- Open Access
Emerging nanotechnology-based therapeutics to combat multidrug-resistant cancer
Journal of Nanobiotechnology volume 20, Article number: 423 (2022)
Cancer often develops multidrug resistance (MDR) when cancer cells become resistant to numerous structurally and functionally different chemotherapeutic agents. MDR is considered one of the principal reasons for the failure of many forms of clinical chemotherapy. Several factors are involved in the development of MDR including increased expression of efflux transporters, the tumor microenvironment, changes in molecular targets and the activity of cancer stem cells. Recently, researchers have designed and developed a number of small molecule inhibitors and derivatives of natural compounds to overcome various mechanisms of clinical MDR. Unfortunately, most of the chemosensitizing approaches have failed in clinical trials due to non-specific interactions and adverse side effects at pharmacologically effective concentrations. Nanomedicine approaches provide an efficient drug delivery platform to overcome the limitations of conventional chemotherapy and improve therapeutic effectiveness. Multifunctional nanomaterials have been found to facilitate drug delivery by improving bioavailability and pharmacokinetics, enhancing the therapeutic efficacy of chemotherapeutic drugs to overcome MDR. In this review article, we discuss the major factors contributing to MDR and the limitations of existing chemotherapy- and nanocarrier-based drug delivery systems to overcome clinical MDR mechanisms. We critically review recent nanotechnology-based approaches to combat tumor heterogeneity, drug efflux mechanisms, DNA repair and apoptotic machineries to overcome clinical MDR. Recent successful therapies of this nature include liposomal nanoformulations, cRGDY-PEG-Cy5.5-Carbon dots and Cds/ZnS core–shell quantum dots that have been employed for the effective treatment of various cancer sub-types including small cell lung, head and neck and breast cancers.
Cancer is a deadly disease characterized by the uncontrolled proliferation of cells. Mutations followed by genetic instabilities result in the initiation, progression and development of tumors . Cancer is one of the leading causes of death globally, accounting for 10 million deaths in 2020 . The main treatment modalities to eradicate different sub-types of cancers are surgery, radiotherapy, chemotherapy, hormone therapy and immunotherapy or a combination of these therapies. Various reports illustrate that chemotherapy often fails in the clinic and accounts for more than 25% of mortality in cancer patients [3,4,5].
Multidrug resistance (MDR) mechanisms limit the efficacy of chemotherapy in cancer cells [6,7,8] and have been considered some of the most challenging obstacles to effective chemotherapy [8, 9]. The reoccurrence of tumors and associated relapse or deaths of cancer patients are mainly attributable to either the intrinsic or acquired phenomenon of MDR. Some cancer cells are inherently unresponsive to certain anticancer drugs . Others acquire resistance to chemotherapy during the course of chemotherapy. This acquired MDR phenomenon is mainly due to repetitive exposure to chemotherapeutic drugs . The ATP-binding cassette (ABC) drug efflux transporters such as P-glycoprotein (P-gp; ABCB1; MDR1), ABCG2 (also called breast cancer resistance protein, BCRP) and MRP-1 (ABCC1) are often overexpressed after the initial treatment regimen [7, 11].
Mechanisms associated with MDR in cancer
The phenomenon of MDR is a complex and multifactorial process, illustrated in Fig. 1. MDR arises due to various mechanisms including overexpression of ABC transporters that efflux chemotherapeutics , mutations in drug targets , the developing adaptation of cancer cells to the microenvironment, and increased efflux of hydrophobic chemotherapeutic drugs. The alteration of drug targets either due to epigenetic changes or secondary mutations in the target protein can result in multidrug-resistant cancer . Principally, cancer cells develop MDR by overexpressing drug efflux transporters . ABC drug transporters energetically fueled by ATP hydrolysis are responsible for the low bioavailability of chemotherapeutic drugs [14, 15]. Cancer cells dynamically adapt to the changing microenvironment. For example, increased oxidative stress contributes to tumor development, and DNA mutations can lead to MDR . Therefore, dynamic activation of the DNA repair system in tumor cells also contributes to MDR [17, 18]. Enhanced DNA repair pathways and chromatin dynamics are known to be associated with the development of MDR in tumor cells [9, 17, 19]. One recent clinical study illustrated the impact of DNA repair on genomic stability and resistance to the anticancer drug treatment of pediatric high-grade gliomas . Cancer cells also become accustomed to hypoxic tissue conditions by overexpression of hypoxia-inducible factor-1α (HIF-1 α). Hypoxia triggers cancer MDR by reducing the efficacy of chemotherapeutic drugs. It may also stimulate the expression of ABC transporter pumps that eventually efflux intracellular chemotherapeutic drugs .
