Nanomedicine Applications in Lung Cancer Drug Resistance Management: Comparison
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Please note this is a comparison between Version 2 by Lindsay Dong and Version 1 by Mohamed Haider.

Lung cancer (LC) is one of the leading causes of cancer occurrence and mortality worldwide. Treatment of patients with advanced and metastatic LC presents a significant challenge, as malignant cells use different mechanisms to resist chemotherapy. Drug resistance (DR) is a complex process that occurs due to a variety of genetic and acquired factors. Identifying the mechanisms underlying DR in LC patients and possible therapeutic alternatives for more efficient therapy is a central goal of LC research. Advances in nanotechnology resulted in the development of targeted and multifunctional nanoscale drug constructs. The possible modulation of the components of nanomedicine, their surface functionalization, and the encapsulation of various active therapeutics provide promising tools to bypass crucial biological barriers. These attributes enhance the delivery of multiple therapeutic agents directly to the tumor microenvironment (TME), resulting in reversal of LC resistance to anticancer treatment. 

  • nanomedicine
  • drug resistance
  • lung cancer

1. Introduction

The therapeutic effectiveness of chemotherapeutic agents is limited due to the development of DR in cancer cells [5][1]. Cancer DR is the ability of the tumor cells to develop a certain mechanism to overcome and resist the cytotoxic or inhibitory effect of the chemotherapeutic agent and therefore reduce the effectiveness of chemotherapy [6][2]. Currently, the failure of chemotherapy due to DR accounts for 90% of clinical metastasis cases [6][2]. To overcome DR, chemotherapeutic agents need to be administered at larger doses with higher frequency, which in turn may result in increased toxicity and lower patient survival rate. Alternatively, a combination of two or more chemotherapeutic agents may be administered to achieve a synergistic effect and reduce the rate of DR [7][3]. This approach has improved the effectiveness of chemotherapy but has not yet eliminated the side effects associated with non-specific uptake by normal cells.

Over the last two decades, nanotechnology has played a major role in the delivery of medicinal agents to overcome the obstacles of conventional therapy [8,9][4][5]. A range of different types of nanocarriers (1 to 500 nm) has been developed for the delivery of drug molecules, nucleic acid, and diagnostic agents [10,11,12,13,14,15][6][7][8][9][10][11].
The use of nanoparticles (NPs) as carriers for chemotherapeutic agents has significantly improved their effectiveness, safety, stability, and pharmacokinetic profile [9,12,16][5][8][12]. Biocompatible nanocarriers can be tailored to suit the pathophysiology of the tumors and enhance the physicochemical properties of the drug and its permeability and retention time due to their unique sizes and possible surface modifications [12,14,16,17][8][10][12][13]. Furthermore, improvement in drug targeting by encapsulation in suitable NPs reduces the adverse effects associated with chemotherapy as normal cells are protected from the cytotoxic effect of the anticancer drugs [12,16,18][8][12][14]. Several strategies have been used for the encapsulation and loading of the therapeutic agent on the nano system. The selected techniques depend on the formulation procedure, carrier system, and physio-chemical properties of the pristine agent (Figure 1). Anticancer drugs may be loaded within the empty core of the NPs (Reservoir system), distributed evenly within the polymer matrix (Matrix system), conjugated covalently to the nanocarrier (Covalently bound system), or have an ionic interaction between oppositely charged ions (Ionic interaction system) [19][15].
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Figure 1.
General therapy loading strategies in nanoparticle systems.

