCLC patients and results in the activation of ALK kinase signaling (37). Although initial ALK TKIs, such as crizotinib, were effective, acquired resistance develops within 1–2 years (38). To overcome resistance to first-generation ALK inhibitors, second-generation ALK inhibitors have been developed. Second-generation ALK inhibitors, represented by ceritinib and alectinib, demonstrate better clinical efficacy (39). Similar to EGFR TKIs, resistance is typically caused by gatekeeper mutations in ALK and activation of bypass pathways such as EGFR, KIT, and SRC signaling (40). The most common ALK resistance mutations were L1196M and G1269A. The remaining ALK resistance mutations included: C1156Y (2%), G1202R (2%), I1171T (2%), S1206Y (2%), and E1210K (2%) (41). EMT and CSC phenotypic switching also decrease sensitivity to ALK TKIs (42). Combining ALK TKIs with inhibitors targeting bypass pathways represents a strategy to overcome resistance. However, multiple compensatory mechanisms ultimately allow cancer cells to evade the effects of a single drug.

Resistance to ROS1 inhibitors

ROS1 rearrangement occurs in 1–2% of NSCLC patients (43). A phase I study called PROFILE 1001 demonstrated that crizotinib exhibits anti-tumor activity in advanced NSCLC patients with ROS1 rearrangement and shows significant efficacy in treating advanced NSCLC with ROS1 rearrangement (44). Other ROS1 inhibitors, such as ceritinib and brigatinib, have also been developed. Resistance may occur due to the presence of dual mutations S1986Y and S1986F in the ROS1 kinase domain. Functional in vitro studies have shown that ROS1 carrying the S1986Y or S1986F mutation confers resistance to crizotinib and ceritinib (45). Furthermore, research suggests that multiple genes can form fusion mutations with ROS1 as partners. Compared to patients with common fusion partners such as CD74 and SDC4, crizotinib has better efficacy for patients with rare fusion partners, which can guide treatment after the development of resistance (46).

Resistance to BRAF inhibitors

The BRAF gene is a member of the Raf kinase family and primarily functions in regulating the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. The mutation rate of BRAF in NSCLC is approximately 4% (47), with BRAFV600E being the predominant mutation (48). These mutations can activate downstream BRAF and induce BRAF phosphorylation, thereby activating MAPK/ERK kinase (MEK)1/2 kinases. Subsequently, MEK1/2 kinases phosphorylate and activate MAPK, ultimately leading to cell proliferation and differentiation (49). Resistance mechanisms include overexpression of BRAF leading to ineffective BRAF inhibitor (BRAFi) and reactivation of the ERK pathway (50). Splicing variants of BRAFV600E can form dimers independently of renin-angiotensin system (RAS), rendering BRAFi ineffective (51). Activation of A-Raf, serine/threonine-protein kinase (ARAF) and v-raf-1 murine leukemia viral oncogene homolog 1 (CRAF) induces resistance to BRAFi. Monotherapy with MEK inhibitors or their combination with other targeted drugs that affect the MAPK pathway has become a strategy for treating NSCLC with BRAF mutations, and it is critical for delaying the occurrence of resistance (52) (Figure 1).

Figure 1 The main pathways and components that cause drug resistance in non-small cell lung cancer. EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; ROS, reactive oxygen species; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; RAS, renin-angiotensin system; BRAF, v-raf murine sarcoma viral oncogene homolog B1; CRAF, v-raf-1 murine leukemia viral oncogene homolog 1; MEK, MAPK/ERK kinase; ERK, extracellular signal-regulated kinase; STAT, signal transducer and activator of transcription; Bcl, B-cell lymphoma; VAV3, Vav3 oncogene.

Resistance to ICIs

ICIs block immune checkpoints CTLA-4, PD-1, or PD-L1, enhancing anti-tumor immunity and significantly improving clinical outcomes in NSCLC (53). CTLA-4 strongly inhibits T cell proliferation by cross-linking with T-cell receptor kinase (TCK) and CD28 (54). PD-1 activates T cells by binding with PD-L1 and PD-L2 (55). However, intrinsic and acquired resistance remains a challenge. Major factors include insufficient antigen presentation, inadequate infiltration and functional deficiency of effector T cells, and immune suppression mechanisms in the tumor microenvironment (TME) (56). Tumors with low mutation burden or antigen processing defects decrease neoantigen presentation and recognition by cytotoxic T cells (57). Resistance can also be generated by excluding T cells from the TME due to vascular abnormalities or chemokine imbalance (58). Upregulation of alternative immune checkpoints [such as T cell immunoglobulin and mucin domain-containing protein 3 (TIM3), LAG3] can inhibit T cell activity (59). Immunosuppressive effects mediated by regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and M2 tumor-associated macrophages (TAMs) enhance the limitations of ICIs (60). Intrinsic β-catenin or phosphatase and tensin homologue (PTEN) signaling defects in cancer cells can also inhibit T cell recruitment (61). Rational design of combination therapies is needed to overcome these multifaceted resistance mechanisms by enhancing antigen presentation and simultaneously blocking compensatory immune inhibitory pathways.