Dysfunctional apoptotic pathways, increased repair of DNA damage, alterations in the cell cycle, and overexpression of cyclin-dependent kinases (CDKs) contribute to the development of resistance to chemotherapeutic drugs in cancer cells . Moreover, defective apoptotic machinery has been associated with treatment failure in cancer clinics. For example, mutations in the p53 tumor suppressor gene or disrupted functions of p53 protein have been found to be responsible for treatment failure and poor prognosis in B- and T-cell Non-Hodgkin’s lymphoma [23, 24]. Rapid metabolism of anticancer drugs and detoxification of drugs by cytochrome P450 are associated with rapid turnover and elimination of anticancer drugs . Therefore, inactivation and detoxification of chemotherapeutic drugs by human cytochrome P450s (CPY) phase I and/or II enzymes can contribute to the development of cancer MDR . A recent report demonstrated that the inter-individual variation in cytochrome P450 expression determines the chemotherapeutic drug efficacy . Furthermore, tumor heterogeneity plays a major role in the development of MDR [27, 28] as cancer stem cells (CSCs) are capable of self-renewal and differentiation . Table 1 shows various ways nanoparticles have been used to combat cancer MDR.
Multidrug resistance and ABC drug efflux transporters
Some of the members of the superfamily of ABC proteins are typically expressed on the plasma membrane. They efflux cytotoxic agents from cells, thereby contributing to clinical MDR [30,31,32,33]. ABC transporters play a major role in the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs . Mammalian P-gp is the most widely studied transporter and it plays a significant role in MDR .
Since the early 1990s many drugs have been evaluated for their possible inhibition of ABC efflux transporters. First-generation P-gp inhibitors such as verapamil, cyclosporine A, quinine, and erythromycin were found to be effective in-vitro but showed inadequate pharmacological limitations, adverse side effects and low affinity towards this transporter during in-vivo experiments [35, 36]. To prevail over the adverse side effects of first-generation inhibitors, researchers modified their structures and these inhibitors, known as second-generation P-gp inhibitors, were developed including dexverapamil, S9788, and PSC-833 also called valspodar (cyclosporine A analog), etc. The second-generation P-gp inhibitors often caused interference with anticancer drugs and affected their pharmacokinetics, resulting in adverse side effects [37, 38]. The third generation of inhibitors such as elacridar, zosuquidar and tariquidar were subsequently tested in clinical studies but also failed to achieve clinical approval due to severe cytotoxic side effects [39, 40].
Fourth-generation inhibitors include natural compounds and several flavonoids with inhibitory effects on ABC efflux pumps. Natural compounds such as curcumin, piperine, tea polyphenol epigallocatechin-3-gallate (EGCG), silibinin, parthenolide, quercetin, capsaicin, carnosic acid, 6-gingerol, procyanidin, limonin, and β-carotene act as inhibitors of P-gp, and can be utilized as chemosensitizing agents to reverse MDR. Natural phytochemicals can sometimes downregulate P-gp expression by modulating different cell signaling pathways. These phytochemicals augment chemotherapy-mediated apoptotic signals in P-gp-overexpressing cells . They have been found to alter the MAPK, PI3K, and GSK signaling pathways that promote the activation of downstream signaling molecules such as AP-1, NF-κB and β-catenin. These signaling molecules interact with transcription factors and initiate the downregulation of P-gp in cancer cells, eventually assisting in the reversal of P-gp-mediated MDR. In one study, for example, Ganesan et al. demonstrated the role of ferulic acid on P-gp modulation to overcome MDR in colchicine-selected KB-ChR-8–5 resistant cells and in the MDR xenograft mouse model via the PI3K/Akt/NF-κB signaling pathway . These natural compounds were established as potential candidates with no toxicity but did not succeed due to minimal solubility and bioavailability, hampering their efficacy. Therefore, they could not be established as potent P-gp inhibitors or successful contenders to reverse chemoresistance [43, 44].
Tyrosine kinase inhibitors as modulators of drug efflux transporters
More than 50 tyrosine kinase inhibitors (TKIs) have been found to be efficient in clinical research and are approved by the US Food and Drug Administration (FDA) for anticancer therapy [45, 46]. Numerous investigations indicated that TKIs in addition to their kinase target also interact with the ABC efflux pumps [47, 48]. These inhibitors were found to competitively bind at the drug-substrate-binding site of the ABC efflux pumps, thereby inhibiting their function and sensitizing the drug-resistant cancer cells. This chemosensitization enhances the intracellular accumulation of drugs in cancer cells. The first generation TKI imatinib reverses the ABCG2-mediated chemoresistance of topotecan  and doxorubicin  in experimental models. Another inhibitor, dacomitinib, was shown to inhibit ABCG2 efflux pumps and enhance drug accumulation and retention, thereby reversing ABCG2-mediated MDR in cancer cells . Combination treatment of dacomitinib and topotecan appreciably inhibits tumor growth as compared to topotecan and/or dacomitinib treatment alone, without any additional toxicity. Narayanan et al. performed an extensive in-vitro study that tested the role of the spleen TKI entospletinib (GS-9973) in the reversal of ABCG2-mediated MDR. Entosletinib was found to reverse resistance to mitoxantrone and doxorubicin in cells overexpressing ABCG2 transporters. The ATPase activity of ABCG2 was enhanced due to the binding of entospletinib at the drug-substrate binding site . Yang et al. reported that sitravatinib interferes with the tumor microenvironment and immune-checkpoint blockade (PD-1) in many cancer models . It also has the potency to reverse MDR mediated by the ABCG2 efflux pump in cancer cells. Combination therapies along with FDA-approved TKIs and established chemotherapeutics are under clinical trials [54, 55]. Major drawbacks of using TKIs as adjuvants with chemotherapy are their poor solubility, adverse toxicity and severe side effects in patients [56, 57].