2. Nanomedicine Applications in Management of Lung Cancer Drug Resistance

2.1. Tumor Microenvironment

Cancer cells can control and influence the function of their environment by releasing complex signaling networks for their own benefits. Thus, cancer cells exist in a dynamic interaction with their surrounding environment that consists of cells and non-cell components, which allows them to evolve and grow, resulting in cancer progression, metastasis, and DR (Figure 2) [20][16]. TME includes stromal cells, which mainly consist of tumor epithelial cells, cancer-associated fibroblasts (CAFs), and immune cells. Non-cellular factors include extracellular matrix (ECM) components, such as growth factors, degradation enzymes, and inflammatory mediators. They also include exosomes and apoptotic bodies, in which they are known as extracellular vehicles (EVs). Moreover, the TME has special unique features, including hypoxia and an acidic environment [21,22,23][17][18][19]. These predominantly arise due to the insufficient blood supply and oxygen deprivation associated with the rapid and uncontrolled proliferation of cancer cells. Reactive oxygen species (ROS) are also generated well beyond their normal levels, which induces further mutations and carcinogenesis at the tumor site. Recent studies have outlined the ability of ROS to engage with CAFs in a two-way cross-talk, where CAFs increase the levels of ROS observed in the tumor tissue, promoting cancer growth and invasiveness, while ROS activate the CAFs through the upregulation of HIF1α [24][20]. The lung TME plays an imminent role in cancer cell resistance by interfering with the pharmacokinetic distribution of the anticancer agent [25][21]. The uncontrolled angiogenic activity, dense desmoplastic stromal layer, and abnormal interstitial and oncogenic pressures compromise the activity of the chemotherapeutics in inducing their cytotoxic activity [26][22]. In addition, the cross-talk between tumor and stromal cells modulates the response to these agents and reduces their potential within the microenvironment [27][23]. Poor immune cell infiltration and activation induced by the harsh conditions surrounding the tumor cells is of great importance to tumor proliferation and metastasis [28][24]. The infiltrating immune cells also play a dualistic role in the tumor tissue by either suppressing or promoting cancer progression according to their type and their effect on manipulating the unique setting of the tumor within the TME. This is highly dependent on the cross talk associated with the ongoing cytokines produced and their interaction with the tumor cells. Several different types of immune cells have been detected in the lung TME, including Natural Killer (NK) cells, T lymphocytes, macrophages, dendritic cells, Myeloid-derived suppressor cells, and B cells; however, their immunomodulatory properties within the tumor tissue have yet to be further explored [29][25]. These barriers lead to a decline in the intracellular accumulation of the anticancer agents, an increase in tumor-acquired resistance, and poorer clinical outcomes.
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Figure 2.
Representation of cellular components of TME in LC.
NPs have long been sought to overcome the limitations associated with the unique tumor setting within LC [25,30,31][21][26][27]. Given their inherent passive targeting enhanced permeation and retention (EPR) properties, alongside their ability to be actively formulated to utilize the internal factors regulating the TME, NPs may well improve the clinical response to the therapy in question [32][28]. Recent studies outlined how novel nano delivery systems could be prepared to exploit current TME hindrances in LC, such as the acidic nature of the microenvironment, increased accumulation of reactive oxygen species (ROS), expression of unique antigens at the tumor site, activation of immunogenic tissue as an immunomodulatory therapy, or external stimuli-triggered drug release, among others, achieving a relatively higher targeted activity in the tumor cell than with conventional therapy [33,34,35,36,37][29][30][31][32][33]. Enhancing the immunotherapeutic outcome of current immunotherapy using NPs in LC has also been explored through the preparation of a combinatorial chemotherapy/immunotherapy Polo-like kinase 1 (PLK1) inhibitor (Volasertib)—loaded mesoporous silica NPs decorated with an PD-L1 antibody. PLK1 is an important mitotic kinase that is overexpressed in LC-promoting oncogenesis and tumor metastasis. PD-L1 expression in tumor cells inhibits tumor-directed cytotoxic CD8+ T cell activity by binding to the PD-1 receptor in T cells and suppressing their function. Therefore, a combinatorial delivery system is for the co-delivery of the PLK1 inhibitor. The PD-L1 antibody is thought to selectively kill tumor cells while upregulating PD-L1 expression in surviving cancer cells and/or increasing the density of tumor-infiltrating lymphocytes, providing an opportunity to achieve a targeted therapeutic activity in a positive feedback manner. The NPs-based immunotherapy showed a significant reduction in the effective doses of volasertib and the PD-L1 antibody by five-fold in a metastatic lung in vivo tumor model by actively mediating CD8+ T cells, allowing the immune cells to induce their cytotoxic activity on the cancer cells. These results clearly demonstrate the influence of targeting the TME on improving the clinical outcomes of current therapy [41][34]. Accordingly, exploiting the molecular pathways and interactions that govern the TME could potentially enhance the current approach to therapy using a novel nano drug delivery systems (DDS).