Nanotechnology strategies to overcome NSCLC resistance

Various nanotechnology-based drug delivery systems have been explored to overcome the limitations of conventional cancer chemotherapy (62). By encapsulating drugs in nanocarriers, issues such as poor water solubility, lack of tumor selectivity, and rapid clearance can be addressed. Additionally, nanocarriers can deliver multiple synergistic drugs simultaneously, providing opportunities to target key resistance pathways and address resistance issues (17). Major nanocarrier platforms used for NSCLC treatment include polymeric nanoparticles, liposomes, dendrimers, micelles, carbon nanotubes, and inorganic nanoparticles (63). Surface functionalization with homing ligands further allows active targeting of tumors (64). Below, we outline how nanotechnology-based drug delivery systems help address various mechanisms of NSCLC resistance.

Overcoming pharmacokinetic resistance

Many chemotherapy drugs have suboptimal pharmacological properties, including low water solubility, high protein binding, and rapid systemic clearance, which limit their bioavailability at tumor sites (65). Encapsulation of hydrophobic drugs in nanocarriers can enhance water solubility and stability, while increasing circulation time by reducing renal clearance and sequestration in the mononuclear phagocyte system (15). Polymeric nanoparticles, liposomes, and micelles prevent premature drug degradation and achieve controlled or stimuli-responsive release to maintain effective drug levels at tumor sites (66). Approaches include the use of poly(lactic-co-glycolic acid) (PLGA)-based nanospheres and polyethyleneimine (PEI)-coated nanospheres. PLGA undergoes hydrolysis in the body to produce biodegradable metabolites, and the resulting mononuclear phagocyte system/nanoparticles (MPs/NPs) exhibit good biocompatibility, biotoxicity, and biodegradability (67,68). PLGA enhances the pharmaceutical/therapeutic performance of anticancer agents, protects drugs from degradation, improves drug stability, and reduces common side effects of cancer drugs, favorably altering their pharmacokinetics and pharmacodynamics. The unique structure of PEI monomers and the presence of numerous primary, secondary, and tertiary amine functional groups in the polymer confer high adhesiveness, cationicity, and reactivity. At physiological pH, positively charged PEI binds to negatively charged heparin sulphate proteoglycans on cell surfaces, facilitating transfection of eukaryotic cells as a gene carrier by binding to DNA (69). The dendritic structure of PEI can protect siRNA and slow down the release rate, allowing more siRNA to enter the cells (70). For example, the encapsulation of bortezomib with hollow mesoporous silica nanospheres can improve the therapeutic efficacy of NSCLC (71). In summary, reconstitution of chemotherapy drugs in nanocarriers enhances pharmacokinetic properties, thereby increasing tumor drug delivery and retention (Figure 2).

Figure 2 The process of constructing, assembling, wrapping, and finally injecting intravenously into mice to the tumor site. PLGA, poly (lactic-co-glycolic acid); PEI, polyethyleneimine.

Enhanced tumor selective drug delivery

The leakage of tumor vascular system combined with impaired lymphatic drainage enhances the permeability and retention (EPR) of nanomaterials in solid tumors, known as passive targeting (72). Nanocarrier delivery also avoids the efflux of free drugs by ABC transporters (73). Active targeting can be achieved by coupling targeting ligands (antibodies, peptides) that overexpress receptors or TME markers. For example, transferrin receptor (TfR)-targeted liposomes and EGFR-targeted polymer nanoparticles have been used to enhance uptake by NSCLC cells (74,75). Ligand-modified nanocarriers achieve a combination of passive and active targeting, further improving the specificity of tumor delivery.

Reducing CSC and EMT-mediated chemotherapy resistance

CSCs exhibit increased expression of ABC transporters, leading to intrinsic drug resistance (20). Nanocarriers can bypass efflux pumps and deliver encapsulated drugs directly to CSCs. For instance, hyaluronic acid-based nanoparticles loaded with cisplatin accumulate more efficiently in lung CSCs than free cisplatin, resulting in reduced tumor growth and metastasis (76). Salinomycin-loaded lipid nanoparticles also decrease the viability of isolated lung CSCs (13). Nanocarriers enhance the inhibition of cell proliferation, increase apoptosis potential, reduce CSCs, and weaken EMT related biomarkers, ultimately increasing the therapeutic effect of 5-FU on colon cancer (77). EMT leads to a phenotype switch to a low-proliferative, stem-like state associated with enhanced chemotherapy resistance (26). However, certain nanocarriers may preferentially target mesenchymal CSC-like cells. For example, PEG-PLGA nanoparticles loaded with paclitaxel exhibit enhanced cytotoxicity against mesenchymal NSCLC cells induced by transforming growth factor-beta (TGF-β) (78). Overall, nanocarrier delivery helps overcome efflux-mediated resistance in CSC and EMT populations.