Small interfering RNA (siRNA) for inhibition of drug efflux transporters
Combining gene therapy with chemotherapeutic agents can sometimes improve therapeutic efficacy. Various types of nucleic acid-based molecules such as small interfering RNAs (siRNAs), plasmid DNA, short hairpin loops and circulating miRNAs enable the regulation of specific genes to regulate and reverse MDR in cancer cells [58, 59]. Donmez and co-workers sensitized resistant breast cancer cells by transfecting with MDR1 siRNA plus doxorubicin to overcome P-gp-mediated cancer MDR. The siRNA targeting the MDR1 gene successfully silenced the MDR1 mRNA by approximately 90% and enhanced the accumulation of doxorubicin in drug-resistant cells . Major obstacles to applying nucleic acid-based drugs are their stability, enzymatic degradation, poor membrane permeability and short half-life.
Nanotechnology-based strategies to overcome MDR
To overcome the inadequacies of existing treatment and therapy, nanomedicine offers innovative, robust and flexible drug design and delivery alternatives based on genetic profiling of individual patients to engender personalized treatment of cancer MDR [61,62,63]. The fascinating physicochemical properties of nanomaterials contribute to the improvement of the therapeutic index of potential chemotherapeutic drugs by enhancing their efficacy and reduced adverse toxic effects. Multimodal nanoformulations composed of materials such as gold, iron or quantum dots, functionalized with ABC efflux pump inhibitors and targeting molecules/peptides, have been shown to improve the pharmacokinetics and biodistribution of chemotherapeutic drugs in multidrug-resistant cancer cells . P-gp inhibitors released in cancer cells from nanocarriers bind at the drug-binding pocket in the transmembrane domains (TMDs) of the transporters and inhibit their drug efflux function . This approach was reported to enhance the therapeutic efficacy of several anticancer drugs [66,67,68]. Similarly, the co-delivery of suitable adjuvants using nanocarriers can improve the anticancer drugs' therapeutic efficacy by targeting the drug detoxification process, DNA repair mechanism and apoptotic cell death [52, 69, 70].
The delivery of nanomaterials to tumor cells is typically achieved by both active and passive mechanisms. In the active mode of nanoparticle uptake, the surface of nanoparticles is decorated with specific targeting ligands such as antibodies or peptides, cell-specific ligands which facilitate uptake of the nanoparticles via receptor-mediated endocytosis. During passive uptake, the nanomaterials tend to accumulate in the tumor interstitial spaces due to long-circulating systemic properties and are selectively taken up by cells due to leaky vasculature and impaired lymphatic systems . Passive uptake is mainly achieved by the enhanced permeability and retention (EPR) effect in cancer cells . The co-delivery of inhibitors of ABC efflux transporters and potent anticancer chemotherapeutic drugs via nanocarriers has been widely explored, accepted and is under clinical investigations to overcome MDR in tumors .
Various nanomaterials found successful for drug delivery and targeting tumors are liposomes, polymeric nanoparticles, micelles, dendrimers, metal nanoparticles, mesoporous silica nanoparticles, graphene nanoparticles, quantum dots and siRNA-conjugated nanomaterials, which all help to reverse the MDR in cancer cells. Dual drug delivery via nanoparticle systems was also developed in which combinations of drugs are co-delivered to cells, and the presence of one drug enhances the bioavailability of another drug [74, 75]. Certain non-ionic surfactants have been investigated for the inhibition of ABC efflux transporters and reversal of MDR, including polyethylene glycol, Tween 80, and Pluronics. These surfactants are known to evade recognition by P-gp, facilitating the intracellular uptake of drugs. Besides surfactants, other nanoformulations such as liposomes, polymeric nanoparticles, metallic nanoparticles, nanoemulsions, and inorganic nanoparticles have been designed with the ability to bypass drug efflux transporters and deliver chemotherapeutic drugs to MDR cancer cells [75,76,77,78,79,80].
Furthermore, the combination of chemotherapeutic drugs with gene therapy, specifically siRNA co-delivery via nanoparticles, was found to be more successful in the reversal of cancer MDR by targeting cellular signaling pathways [81, 82]. Nanocarriers provide stability to siRNA, thereby preventing its rapid degradation and clearance in the cellular system . Anselmo et al. provided an update on several nanoparticles which showed improved therapeutic abilities in clinical studies and listed the approval status of promising nanosystems to improve human health from the early 1990s to 2019 . In recent years, nanosystems have gained more attention for the delivery of chemotherapeutic drugs with suitable adjuvants to circumvent MDR in different cancer subtypes. Figure 2a shows the number of research articles published during the years 2001–2021 on the reversal of cancer MDR in various experimental models via chemotherapeutic drugs and/or adjuvant-conjugated nanomaterials. In the last 10 years, the number of such articles has quadrupled. The Venn diagram in Fig. 2b categorizes a total of 195,591 published research articles on nanotechnology. More than 42,950 of them involved cancer research, with 4679 (10%) of the nanotechnology and cancer articles specifically dealing with multidrug resistance.