2.2. Multidrug Resistance

Tumor multidrug resistance (MDR) remains a major obstacle that continues to hinder the effective progression of current curative cancer therapy in LC [42][35]. Innate and acquired phenotypes have been frequently identified as major cancer cell defense mechanisms following exposure to chemotherapeutic regimens [43][36]. Until now, several MDR mechanisms have been increasingly linked to members of the ATP-binding cassette (ABC) membrane pumps with 48 identified genes [44][37]. A number of these efflux transporters, including P-glycoprotein (P-gp; ABCB1; MDR1), breast cancer resistance protein (BCRP; ABCG2), and MDR-associated protein 1 (MRP1; ABCC1), have been recognized as reducing the efficacy of anticancer agents in tumor cells through a noticeable decrease in their intracellular accumulation in an ATP-dependent manner (Figure 3) [45][38]. Commonly used chemotherapeutic agents, including taxanes, platinum compounds, and gemcitabine, fall victim to these pathways [46,47,48,49][39][40][41][42].
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Figure 3.
Drug efflux from the intracellular compartment of cancer cells.
Other non-ABC drug transporters in LC, such as lung resistance protein (LRP), have shown their ability in reducing the biodistribution of anticancer agents in the tumor microenvironment, reducing the overall efficacy of the medication regimen [44,50][37][43]. In a study that examined the mortality rate of patients expressing MDR and LRP transporters in NSCLC, survival rates were greatly diminished upon overexpression of these efflux transporters when compared to pump-free tumors, showing their imminent role in the chemoresistance of the disease [51][44]. Drug transporter-independent mechanisms also play a prominent role in the development of MDR in LC. An important superfamily of antiapoptotic proteins known as the B-cell lymphoma (Bcl-2) appear to be upregulated in LC, promoting cytotoxic resistance through the dysregulation of apoptosis in tumor cells [52,53,54][45][46][47]. In addition, mutations in the p53 transcriptional factors that regulate the expressions of numerous genetic materials have brought about considerable MDR in LC [55,56,57][48][49][50]. Thus, there is a substantial need for the development of novel systems to overcome the MDR shortcomings of current chemotherapy.
The use of NPs to overcome other MDR pathways in LC by encapsulating genetic materials has also been explored. It was suggested that NPs inhibit the expression and function of efflux transporters by targeting microRNAs (miRNA), which are special non-coding RNAs that play an important role in protein expression and cellular transfection [63][51]. Shutting Ma et al. co-loaded survivin siRNA and a tetravalent platinum complex of cisplatin (Pt (IV)) prodrug into a protamine/hyaluronic acid nanocarrier coated with polyglutamic acid (PGA) for the treatment of platinum-resistant LC. Survivin is a cancer biomarker and a member of the anti-apoptosis family that has been found to be overly expressed in drug-resistant tumor cells. Silencing this pathway using siRNA was investigated in this study to observe its relative efficacy in overcoming CIS transporter-independent MDR pathways. Survivin siRNA was loaded into an NPs to overcome its poor biodistribution in vivo and achieve increased intracellular accumulation. Cytotoxicity results in 2D A549/cDDP cell lines after 24 h revealed a slight increase in % apoptosis in the co-loaded formulation relative to CIS. This unexpected poor outcome drove the researcher to further investigation since the drug release from the NP formulation was achieved after 191 h (97.3% for pH 5.0, 29.7% for pH 6.5). Western blot analysis showed that the amount of survivin protein expression of NP-siRNA/Pt (IV) was higher than that of the survivin siRNA due to the incomplete in-vitro release of survivin siRNA from the NP after 24 h. In vivo experiments performed on A549/DDP tumor-bearing nude mice showed that treatment with the co-encapsulated formulation resulted in highest tumor inhibition rates (82.46%) compared to free CIS (62.52%) after 14 days of treatment. Therefore, despite the poor 2D cellular outcomes, in vivo models demonstrated higher efficacy, with the dual loaded formulation highlighting the importance of in vivo models in exploring the potential of these formulations. However, it would have been interesting to also compare these results to free siRNA in vitro and in vivo to visualize the importance of loading such entities in NPs over the free agents [64][52].