Modulating pro-survival signaling networks

Carcinogenic pathways such as phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), Ras/Raf/MEK/ERK, and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) promote cancer cell survival, proliferation, and metastasis, representing major resistance mechanisms (79). Nanocarriers can deliver inhibitors targeting these key nodes to shut down aberrant pro-survival signaling. Co-encapsulation of mTOR inhibitor rapamycin and paclitaxel in folate-targeted nanoparticles enhances apoptosis and tumor regression in NSCLC xenografts compared to individual drugs alone (80). Lipid-polymer hybrid nanoparticles co-loaded with EGFR siRNA and cisplatin also improve EGFR downregulation and cytotoxicity (81). Other studies utilize nanoparticle co-delivery of MEK + Bcl-2 inhibitors or STAT3 + paclitaxel to block pro-survival signaling and enhance sensitivity of NSCLC cells to chemotherapy (82,83). These combinatorial approaches demonstrate the utility of nanocarriers in simultaneously modulating multiple resistance nodes to improve therapeutic efficacy.

Modulating the tumor immune microenvironment

Immune response plays a crucial role in cancer treatment outcomes. Nanotechnology-based delivery of immune modulators offers opportunities to reverse immune suppression and enhance anti-tumor immunity in the TME to overcome resistance (84). Liposome-based delivery of anti-CTLA4 antibody enhances tumor-infiltrating T cells and cytotoxic activity (85). Nanoparticle delivery of anti-PD1 antibody demonstrates improved pharmacokinetics and anti-tumor efficacy compared to free antibodies (86). Delivery of immune-stimulating cytokines by nanocarriers promotes dendritic cell maturation and activation of cytotoxic T cells (87). For instance, exosome-mimetic nanovesicles loaded with interleukin-2 (IL-2) and TGF-β increase the infiltration of NK cells in tumors (88). Nanocarriers can also deliver chemotherapy drugs, metabolites, or siRNA to modulate immune-suppressive cell populations. Platinum-albumin nanoparticles reduce MDSCs, while gemcitabine-geranylgeraniol nanoparticles decrease M2 macrophages, collectively enhancing immune therapy (89,90). Overall, nanomedicine-based immunotherapy approaches hold promise in overcoming immune-related resistance mechanisms.

Stimuli-responsive triggered drug release

Customized nanocarriers are designed to release their payload in response to TME cues, enhancing site-specific drug delivery while avoiding systemic toxicity (91). pH-sensitive nanocarriers utilize the acidic tumor stroma to trigger selective drug release. Temperature-sensitive liposomes and polymers have been designed to trigger drug release at mild hyperthermia. Oxidation-reduction-sensitive platforms utilize the higher levels of glutathione in tumors to trigger payload release. Matrix metalloproteinase (MMP) responsive and enzyme-activatable systems further enable localized drug activation. Stimuli-triggered nanodelivery achieves on-demand drug release to improve the pharmacokinetics at the tumor site while avoiding systemic exposure.

Innovative applications and strategic optimization of nanoparticles in cancer therapy

Compared to treatment strategies without nanoparticles, the use of nanoparticle-based combinatorial strategies may inherently carry certain toxicity risks, such as potential cellular damage upon cellular uptake of nanoparticles and activation of the immune system. To mitigate these toxicity risks associated with nanoparticles, we propose the following measures: optimizing nanoparticle design by selecting biocompatible materials and refining particle size, shape, and surface properties to minimize cellular uptake and immune responses; conducting rigorous toxicity assessments, encompassing acute, long-term, and genetic toxicities; and addressing the cost concerns related to nanoparticles, which may involve higher expenses in preparation, purification, characterization, and clinical application. Scaling up production and fostering technological innovations can help reduce the cost per unit of nanoparticles. Additionally, securing policy support and financial subsidies from governments and relevant institutions is crucial to facilitating the clinical translation and application of nanoparticles.

In clinical practice, patients often receive first-line therapy initially and then switch to second-line therapy upon developing drug resistance. However, nanoparticle-based combinatorial strategies offer a new perspective and potential solutions. For instance, for patients known to have specific resistance mechanisms or a high risk of developing resistance, nanoparticle-based combinatorial strategies can be introduced during first-line therapy to prevent or delay the onset of resistance. For patients who develop resistance during first-line therapy, these strategies can serve as an effective second-line or subsequent treatment option. In such cases, nanoparticles can deliver drugs targeted at the resistance mechanisms, such as targeted therapies against specific resistant mutations or immunomodulators, to overcome resistance and restore therapeutic efficacy. Furthermore, nanoparticles can simultaneously deliver multiple drugs with synergistic effects, further enhancing treatment outcomes.

No single drug can address the multiple resistance mechanisms in NSCLC, and a nanoparticle-based combination strategy is a viable solution. Nanocarriers provide a platform for simultaneously delivering synergistic drug combinations targeting non-overlapping resistance pathways (17). We focus on integrating drugs with different mechanisms into nanocarriers or utilizing dual-functional nanotherapies to address multiple levels of resistance. This rational combination approach is expected to overcome the inherent limitations of single treatments for NSCLC.