ABC transporters are overexpressed by brain endothelial cells that form the blood–brain barrier (BBB) and are involved in the efflux of toxic foreign compounds as well as blood-derived compounds. These transporters prevent chemotherapeutic drugs from reaching their target site of action within the brain [85, 86]. Several polymeric, liposome-based and metallic nanoformulations were found to be suitable carriers to cross the BBB for controlled and sustained drug delivery. The surfaces of these nanoformulations were modified to enable them to cross the BBB for accurate diagnosis and to deliver appropriate anticancer drugs to treat brain tumors [87, 88]. Gregory et al. reported the efficacy of iRGD functionalized albumin-based synthetic protein nanoparticles (SPNPs) to deliver siRNA specific for STAT3 into intracranial GBM tumors. STAT3 siRNA-loaded SPNPs showed efficient penetration of the BBB, significant downregulation of the STAT3 expression and tumor regression in both GL26 glioma cell and GL26 syngeneic mouse models . The use of transferring receptor (TR)-targeted liposomal nanoformulation was found to significantly enhance the delivery of cisplatin across the BBB for the treatment of brain tumors in C6 cells and Wistar rats .
Over the past decade, photodynamic therapy (PDT) has attracted substantial attention as an efficacious alternative treatment approach to overcome MDR. Delivery of photosensitizers and drugs simultaneously is difficult. It was found that PDT could also be improved by employing nanomaterials to mitigate MDR . PDT mainly eradicates cancer cells through the transfer of energy from light-activated photosensitizers to oxygen and generates intracellular oxidative stress via reactive oxygen species (ROS) . The resultant intracellular ROS decreases the expression of membrane efflux proteins and anti-apoptotic Bcl-2 family proteins . Due to disruption of mitochondrial membranes, the level of intracellular ATP declines and the activity of ATP-dependent ABC proteins is subsequently decreased. Guo and co-workers revealed the use of a nanosized hydrogel-like polyprodrug of platinum (IV) complex that has long-term circulation, tumor accumulation and also generates a high level of intracellular ROS. The elevated level of ROS downregulates the expression of MDR-associated protein 1 (MRP1), thus reversing MDR in A549R cells and in A549 tumor-bearing BALB/c mice model . Li et al. demonstrated the role of mitoxantrone loaded poly (ε-caprolactone)-pluronic F68-poly (ε-caprolactone)/PLGA-PEG-PLGA) mixed nanomicelles to reverse MDR in MCF-7/ADR cells under exposure of near-infrared (NIR) light. These nanomicelles upon irradiation with NIR light generate higher levels of ROS, thus decreasing P-gp activity, leading to improved, higher concentrations of intracellular drugs and further cell apoptosis. This approach reverses MDR via nano-mediated PDT . Figure 3 summarizes the strategies of different multimodal nanosystems functionalized with various targeting molecules to deliver drugs. These nanosystems are able to reverse MDR under the influence of various stimuli depending on the tumor microenvironment.
Nanocarrier-based drug delivery systems to overcome MDR
Polymeric nanomaterials have been found to play a crucial role in the delivery of dual chemotherapeutic drugs for the reversal of MDR. In fact, a polymeric liposome was the first nanoformulation approved by FDA to be used as a nanotechnology-based anticancer therapeutic . These nanoparticles are colloidal, biocompatible and biodegradable nanomaterials that entrap or encapsulate hydrophobic drugs such as cyclosporin, curcumin, paclitaxel and oxaliplatin in their matrices to improve their bioavailability in cells . Table 2 lists the various types of polymeric nanomaterials that have been investigated for the reversal of cancer MDR. These nanomaterials are highly stable and have the intrinsic property of sustained and controlled drug release as compared to liposomes and micelles. Natural biopolymers such as chitosan, sodium alginate as well as some other synthetic polymers including hydroxypropyl methylcellulose (HPMC), Poly (lactic-co-glycolic acid) (PLGA), Poly-l-lysine (PLL), and N-(2-hydroxypropyl)-methacrylamide (HPMA) are commonly used for nanoformulation synthesis and drug delivery . Polymeric nanoparticles provide sustained release of drugs, prevent drug metabolism and detoxification and have a long circulation time, avoiding clearance from the system and enhancing uptake within cells . Many polymeric nanoparticles loaded with chemotherapeutic drugs and P-gp inhibitors have been studied to modulate ABC efflux transporters and enhance the intracellular accumulation of anticancer drugs in MDR tumor cells [99,100,101]. Le and co-workers, for example, evaluated doxorubicin-loaded liponanoparticles (LNPs) in order to bypass the P-gp efflux mechanism in doxorubicin-resistant MCF-7/ADR breast cancer cells. The drug-loaded polymeric nanoparticles significantly increased the accumulation of doxorubicin in the nuclei of drug-resistant cells . In another study, curcumin and nutlin-3a in PLGA functionalized with folate reversed MDR through downregulation of MRP1 via inhibition of NF-κB in retinoblastoma Y79 cells . Figure 4 shows different types of nanomaterials such as organic polymer, lipid, metallic and quantum dost-based nanomaterials functionalized with various ligand molecules for the co-delivery of chemotherapeutic drugs to overcome cancer MDR in resistant cells.