2.3. Cancer Stem Cells

Currently, it is well accepted that a subpopulation of LC cells residing within the tumor tissue exhibits unique biological phenotypes and characteristics with stem cell capacities, including lineage differentiation and self-renewal [66][53]. In addition, they can further undergo invasion, metastasis, tumorigenesis, chemoresistance, and tumor relapse and can escape immune surveillance. These cells will be henceforth referred to as cancer stem cells (CSCs) [67][54]. Studies have shown the vital role CSCs play in the occurrence and development of LC tissue, outlining their significance in mediating all cancer hallmarks. Recent studies suggest that the “stemness” of tumor cells may be caused by genetic mutations to specific genes, including TP53, or acquired through the activity of cancer microenvironment substances, such as interleukins, nitric oxide, or hypoxic conditions. This situates the CSCs within a setting rich with external signals, such as cytokines, growth factors, extracellular matrices, and other physicochemical factors and surrounded by a variety of cells, such as immune cells, stromal cells, endothelial cells, and perivascular cells [66,67,68,69,70][53][54][55][56][57]. Several biomarkers have already been identified within LC, including ALDH1, CD133, CD44, CD166, CD20, and others [68][55]. Understanding the CSC environment may well provide effective therapeutic strategies to overcome the aforementioned barriers, thereby achieving an improved therapeutic outcome and a lower rate of tumor recurrence.
The use of NPs to selectively target the overexpressed biomarkers and improve the therapeutic activity of cytotoxic agents on CSCs has been explored. Hyaluronic acid functionalized/all-trans-retinoic acid- (ATRA) loaded albumin-based cationic NPs were prepared and evaluated in CD44 overexpressed CSCs in in vivo lung metastasized tumor models. Pharmacokinetic biodistributions revealed a selective uptake of the HA-decorated NPs in the tumor tissue of the mouse, with a significant reduction in tumor growth relative to the pristine drug [71][58]. Similarly, Dandan Liu et al. formulated a heat shock protein inhibitor-loaded silica-coated Fe3O4 magnetic NP decorated with anti-CD20 CSCs-specific antibodies to kill both cancer cells and CSCs. The multifunctional thermoresponsive/immunomodulant/chemotherapeutic NPs demonstrated an almost 98% eradication of human lung CSCs within 30 min of external application of an alternating magnetic field (AMF). Further in vivo studies revealed that the combinatorial therapy significantly suppressed tumor growth and metastasis in lung CSC xenograft-bearing mice, demonstrating a relatively high efficacy while maintaining good biocompatibility and targeting capability [72][59]. This illustrated that such NPs could effectively serve as a platform for further exploration on selective antitumor activity on normal cancer cells and CSCs alike.

2.4. Metabolic Inactivation of the Anticancer Drugs

Drug detoxification is considered a key resistance mechanism in several types of malignant tumors (Figure 4). Each population of cancer cells can respond differently to anticancer drugs due to the associated genomic variation [78][60]. The metabolism of chemotherapeutic agents can progress intracellularly and/or extracellularly, eventually affecting the overall efficacy of the given anticancer agent [79][61].
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Figure 4.
Different mechanisms of DR in LC.
The metabolism of anticancer drugs in the body involves two phases. In the initial phase, cytochrome-P450 (CYP-P450) enzymes may act on the functional groups of the anticancer drugs and modify them by oxidation, reduction, or hydrolysis reactions. Examples of functional groups include hydroxyl (-OH), amino (-NH2), and carboxylic acid (-COOH). The second phase involves further modification of those altered functional groups by glucuronidation, sulfonation, and conjugation of the amino acid, creating more hydrophilic and polar drug metabolites that are readily excreted [80][62]. Metabolism may also involve methylation and acetylation reactions, which could terminate the activity of the drugs. These conjugation reactions normally occur in specialized cells in the liver to protect the host from the toxicity of anticancer drugs [81,82,83][63][64][65]. However, similar pathways have been demonstrated at the tumor site in many types of cancer, including LC [83][65]. Augmented metabolic activation in cancer cells can eventually influence the pharmacokinetics and/or pharmacodynamics of anticancer drugs [84,85][66][67].
For anticancer prodrugs, such as cyclophosphamide, the concentration of the active drug molecules at the tumor site is dependent on the metabolism of the prodrug, and therefore, the metabolic activity can be a limiting factor for the effectiveness of the treatment. The overproduction of specific enzymes at tumor sites can be used to render a prodrug into cytotoxic metabolites strictly at those sites [86][68].