Blocking multiple survival signaling nodes

Aberrant activation of interlinked oncogenic signaling, including EGFR/MAPK/PI3K pathways, frequently occurs in NSCLC, providing survival advantages and resistance to targeted therapies (92). Co-delivery of inhibitors targeting EGFR, MEK, and other key nodes using nanocarriers may achieve enhanced pathway inhibition. PLGA nanoparticles loaded with gefitinib and the PI3K inhibitor LY294002 overcome compensatory signaling by simultaneously blocking EGFR and PI3K (93). Combining inhibition of EGFR tyrosine kinase and downstream survival signals can prevent or delay acquired resistance caused by pathway reactivation or bypass mechanisms.

DNA repair inhibition plus DNA damaging agents

Platinum-based drugs such as cisplatin exert cytotoxicity by inducing DNA damage (94). Resistance mechanisms include enhanced nucleotide excision DNA repair. Co-delivery of platinum drugs with DNA repair inhibitors can enhance anticancer efficacy. Indeed, liposomal nanoparticles co-loaded with cisplatin and curcumin enhance DNA damage and cell apoptosis in NSCLC compared to the individual use of any drug (95). This demonstrates the potential of combining standard chemotherapy with the use of nanocarriers targeting relevant resistance pathways.

Induction of immunogenic cell death (ICD) plus immune activation

The opportunity for synergistic enhancement of antitumor immunity is provided by ICD induced by selective anticancer drugs combined with immune stimulation (96). Nanocarriers can co-deliver drugs that induce ICD (such as doxorubicin and oxaliplatin) with immune-stimulating cytokines (IL-2, IFN-γ) or checkpoint inhibitors. Co-encapsulation of oxaliplatin and Toll-like receptor 3 (TLR3) agonist poly(I:C) in micelles leads to synergistic induction of ICD (97). Co-delivery of dendrimer-based multi-doxorubicin and TLR7/8 agonist resiquimod also enhances cytotoxicity and immune activation (98). Combining nanocarrier-mediated ICD induction with immune checkpoint blockade or adoptive T-cell therapy can further enhance therapeutic immune responses and improve the treatment of NSCLC.

Targeting CSCs + bulk tumor cells

CSCs are a resistant subpopulation capable of tumor regeneration after chemotherapy (20). Clearing CSCs and bulk tumor cells is crucial for preventing relapse. In in vitro experiments, nanoparticles co-loaded with salinomycin selectively targeted CSCs and paclitaxel killed bulk tumor cells, reducing the survival capacity of both populations (99). In vivo co-administration of the CSC inhibitor metformin and the chemotherapy drug docetaxel suppressed lung tumor growth and metastasis compared to monotherapy (100). Rational integration of CSC-targeting drugs with standard therapies into nanocarriers may help prevent the persistence-driven resistance caused by CSCs.

Conclusions

In conclusion, multiple mechanisms, including target alterations, bypass signaling, phenotypic switching, CSC persistence, and immune suppression, contribute to chemoresistance in NSCLC. Nanotechnology-based delivery systems offer opportunities to overcome intracellular, pharmacokinetic, and microenvironment-mediated resistance by enhancing tumor drug accumulation, targeted delivery, controlled release, and combination therapy. Early clinical studies have demonstrated the safety and efficacy of nanoscale formulations of chemotherapy drugs, including paclitaxel, cisplatin, and doxorubicin, in various solid tumors (101). However, the development of nanomedicines is still hindered by challenges such as reproducible large-scale production, batch-to-batch variability, and cost. Further research is needed to identify optimal nanoparticle designs, drug combinations, and treatment strategies to address resistance in NSCLC.

Future directions should emphasize the rational integration of novel insights into NSCLC resistance mechanisms with innovative nanotechnology-based solutions. Key research directions include: (I) elucidating how nanocarrier characteristics influence delivery and efficacy against specific NSCLC resistant phenotypes using advanced in vitro models; (II) systematically screening nanoparticle formulations and drug combinations in vivo to model resistance mechanisms from patient-derived xenografts representing diverse resistant populations; (III) optimizing stimulus-responsive nanocarriers to achieve dynamic control of drug release kinetics in the TME, improving pharmacokinetics; (IV) developing new targeting approaches using ligand-modified nanocarriers against NSCLC stem-like cells and immune-suppressive TME; (V) designing combined nanotherapeutic strategies that concurrently modulate multiple resistance nodes (e.g., DNA repair inhibition + platinum drug delivery); (VI) translating promising nanomaterial formulations into large-scale cGMP production processes and conducting clinical trials in NSCLC patients; (VII) correlating clinical outcomes with tumor molecular profiles to identify biomarker features associated with response to nanotherapeutic interventions.