Liposomal nanoformulations are spherical vesicles that encompass amphiphilic phospholipids and cholesterol associated with an aqueous lumen. Liposomes can allow the encapsulation of both hydrophobic as well as hydrophilic chemotherapeutic drugs within their cores. A liposomal nanoformulation was the first clinically approved nanosystem for anticancer drug delivery . Table 2 provides a comprehensive list of various liposomal and solid lipid nanoformulations used for the reversal of MDR. Liposomes can also be utilized as a co-delivery system to deliver a chemotherapeutic agent along with inhibitors to sensitize cancer cells to anticancer drugs . In one study, the co-encapsulation of doxorubicin and verapamil in liposomal-mediated delivery was found to overcome P-gp-mediated MDR in human breast cancer cells with reduced toxicity in vital non-target organs . Tang and co-authors synthesized a liposomal formulation and decorated its surface with octa-arginine (R8), which acts as a cargo peptide and delivers the liposomal formulation into cells. This nanoformulation was revealed to cause significant inhibition of tumor growth in female nude mice with negligible distribution in healthy tissues and organs. Thus, liposomal nanoformulations offer a platform for co-administration of chemotherapeutic drugs in combination with inhibitors of ABC drug transporters to eliminate MDR in both cellular and animal models [105,106,107,108]. Several liposomal nanoformulations of chemotherapeutic drugs are under clinical studies and approved by the FDA for the treatment of different subtypes of cancers [109, 110]. These liposomal nanoformulations can deliver the drugs for maximal synergy at a specific molar ratio suitable for the tumor microenvironment. For example, the FDA-approved nanoliposome Vyxeos was used for the co-delivery of cytarabine and daunorubicin to achieve effective treatment of acute myeloid leukemia (AML) .
Micelles are specialized nanomaterials obtained by self-assembly of hydrophilic and hydrophobic blocks in an aqueous environment with a hydrophobic core. The hydrophobic core has the advantage of being able to entrap hydrophobic drugs within its core. Polymers such as poly (aspartic acid) (PAA), poly (caprolactone) (PCL), poly (lactic-co-glycolide) (PLG) and polyethylene glycol (PEG) are used for micelle formation. Table 3 shows recent developments in the application of various nanomicelles to overcome cancer MDR. Several polymeric micelles loaded with certain chemotherapeutic agents (doxorubicin, cisplatin and paclitaxel) have been evaluated for their anticancer efficacy in experimental as well as clinical studies. Lv et al. demonstrated the use of polymeric micelles (PEG2k-PLA5k) for co-delivery of doxorubicin with curcumin to reverse MDR via dual-drug based nanomicelles in drug-resistant MCF-7/ADR cells and in a xenograft model . Nanomicelles were also used for co-delivery of P-gp-specific siRNA and anticancer drugs in a single system for synergistic and effective anticancer therapy. For example, Zhang et al. applied a triblock polymer (NSC-PLL-PA) for co-delivery of si-MDR1 RNA and doxorubicin to resistant HepG2/ADM cells and a xenograft model. Moreover, nanomicelles were observed to accumulate in tumors 24 h post-injection and inhibit tumor growth . Various polymeric nanomicelles have been found to be effective and have achieved success in different clinical stages. Genexol-PM, nanomicelles loaded with paclitaxel, has been approved by the FDA for use in patients to treat breast cancer. Preclinical in-vivo studies revealed a threefold increase in the maximum tolerated dose of paclitaxel and enhanced antitumor activity as compared to the free drug. Another advantage of using nanomicelles is their hydrophilic outer shells. Such micellar nanomaterials have prolonged circulation time and accumulate in tumor tissues via the EPR mechanism .
Nanoemulsions (oil/water) are biocompatible, highly stable nano-size (10–1000 nm) emulsions that are frequently used to entrap and improve the delivery of hydrophobic drugs and pharmaceutically active compounds . Table 3 shows various nanomicelles and nanoemulsions that have been used to overcome cancer MDR. Through nanoemulsion, the co-administration of a different combination of chemotherapeutic drugs and/or efflux transporter modulators can efficiently be introduced into cancer cells. These nanoemulsions play a significant role to overcome MDR . Albumin-bound nanoparticles (nab™) have been widely used for tumor treatment due to elevated albumin accumulation within tumors. The nab-paclitaxel nanoformulation (Abraxane®) was given FDA approval for the treatment of metastatic breast cancer and non-small cell lung cancer . Co-delivery of docetaxel and thymoquinone in borage oil-based nanoemulsion reduces the concentration necessary for effective treatment in breast cancer (MCF-7 and MDA-MB-231) cells as compared to drug-free treatment .