2.5. Inhibition of the Cell Death

Among the many mechanisms put in place by cancerous cells in chemoresistance is indeed the evasion of apoptosis program (Figure 4). Apoptosis, also known as type I cell death, is a regulated cell death (RCD) characterized by alterations in cell morphology, shrinkage of cytoplasm, plasma membrane blebbing, and chromatin condensation, which result in the formation of small vesicles, known as apoptotic bodies [118,119][69][70]. It is well known that dysregulated apoptosis in cancer cells promotes resistance to anticancer drugs [120,121][71][72].
Apoptosis consists of two distinct pathways: intrinsic and extrinsic. Stress stimuli, such as DNA damage, initiate the intrinsic apoptotic pathway and trigger mitochondrial outer membrane permeabilization (MOMP), which eventually promotes the activation of caspase-9. In turn, caspase-9 activates the caspases-3, -6, and -7 responsible for apoptosis execution. On the other hand, the extrinsic apoptotic process starts with the binding of specific ligands to cell surface death receptors, activating caspase-8 and subsequently the other executioner caspases [121][72]. Cancer cells escape the apoptosis program, exploiting several mechanisms, which not only results in primary tumor progression and metastasis but also abrogation of therapeutic response to chemotherapy [122][73].
Gene mutations have been observed to be one of the many factors implicated in apoptosis evasion by cancer cells. This involves the generation of abnormal transcription products, leading to a loss or gain of function for several proteins, dysregulation of cellular homeostasis, and resistance to apoptosis. Examples of gain function mutations are represented by the catalytic subunit of PI3K (PI3KCA) mutations (E542K, E545K and H1047K) that cause sustained PI3K pathway activation. Instead, loss function mutations can occur at the expense of BAX, p53, and Phosphatase Tensin Homolog (PTEN) genes [123,124,125,126][74][75][76][77]. The modulation of extrinsic and intrinsic apoptotic signals effects can be reconducted to a family of structurally distinct inhibitor of apoptosis proteins (IAPs): cellular (cIAP1, cIAP2), surviving, X-linked (XIAP), neuronal (NIAP), livin, BIR-ubiquitin conjugating enzyme (BRUCE), and testis specific (Ts-IAP). IAPs expression is specifically upregulated during diseases progression and DR onset, hence the interest towards IAPs as potential targets for resistant cancer treatment [127,128][78][79]. For instance, X-linked IAP (XIAP) is upregulated in LC cells and enhances apoptosis inhibition. Several approaches have been explored to date on the use of pro-apoptotic NPs as potential chemoresistance therapy in human LC. For instance, a novel pro-apoptotic drug–drug conjugate was obtained by Shim and co-workers through the conjugation of the pro-apoptotic peptide drug (SMAC; Ala-Val-Pro-Ile-Ala-Gln, AVPIAQ) and cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to DOX, resulting in SMAC-FRRG-DOX that self-assembled into NPs. Upon cellular uptake, the NPs were cleaved to obtain pro-apoptotic SMAC and cytotoxic DOX specifically in cancer cells that overexpress cathepsin B, inducing a synergic effect of the combined molecules in a metastatic LC model [133][80].