In general, advancing these research pathways will provide innovative nanomedical platforms to address the complex heterogeneity and resistance pathways in NSCLC. By offering new treatment options for patients with platinum-refractory disease or those making progress in targeted and immune therapies, nanotechnology-based drug delivery systems have tremendous potential to make a clinical impact and improve prognosis in this deadly malignancy. Continuous collaboration among nanomaterial engineering, precision medicine, and clinical oncology is a necessary prerequisite for translating promising concepts into translational solutions to overcome NSCLC resistance.

Acknowledgments

Funding: This study was supported by grants from Wu Jieping Medical Foundation (No. HXKT20221037), National Science Fund Subsidized Project (No. 82300412), Science and Technology Bureau of Nantong (No. JC2021184), and Nantong University Affiliated Hospital Doctoral Research Start-up Fund Project (No. Tdb2005).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1078/rc

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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-1078/coif). The authors have no conflicts of interest to declare.

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References

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. [Crossref] [PubMed]
2. Hirsch FR, Scagliotti GV, Mulshine JL, et al. Lung cancer: current therapies and new targeted treatments. Lancet 2017;389:299-311. [Crossref] [PubMed]
3. Löfling L, Bahmanyar S, Kieler H, et al. Temporal trends in lung cancer survival: a population-based study. Acta Oncol 2022;61:625-31. [Crossref] [PubMed]
4. Huang J, Deng Y, Tin MS, et al. Distribution, Risk Factors, and Temporal Trends for Lung Cancer Incidence and Mortality: A Global Analysis. Chest 2022;161:1101-11. [Crossref] [PubMed]
5. Rossi A, Di Maio M. Platinum-based chemotherapy in advanced non-small-cell lung cancer: optimal number of treatment cycles. Expert Rev Anticancer Ther 2016;16:653-60. [Crossref] [PubMed]
6. Pao W, Chmielecki J. Rational, biologically based treatment of EGFR-mutant non-small-cell lung cancer. Nat Rev Cancer 2010;10:760-74. [Crossref] [PubMed]
7. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:113-25. [Crossref] [PubMed]
8. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54. [Crossref] [PubMed]
9. Gainor JF, Shaw AT. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J Clin Oncol 2013;31:3987-96. [Crossref] [PubMed]
10. Nagasaki J, Ishino T, Togashi Y. Mechanisms of resistance to immune checkpoint inhibitors. Cancer Sci 2022;113:3303-12. [Crossref] [PubMed]
11. Garbayo E, Pascual-Gil S, Rodríguez-Nogales C, et al. Nanomedicine and drug delivery systems in cancer and regenerative medicine. Wiley Interdiscip Rev Nanomed Nanobiotechnol 2020;12:e1637. [Crossref] [PubMed]
12. Bertrand N, Wu J, Xu X, et al. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Deliv Rev 2014;66:2-25. [Crossref] [PubMed]
13. Mohanty A, Uthaman S, Park IK. Utilization of Polymer-Lipid Hybrid Nanoparticles for Targeted Anti-Cancer Therapy. Molecules 2020;25:4377. [Crossref] [PubMed]
14. Danhier F. To exploit the tumor microenvironment: Since the EPR effect fails in the clinic, what is the future of nanomedicine? J Control Release 2016;244:108-21. [Crossref] [PubMed]
15. Curić A, Reul R, Möschwitzer J, et al. Formulation optimization of itraconazole loaded PEGylated liposomes for parenteral administration by using design of experiments. Int J Pharm 2013;448:189-97. [Crossref] [PubMed]
16. Huang J, Li Y, Orza A, et al. Magnetic Nanoparticle Facilitated Drug Delivery for Cancer Therapy with Targeted and Image-Guided Approaches. Adv Funct Mater 2016;26:3818-36. [Crossref] [PubMed]
17. Huang S, Zhao Q. Nanomedicine-Combined Immunotherapy for Cancer. Curr Med Chem 2020;27:5716-29. [Crossref] [PubMed]
18. Holohan C, Van Schaeybroeck S, Longley DB, et al. Cancer drug resistance: an evolving paradigm. Nat Rev Cancer 2013;13:714-26. [Crossref] [PubMed]
19. Wu S, Singh RK. Resistance to chemotherapy and molecularly targeted therapies: rationale for combination therapy in malignant melanoma. Curr Mol Med 2011;11:553-63. [Crossref] [PubMed]
20. Singh A, Settleman J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010;29:4741-51. [Crossref] [PubMed]
21. Wium M, Ajayi-Smith AF, Paccez JD, et al. The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications. Cancers (Basel) 2021;13:1521. [Crossref] [PubMed]