Dendrimers are nano-size hyper-branched, spherical polymeric nanomaterials with symmetric core and end groups that facilitate surface conjugation and modification. Anbazhagan et al., employed polyamidoamine (PAMAM) dendrimers for the co-delivery of ferulic acid and paclitaxel. These dual-drug loaded PAMAM dendrimers were also decorated with arginyl-glycyl-aspartic acid (RGD) to combat MDR mediated by P-gp in drug-resistant KB ChR-8–5 cells. These results revealed the enhanced intracellular accumulation of paclitaxel in cells and also indicated increased pro-apoptotic protein expressions of caspase 3, caspase 9, p53 and Bax . Similarly, Liu et al. demonstrated the role of dual-functionalized PAMAM dendrimers in the inhibition of P-gp function in Caco-2 and MDCK/MDR1 cells .
Several metals and metal oxides have attracted intense biomedical attention for their use as nanomaterials in diagnosis, drug delivery and therapy. Gold (Au) and iron oxide nanoparticles (Fe3O4 NPs) have intrinsic properties that make them ideal nanosystems to facilitate therapies using radiation, photodynamics and hyperthermia. Iron oxide nanoparticles can be utilized as a contrast agent to improve conventional MRI imaging . Various metallic nanomaterials used for the reversal of drug resistance are listed in Table 4.
Green synthesized metal nanomaterials have attracted enormous attention and have been exploited for their biomedical applications. These green synthesized nanomaterials are prepared by using different plant parts, natural compounds, and microorganisms. Many reports have demonstrated the use of biosynthesized nanomaterials of different metals on cancer sub-types. Saravanan et al. in their systematic report elaborated comprehensive insights regarding the significant role of biogenic AuNPs in breast cancer treatment and molecular mechanisms for anticancer activity in in-vitro studies. The biogenic nanoparticles facilitate excessive production of ROS and apoptotic enzymes that contributes to higher cytotoxicity in cancer cells . Mostafavi et al. described the efficiency of biogenic AgNPs and AuNPs for antineoplastic activity against leukemic models . Barabadi et al. provided detailed information regarding the application of biologically synthesized AgNPs against lung cancer. Biogenic AgNPs were revealed to have elevated in-vitro anticancer efficacy, thereby facilitating the reversal of cancer MDR . Another systematic review by Barabadi et al. demonstrated the relevance of biologically synthesized AuNPs for the diagnosis and treatment of lung, colorectal and cervical cancer cell lines using animal models [125,126,127].
Several reports indicate that metal nanomaterials are able to interfere with drug efflux transporters and cause the reversal of drug resistance by increasing drug retention and cellular bioavailability [80, 128,129,130,131]. Cheng et al. demonstrated the co-delivery of daunorubicin and 5-bromotetrandrin via magnetic nanoparticles (DNR/BrTet MNPs) to reverse P-gp-mediated MDR in K562/A02 leukemia cells. Their findings indicate that the transcriptional downregulation of the MDR1 gene further aids in the reversal of MDR . Noruzi et al. evaluated the effect of trimethoxusilylpropyl ethylenediamine triacetic acid (EDT)-coated and doxorubicin-conjugated iron oxide nanoparticles on human glioblastoma U251 cells and a mouse model for reversal of MDR. Their findings indicate that drug-conjugated magnetic nanoformulation activates multiple mechanisms to overcome drug resistance. It inhibited cell proliferation and enhanced apoptotic cell death. Furthermore, downregulation of the DNA repair gene and upregulation of caspase 3 and p53 genes were observed in U251 cells . AuNPs have been found to contribute to the enhancement of chemotherapy and radiation in a size-dependent manner. Jiang et al. conjugated 2-(9-anthracenylmethylene)-hydrazinecarbothioamide (ANS) and 6-mercaptopurine (6-MP) with AuNPs and evaluated the resulting toxicity and drug resistance in MCF-7/ADR cells. Their findings indicated that smaller AuNPs have more efficient binding with P-gp, whereas larger-size nanoparticles avoid effective recognition by P-gp . Rathinaraj et al. demonstrated the exploitation of folate-gold-bilirubin (FGB) nanoconjugates to overcome P-gp-mediated MDR in P-gp-overexpressing KB-ChR-8–5 cells and in a xenograft mouse model. The results indicated the FGB nanoconjugate proved to be a potent inhibitor as compared to bilirubin and AuNPs alone. FGB nanoconjugates also induced intracellular ROS and initiated DNA strand breakage and other apoptotic changes in P-gp-overexpressing cells. The xenograft model treated with FGB nanoconjugates also revealed suppression of tumor growth with pronounced apoptosis . Dearden et al. demonstrated that drug-functionalized gold nanorods (AuNRs) mediated P-gp trafficking in P-gp + J774.2 cells. Treatment with AuNRs containing azithromycin (Azith-AuNRs), clarithromycin (Clarith-AuNRs) and tricyclic ketolide (TriKeto-AuNRs) led to ligand-dependent accumulation and inhibition of the efflux of these nanorods by P-gp. Increased intracellular accumulation of AuNRs was observed for nanorods conjugated with P-gp substrates (Azith-AuNRs and Clarith-AuNRs), while nanorods conjugated with low-affinity P-gp substrates (TriKeto-AuNRs) was unaffected .