2.6. Alteration of Drug Targets

Resistance to chemotherapeutic agents can be due to alteration in their targets at the tumor sites. These changes occur due to molecular modifications that may begin by mutation in DNA and alterations in protein expression, resulting in a decrease in the affinity of the drugs with their binding targets and DR (Figure 4). For example, treatment of SCLC with DOX in combination with platinum drugs inhibits the topoisomerase enzymes in the cells by intercalation between the DNA bases, causing inhibition to the enzyme gyrase that is responsible unwinding the structure of DNA during the DNA replication and ultimately causing DNA breakage. Many of resistant cancer cells can survive this treatment by modifying topoisomerase II gene expression and hence altering the target of DOX [78,139][60][81]. A similar DR mechanism was also reported for anticancer drugs that target specific signaling kinases, such as the epidermal growth factor receptor (EGFR) family [26,140,141][22][82][83]. In this case, a mutation commonly occurs in the receptor kinase, leading to over-activation of these kinases and their downstream signaling molecules such as Ras, Src, and MEK. Many of these kinases become constitutively active and promote uncontrollable cell growth. In some cancers, if the drug targets molecules of the signaling pathways, the resistant cancer cells tend to activate alternative molecules. The mutations in the EGFR in anaplastic lymphoma kinase (ALK) fusion gene-positive LC after the patient was treated with crizotinib serve as an example. Acquired resistance to the drug occurred via (ALK)-mutations, such as EGFR (L1196M and C1156Y), and some patients had other mechanisms of resistance with both mutations and increase in ALK gene copy number [142,143,144][84][85][86]. The single-nucleotide mutations, such as L1196 and G1269A, were reported in some cases to cause crizotinib resistance in NSCLC [145][87]. However, sometimes, the same effect of the mutation that causes over-activation can be found via gene overexpression. Overexpression of certain receptors in some LCs with a mutation in the EGFR tyrosine kinase domain causes drug-acquired resistance that may occur after the long-term use of drugs inhibitors targeting this kinase [145][87]. EGFR-targeted liposomal nanoparticles (EGFR-LP) were developed for the treatment of NSCLC resistance to drugs as erlotinib and afatinib, determined by mutations in the tyrosine kinase (TK) domain of EGFR [146][88]. Ramanathan and colleagues have re-ported a novel DNA-based colorimetric assay for the detection of early EGFR mutation using unmodified gold nanoparticles (GNPs) [147][89].

2.7. Enhancing DNA Repair

DNA repair involves a tangled network of repair mechanisms dictated by the specific kind of stimuli and damage to which cells are exposed (Figure 4). These mechanisms include mismatch repair (MMR), nucleotide excision repair (NER), base excision repair (BER), direct reversal (MGMT, ABH2, ABH3), homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways. For instance, ionizing radiation induces double-strand breaks (DSBs) mainly repaired by nonhomologous end joining (NHEJ) pathways. On the other hand, mono- and bifunctional alkylators can induce DNA-base modifications interfering with DNA synthesis, which can be reversed in a mismatched repair-dependent manner [44,164,165][37][90][91]. Inhibition of DNA repair systems may be a potential strategy to sensitize cancer cells to chemotherapeutic drugs and increase their efficacy. However, even if disrupting DNA repair systems may block the resistance to chemotherapeutic agents, it can also be responsible for the development of new mutations due to genomic instability [166][92]. CIS-resistant cancer cells showed higher levels of DNA damage repair. In addition, it was noted that inhibition of NER pathways can significantly enhance tumor cells’ sensitivity to CIS. The enhanced DNA repair capability in lung-CSCs was associated with an extensive activation of DNA repair genes in response to CIS treatment, suggesting it may be the main mechanism involved in resistance insurgence [167,168][93][94]. Studies have also highlighted an inverse correlation of ERCC1 (NER pathways) with response to platinum therapy in LC [169][95]. Apurinic/apyrimidinic endonuclease 1 (APE1) is considered a crucial BER pathway protein due to its activity as intermediate in the processing of potentially cytotoxic DNA damage sites. Moreover, APE1 seems to have a dual role, depending on its cellular localization, where it carries out DNA repair in the nucleus. However, in the cytoplasm, its primary role is assumed to be the regulation of mitochondrial DNA repair, possibly together with the regulation of various transcription factors. In LC cells, APE1 is often overexpressed, especially in CIS-resistant cancers [170,171][96][97].