22. Alhegaili AS. Role of DNA Repair Deficiency in Cancer Development. Pak J Biol Sci 2023;26:15-22. [Crossref] [PubMed]
23. Yong L, Shi Y, Wu HL, et al. p53 inhibits CTR1-mediated cisplatin absorption by suppressing SP1 nuclear translocation in osteosarcoma. Front Oncol 2022;12:1047194. [Crossref] [PubMed]
24. Zhao Q, Liang G, Guo B, et al. Polyphotosensitizer-Based Nanoparticles with Michael Addition Acceptors Inhibiting GST Activity and Cisplatin Deactivation for Enhanced Chemotherapy and Photodynamic Immunotherapy. Adv Sci (Weinh) 2023;10:e2300175. [Crossref] [PubMed]
25. Delbridge AR, Grabow S, Strasser A, et al. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat Rev Cancer 2016;16:99-109. [Crossref] [PubMed]
26. Fischer KR, Durrans A, Lee S, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature 2015;527:472-6. [Crossref] [PubMed]
27. Li AR, Chitale D, Riely GJ, et al. EGFR mutations in lung adenocarcinomas: clinical testing experience and relationship to EGFR gene copy number and immunohistochemical expression. J Mol Diagn 2008;10:242-8. [Crossref] [PubMed]
28. Yun CH, Mengwasser KE, Toms AV, et al. The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A 2008;105:2070-5. [Crossref] [PubMed]
29. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039-43. [Crossref] [PubMed]
30. Ramalingam SS, Vansteenkiste J, Planchard D, et al. Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC. N Engl J Med 2020;382:41-50. [Crossref] [PubMed]
31. Yu X, Sheng J, Pan G, et al. Real-world utilization of EGFR TKIs and prognostic factors for survival in EGFR-mutated non-small cell lung cancer patients with brain metastases. Int J Cancer 2021;149:1121-8. [Crossref] [PubMed]
32. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013;19:2240-7. [Crossref] [PubMed]
33. Kashima K, Kawauchi H, Tanimura H, et al. CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation. Mol Cancer Ther 2020;19:2288-97. [Crossref] [PubMed]
34. Prahallad A, Sun C, Huang S, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012;483:100-3. [Crossref] [PubMed]
35. Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26. [Crossref] [PubMed]
36. Thomas QD, Firmin N, Mbatchi L, et al. Combining Three Tyrosine Kinase Inhibitors: Drug Monitoring Is the Key. Int J Mol Sci 2023;24:5518. [Crossref] [PubMed]
37. Solomon BJ, Mok T, Kim DW, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med 2014;371:2167-77. [Crossref] [PubMed]
38. Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med 2012;4:120ra17. [Crossref] [PubMed]
39. Horn L, Wang Z, Wu G, et al. Ensartinib vs Crizotinib for Patients With Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer: A Randomized Clinical Trial. JAMA Oncol 2021;7:1617-25. [Crossref] [PubMed]
40. Lovly CM, McDonald NT, Chen H, et al. Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med 2014;20:1027-34. [Crossref] [PubMed]
41. Gainor JF, Dardaei L, Yoda S, et al. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer. Cancer Discov 2016;6:1118-33. [Crossref] [PubMed]
42. Wang F, Ying HQ, He BS, et al. Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway. Oncotarget 2015;6:7899-917. [Crossref] [PubMed]
43. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-70. [Crossref] [PubMed]
44. Shaw AT, Riely GJ, Bang YJ, et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): updated results, including overall survival, from PROFILE 1001. Ann Oncol 2019;30:1121-6. [Crossref] [PubMed]
45. Facchinetti F, Loriot Y, Kuo MS, et al. Crizotinib-Resistant ROS1 Mutations Reveal a Predictive Kinase Inhibitor Sensitivity Model for ROS1- and ALK-Rearranged Lung Cancers. Clin Cancer Res 2016;22:5983-91. [Crossref] [PubMed]
46. Ou SI, Nagasaka M. A Catalog of 5' Fusion Partners in ROS1-Positive NSCLC Circa 2020. JTO Clin Res Rep 2020;1:100048. [Crossref] [PubMed]
47. Negrao MV, Raymond VM, Lanman RB, et al. Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations. J Thorac Oncol 2020;15:1611-23. [Crossref] [PubMed]
48. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature 2002;417:949-54. [Crossref] [PubMed]
49. Murphy T, Hori S, Sewell J, et al. Expression and functional role of negative signalling regulators in tumour development and progression. Int J Cancer 2010;127:2491-9. [Crossref] [PubMed]
50. Johnson DB, Menzies AM, Zimmer L, et al. Acquired BRAF inhibitor resistance: A multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. Eur J Cancer 2015;51:2792-9. [Crossref] [PubMed]