Quantum dots (QDs) are nanosized semiconductor particles with advantageous optical and electrical properties that have been successfully employed in several biomedical applications. QDs generate intracellular ROS, thereby causing cancer cell death through oxidative DNA damage . Furthermore, QDs and carbon-based nanomaterials have been employed to conjugate drugs, antibodies and adjuvants to enhance anticancer therapeutic efficacy [137, 138]. In one study, P-gp-miR-34b and P-gp-miR-185 conjugated with CdSe/ZnS-MPA QDs and CdSe/ZnS-GSH QDs significantly inhibited P-gp expression in lung cancer A549 cells . Graphene-based QDs (GQDs) have also been evaluated for their ability to modulate P-gp-mediated MDR. Single GQDs are able to downregulate multiple MDR-linked genes by interacting with their respective C-rich promoters. Furthermore, increased drug uptake and retention were observed along with suppression of MDR-related genes in MCF-7/ADR cells . Table 5 lists published reports on the reversal of cancer MDR by QDs and carbon-based nanomaterials.
Mesoporous silica nanoparticles (MSNs)
Mesoporous silica nanoparticles are nanosize drug carriers that have gained attention as versatile drug delivery vehicles having a large surface area, high stability, negligible toxicity, customized pore size and ease of encapsulating various biogenic molecules. Table 5 lists mesoporous nanoparticles that have been used to overcome MDR. Liu and co-workers demonstrated the co-delivery of quercetin (a P-gp inhibitor) and paclitaxel in chondroitin sulphate-coated MSNs to reverse P-gp-mediated MDR. Their results indicated that increased drug release is dependent on the redox environment in MCF-7/ADR drug-resistant cells, ultimately resulting in downregulation of P-gp expression. In another report, higher intracellular drug retention, associated apoptosis and improved antitumor activity were observed in resistant cells and female nude BALB/c mice . Also, Zhao et al. confirmed that pH-sensitive MSNs co-polymerized with d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) successfully deliver doxorubicin to resistant MCF-7/ADR cells. These MSNs showed clathrin-mediated endocytosis, and higher drug uptake and retention. The TPGS moiety of nanoformulation contributed exclusively to the inhibition of P-gp drug efflux in tumor-bearing SCID mice  and demonstrated the significant reversal of drug resistance.
Recent advancements in nanotechnology to overcome MDR
Numerous engineered nanomaterials have emerged recently with the ability to deliver multiple agents such as chemotherapeutic drugs, adjuvants, and nucleic acids (DNA, siRNA, mRNA) to overcome MDR. These nanomaterials help to overcome MDR achieved by both efflux pump-mediated and efflux pump-independent mechanisms [101, 143].
Nanomediated approaches to combat drug efflux pump-mediated MDR
P-gp transporters play a role in the development of clinical MDR in several cancer subtypes . Therefore, inhibition of P-gp transport function has been considered an appropriate strategy to overcome MDR in cancer cells. Smart engineered nanomaterials have come to the rescue and have been shown to reverse efflux pump mediated-MDR by successfully altering the pharmacokinetic parameters that facilitate drug retention . Several nonionic surfactants (Tween 80, vitamin E/TPGS, Brij 35, Pluronic, PEG and PEO, etc.) are now known to be able to inhibit P-gp activity . These surfactants form strong hydrogen bonds with the transmembrane sequence of P-gp and engage the drug binding sites, enhancing drug absorption and retention. In one study, phosphatidylethanolamine (PE) conjugated with PEG (PEG-PE/vitamin E)-based nanomicelles were synthesized to co-encapsulate paclitaxel and curcumin for delivery to human ovarian adenocarcinoma SK-OV-3TR paclitaxel-resistant cells. The results of that study indicated successful delivery of drugs and inhibition of tumor growth in female nude mice by nanomicellar-mediated delivery . Shafiei et al. conjugated TPGS-PLGA with doxorubicin and metformin for the co-delivery of P-gp inhibitor and chemotherapeutic drugs to inhibit drug efflux . Drug delivery by polymer lipid nanoparticles (PLNs) has been shown to enhance chemotherapeutic efficacy and retention in resistant cells. Wong et al. conjugated doxorubicin with PLNs and evaluated their potential for drug delivery and P-gp inhibition in MDA435/LCC6/MDR1 and EMT6/AR1 resistant cell lines. The nanoformulations were able to bypass the efflux pumps as they were phagocytized into cells, thereby enhancing doxorubicin accumulation and retention in resistant cells as compared to free doxorubicin . Joshi et al. demonstrated the reversal of hypoxia-mediated drug