2.8. Gene Amplification

DR due to gene amplification is estimated to occur in 10% of the cancers. It involves an increase in the number of copies of certain oncogenes inside the resistant cancer cells to several hundred times more than the drug-sensitive cancer cells. This eventually lead to the production of related oncoproteins in large amounts per cell (Figure 4). For instance, the MET gene amplification is found to affect 5–20% of EGFR-TKI-treated NSCLC patients who develop resistance to TKI drugs. HER2 amplification also has been recognized as a rare resistant mechanism in lung adenocarcinoma occurring in 1–2% of total cases in patients and tends to be up to 13% in NSCLC patients with resistance to EGFR-TKIs [176,177,178,179][98][99][100][101]. The MET is a proto-oncogene that encodes itself into MET proteins (c-MET), which can result in an increase in tyrosine kinase signaling and excessive cellular division [180][102]. There is a link between the MET and the third-generation EGFR-TKIs resistance in the EGFR mutant (EGFRm) NSCLC cell line (HCC827/ER). Acquired resistance to erlotinib due to the amplified MET gene in the cells and associated with hyperactivated MET protein also leads to resistance to both osimertinib and rociletinib [181][103]. The use of a small-molecule MET inhibitor or genetic knockdown to the expression of MET successfully increased the sensitivity of HCC827/ER cells to osimertinib and effectively inhibited the cell growth in vitro and in vivo [181,182][103][104].
The amplification of genes was also detected in the MDR1/ABCB1 chromosomal region that encodes the P-gp (P-gp/ABCB1) with overexpression of the ATP-binding cassette pumps in resistant LC cells after being treated with PTX. This resulted in a decrease in cellular accumulation of PTX, an increase in its efflux out of the cancer cells, and the development of resistance to the drug [47,183,184,185][40][105][106][107]. The encapsulation of chemotherapeutic agents into NPs or their conjugation to polymeric carriers allow them to evade the ABC drug efflux pumps as they become unrecognizable as substrates to be exported. In one study, anti-MRP-1 and anti-Bcl2 siRNA were encapsulated in combination with DOX in liposomes. The DDS targeted both pump and non-pump mediated cellular LC resistance, leading to suppression of efflux pumps and an increase in drug accumulation inside resistant LC cells [186][108].

2.9. Epigenetic Alteration Caused Drug Resistance

Although all cells of the human body have the same exact genes, epigenetic alterations regulate the way genome can be read. These are changes in the chemical structure of DNA that do not change the nucleotide coding sequence but have a profound effect on gene expression. Epigenetic alterations may occur due to the adding of and exposure to environmental factors, such as diet, exercise, drugs, and chemicals [187,188,189][109][110][111]. Methylation and acetylation of DNA are two well-studied epigenetic events that significantly alter the expression of genes, resulting in the upregulation of oncogenes and/or downregulation of tumor suppressor genes and development of cancer DR [190][112]. In eukaryotes, histones mainly serve as a structure guide for several enzymes to provide the necessary platform for RNA polymerase access to its target. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are essential enzymes that regulate histone acetylation, which is the pivotal focus of several studies on post-translational modification mechanisms. Most of the common features displayed by cancerous cells, such as the evasion of apoptosis, increased angiogenesis, and metastasis progression can be linked to epigenetic modulation and to HDAC. A number of studies highlighted the multiple roles of HDAC, suggesting it as a potential target for chemotherapy and establishing the basis for the development and use of HDAC inhibitors (HDACi) as co-adjuvant for many anticancer agents for treatment of NSCLC [191,192][113][114]. PTX co-administration with HDACi SNOH-3 showed reversed DR in PTX-resistant NSCLC cells characterized by overexpression of HDAC1 [193][115]. Sharma et al. demonstrated the ability of a subset of stem-like cells in NSCLC cell lines to undergo chromatin remodeling following treatment with erlotinib and CIS, which allow the development of drug insensitivity [194][116]. However, despite the myriad of pre-clinical work supporting HDACi efficacy as adjuvant of chemotherapy in treatment of NSCLC, they have demonstrated modest efficacy as single agents in clinical trials. The use of nanocarriers for the delivery of epigenetic agents has noticeably enhanced their ability as co-adjuvants to re-sensitize cancer cells after the onset of anticancer DR. Studies on using HDACi-loaded NPs in combination with chemotherapy and radiotherapy demonstrated the enhancement of anti-proliferative effects [195][117]. For example, to improve the bioavailability of the histone deacetylase inhibitor vorinostat (VOR) and its efficacy in the treatment of multidrug resistant cancers, solid lipid NPs (SLNs) were used as carriers. Treatment of resistant LC cell line with VOR-SLNs resulted in improved efficacy, elevated payload capacity, and a sustained release profile. The results also showed that lower doses of VOR-SLNs were required to obtain the same cytotoxic effect as free-VOR [196][118].

2.10. Clinical Studies Using Nanotechnology for Management of DR in LC

In 2012, the FDA approved the first nano-formulation for treatment of NSCLC patients, Abraxane, which consists of solvent-free albumin-bound PTX-NPs based on its significant improved clinical trial outcomes [212][119]. Other nano-formulations have been the subject of various clinical trials and showed promising therapeutic outcomes in the treatment of resistant LC (http://www.clinicaltrials.gov).

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