51. Vido MJ, Le K, Hartsough EJ, et al. BRAF Splice Variant Resistance to RAF Inhibitor Requires Enhanced MEK Association. Cell Rep 2018;25:1501-1510.e3. [Crossref] [PubMed]
52. Han J, Liu Y, Yang S, et al. MEK inhibitors for the treatment of non-small cell lung cancer. J Hematol Oncol 2021;14:1. [Crossref] [PubMed]
53. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
54. Watanabe T, Ishino T, Ueda Y, et al. Activated CTLA-4-independent immunosuppression of Treg cells disturbs CTLA-4 blockade-mediated antitumor immunity. Cancer Sci 2023;114:1859-70. [Crossref] [PubMed]
55. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 2008;26:677-704. [Crossref] [PubMed]
56. Sharma P, Hu-Lieskovan S, Wargo JA, et al. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 2017;168:707-23. [Crossref] [PubMed]
57. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499:214-8. [Crossref] [PubMed]
58. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature 2017;541:321-30. [Crossref] [PubMed]
59. Koyama S, Akbay EA, Li YY, et al. Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun 2016;7:10501. [Crossref] [PubMed]
60. Marvel D, Gabrilovich DI. Myeloid-derived suppressor cells in the tumor microenvironment: expect the unexpected. J Clin Invest 2015;125:3356-64. [Crossref] [PubMed]
61. Spranger S. Mechanisms of tumor escape in the context of the T-cell-inflamed and the non-T-cell-inflamed tumor microenvironment. Int Immunol 2016;28:383-91. [Crossref] [PubMed]
62. Shi J, Kantoff PW, Wooster R, et al. Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 2017;17:20-37. [Crossref] [PubMed]
63. Bor G, Mat Azmi ID, Yaghmur A. Nanomedicines for cancer therapy: current status, challenges and future prospects. Ther Deliv 2019;10:113-32. [Crossref] [PubMed]
64. Danhier F, Ucakar B, Magotteaux N, et al. Active and passive tumor targeting of a novel poorly soluble cyclin dependent kinase inhibitor, JNJ-7706621. Int J Pharm 2010;392:20-8. [Crossref] [PubMed]
65. Savla R, Taratula O, Garbuzenko O, et al. Tumor targeted quantum dot-mucin 1 aptamer-doxorubicin conjugate for imaging and treatment of cancer. J Control Release 2011;153:16-22. [Crossref] [PubMed]
66. Sun T, Zhang YS, Pang B, et al. Engineered nanoparticles for drug delivery in cancer therapy. Angew Chem Int Ed Engl 2014;53:12320-64. [Crossref] [PubMed]
67. Acharya S, Sahoo SK. PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Adv Drug Deliv Rev 2011;63:170-83. [Crossref] [PubMed]
68. Ding D, Zhu Q. Recent advances of PLGA micro/nanoparticles for the delivery of biomacromolecular therapeutics. Mater Sci Eng C Mater Biol Appl 2018;92:1041-60. [Crossref] [PubMed]
69. Jere D, Jiang HL, Arote R, et al. Degradable polyethylenimines as DNA and small interfering RNA carriers. Expert Opin Drug Deliv 2009;6:827-34. [Crossref] [PubMed]
70. Chang PKC, Prestidge CA, Bremmell KE. Interfacial analysis of siRNA complexes with poly-ethylenimine (PEI) or PAMAM dendrimers in gene delivery. Colloids Surf B Biointerfaces 2017;158:370-8. [Crossref] [PubMed]
71. Shen J, Song G, An M, et al. The use of hollow mesoporous silica nanospheres to encapsulate bortezomib and improve efficacy for non-small cell lung cancer therapy. Biomaterials 2014;35:316-26. [Crossref] [PubMed]
72. Nakamura Y, Mochida A, Choyke PL, et al. Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer? Bioconjug Chem 2016;27:2225-38. [Crossref] [PubMed]
73. Miller MA, Gadde S, Pfirschke C, et al. Predicting therapeutic nanomedicine efficacy using a companion magnetic resonance imaging nanoparticle. Sci Transl Med 2015;7:314ra183. [Crossref] [PubMed]
74. Mohd Zaffarin AS, Ng SF, Ng MH, et al. Pharmacology and Pharmacokinetics of Vitamin E: Nanoformulations to Enhance Bioavailability. Int J Nanomedicine 2020;15:9961-74. [Crossref] [PubMed]
75. Patil YB, Toti US, Khdair A, et al. Single-step surface functionalization of polymeric nanoparticles for targeted drug delivery. Biomaterials 2009;30:859-66. [Crossref] [PubMed]
76. Han Y, Wen P, Li J, et al. Targeted nanomedicine in cisplatin-based cancer therapeutics. J Control Release 2022;345:709-20. [Crossref] [PubMed]
77. Azarifar Z, Amini R, Tanzadehpanah H, et al. In vitro co-delivery of 5-fluorouracil and all-trans retinoic acid by PEGylated liposomes for colorectal cancer treatment. Mol Biol Rep 2023;50:10047-59. [Crossref] [PubMed]
78. Meylina L, Muchtaridi M, Joni IM, et al. Nanoformulations of alpha-Mangostin for Cancer Drug Delivery System. Pharmaceutics 2021;13:1993. [Crossref] [PubMed]
79. Asati V, Mahapatra DK, Bharti SK. PI3K/Akt/mTOR and Ras/Raf/MEK/ERK signaling pathways inhibitors as anticancer agents: Structural and pharmacological perspectives. Eur J Med Chem 2016;109:314-41. [Crossref] [PubMed]
80. Fan S, Zheng Y, Liu X, et al. Curcumin-loaded PLGA-PEG nanoparticles conjugated with B6 peptide for potential use in Alzheimer's disease. Drug Deliv 2018;25:1091-102. [Crossref] [PubMed]
81. Busa P, Kankala RK, Deng JP, et al. Conquering Cancer Multi-Drug Resistance Using Curcumin and Cisplatin Prodrug-Encapsulated Mesoporous Silica Nanoparticles for Synergistic Chemo- and Photodynamic Therapies. Nanomaterials (Basel) 2022;12:3693. [Crossref] [PubMed]
82. He Z, Huang J, Xu Y, et al. Co-delivery of cisplatin and paclitaxel by folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles for the treatment of non-small lung cancer. Oncotarget 2015;6:42150-68. [Crossref] [PubMed]
83. Fan L, Li F, Zhang H, et al. Co-delivery of PDTC and doxorubicin by multifunctional micellar nanoparticles to achieve active targeted drug delivery and overcome multidrug resistance. Biomaterials 2010;31:5634-42. [Crossref] [PubMed]
84. Yang J, Kopeček J. Macromolecular therapeutics. J Control Release 2014;190:288-303. [Crossref] [PubMed]
85. Singh P, Pandit S, Mokkapati VRSS, et al. Gold Nanoparticles in Diagnostics and Therapeutics for Human Cancer. Int J Mol Sci 2018;19:1979. [Crossref] [PubMed]
86. Yu X, Fang C, Zhang K, et al. Recent Advances in Nanoparticles-Based Platforms Targeting the PD-1/PD-L1 Pathway for Cancer Treatment. Pharmaceutics 2022;14:1581. [Crossref] [PubMed]
87. Sherje AP, Jadhav M, Dravyakar BR, et al. Dendrimers: A versatile nanocarrier for drug delivery and targeting. Int J Pharm 2018;548:707-20. [Crossref] [PubMed]
88. Fan Y, Kuai R, Xu Y, et al. Immunogenic Cell Death Amplified by Co-localized Adjuvant Delivery for Cancer Immunotherapy. Nano Lett 2017;17:7387-93. [Crossref] [PubMed]
89. Zhao J, Du G, Sun X. Tumor Antigen-Based Nanovaccines for Cancer Immunotherapy: A Review. J Biomed Nanotechnol 2021;17:2099-113. [Crossref] [PubMed]
90. Chacon EL, Bertolo MRV, de Guzzi Plepis AM, et al. Collagen-chitosan-hydroxyapatite composite scaffolds for bone repair in ovariectomized rats. Sci Rep 2023;13:28. [Crossref] [PubMed]
91. Xu X, Ho W, Zhang X, et al. Cancer nanomedicine: from targeted delivery to combination therapy. Trends Mol Med 2015;21:223-32. [Crossref] [PubMed]
92. Cui JJ, Tran-Dubé M, Shen H, et al. Structure based drug design of crizotinib (PF-02341066), a potent and selective dual inhibitor of mesenchymal-epithelial transition factor (c-MET) kinase and anaplastic lymphoma kinase (ALK). J Med Chem 2011;54:6342-63. [Crossref] [PubMed]
93. Ghosh B, Biswas S. Polymeric micelles in cancer therapy: State of the art. J Control Release 2021;332:127-47. [Crossref] [PubMed]
94. Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 2014;740:364-78. [Crossref] [PubMed]
95. Yallapu MM, Maher DM, Sundram V, et al. Curcumin induces chemo/radio-sensitization in ovarian cancer cells and curcumin nanoparticles inhibit ovarian cancer cell growth. J Ovarian Res 2010;3:11. [Crossref] [PubMed]
96. Kroemer G, Galluzzi L, Kepp O, et al. Immunogenic cell death in cancer therapy. Annu Rev Immunol 2013;31:51-72. [Crossref] [PubMed]
97. Shen F, Feng L, Zhu Y, et al. Oxaliplatin-/NLG919 prodrugs-constructed liposomes for effective chemo-immunotherapy of colorectal cancer. Biomaterials 2020;255:120190. [Crossref] [PubMed]
98. Wang-Gillam A, Plambeck-Suess S, Goedegebuure P, et al. A phase I study of IMP321 and gemcitabine as the front-line therapy in patients with advanced pancreatic adenocarcinoma. Invest New Drugs 2013;31:707-13. [Crossref] [PubMed]
99. Li L, Cui D, Ye L, et al. Codelivery of salinomycin and docetaxel using poly(D,L-lactic-co-glycolic acid)-poly(ethylene glycol) nanoparticles to target both gastric cancer cells and cancer stem cells. Anticancer Drugs 2017;28:989-1001. [Crossref] [PubMed]
100. Kuai R, Yuan W, Li W, et al. Targeted delivery of cargoes into a murine solid tumor by a cell-penetrating peptide and cleavable poly(ethylene glycol) comodified liposomal delivery system via systemic administration. Mol Pharm 2011;8:2151-61. [Crossref] [PubMed]
101. Bobo D, Robinson KJ, Islam J, et al. Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date. Pharm Res 2016;33:2373-87. [Crossref] [PubMed]