resistance in resistant A2780/ADR and MCF-7/ADR cell lines as well as in 3D spheroid cultures via co-delivery of doxorubicin and anti-P-gp siRNA (siP-gp)-conjugated PEGylated nanoparticles. The siRNA inhibits MRP1 gene expression under hypoxic conditions, thereby increasing doxorubicin delivery to MDR cells . Lamprecht et al. demonstrated the role of etoposide-conjugated lipid nanocapsules in the reversal of P-gp-mediated MDR in C6, F98 and 9L glioma cells. Etoposide intracellular efficiency was enhanced by lipid nanocapsules in P-gp-overexpressing MDR cells . Some studies have been conducted to reverse MDR1 membrane pump-mediated cancer MDR with the employment of thermosensitive polymeric nanomaterials. Interestingly, Fan et al. developed beta cyclodextrin (β-CD)-based temperature-sensitive supramolecular nanoparticles by utilizing PEG-PNIPAAm for delivery of paclitaxel (β-CD-g-(PEG-v-PNIPAAm)7/PTX) and doxorubicin (β-CD-g-(PEG-v-PNIPAAm)7/Dox) both in-vitro (HepG2/MDR1 and H460/MDR1 cells) and in-vivo (HepG2/MDR1 bearing xenograft BALB/c mice). These novel nanoparticles facilitate the reversal of cancer MDR by enhancing the cellular uptake of nanoparticulated drugs, intracellular drug retention, and inhibiting pump-mediated drug resistance . Cheng and co-workers developed a novel star-like thermoresponsive nanocarrier by using β-CD grafted with a copolymer of PNIPAAm-b-POEGA to form an inclusion complex for the delivery of doxorubicin and paclitaxel in HepG2/MDR1 and H460/MDR1 cells. Nanocarriers (β-CD-g-(PNIPAAm-b-POEGA)x/PTX@NPs) were highly stable and demonstrated enhanced cellular uptake of chemotherapeutic drugs. The nanocarriers were used at 37 °C (normal body temperature), thereby inhibiting MDR1-mediated cancer drug resistance. The β-CD-g-(PNIPAAm-b-POEGA)x/PTX@NPs) were shown to have an improved therapeutic effect attributable to enhanced cellular uptake and partial destruction of MDR1 membrane pumps with PEGylated nanocarriers in an in-vivo HepG2/MDR1 tumor xenograft nude mouse model . Han et al. described the application of a PEGylated PLA nanosystem for the combined delivery of cyclosporine A and gefitinib in in-vitro and in-vivo cancer resistance models. Their findings indicated that the nanosystem disrupts EGFR-mediated downstream signaling cascades and eventually inhibits tumor growth and invasion. It also inactivates the function of the signal transducer and the activator of transcription-3 (STAT-3)-mediated signaling .
Nanodiamonds are carbon nanoparticles that offer binding sites for certain therapeutic agents. Reversible binding allows sustained release of drug at the target site, thereby achieving excellent biocompatibility. Chow et al. showed that nanodiamonds are an ideal drug delivery system that offers biocompatibility, drug conjugation, controlled release and enhanced aqueous dispersion properties. Nanodiamonds alter the tumor efflux pumps, hence facilitating doxorubicin intracellular retention and pronounced apoptosis in various human and murine breast cancer resistant cells and in a xenograft model .
Calcium phosphate-based nanomaterials are also used for the reversal of P-gp-mediated drug resistance via energy-dependent inhibition of efflux transporters . Calcium phosphate nanoparticles loaded with doxorubicin decorated with an RGD peptide were evaluated for targeting MDR cells for reversal of P-gp-mediated drug resistance by inducing intracellular calcium ion bursting and designated as tumor Targeting Calcium ion NanoGenerator (TCaNG). The mechanism of action of this nanosystem was an initial burst of Ca2+ ions within mitochondria, which curbs cellular respiration by disturbing mitochondrial calcium ion homeostasis, blocking ATP production and further inhibiting P-gp-mediated cell resistance. Hypoxia conditions generated within cells due to suppressed cellular respiration also downregulate the hypoxia-inducible factor-1 alpha (HIF-1α) gene and inhibit expression of the P-gp efflux transporter. The study revealed that the TCaNG nanosystem inhibits the biosynthesis as well as functional activity of P-gp transporters and facilitates the reversal of tumor drug resistance in MCF-7/ADR resistant cells and nude mice . These multi-targeted nanomaterials could be advantageous in preclinical and clinical applications.
Certain natural compounds have also been used to inhibit drug efflux transporters. Zhao et al. demonstrated the co-delivery of curcumin and paclitaxel via core–shell polymeric NPs in human ovarian cancer SKOV3 and SKOV3-TR30 cells and in tumor-bearing xenograft mice to reverse drug resistance. Their results demonstrated that the NPs are internalized via CD44 receptors present on the surface of ovarian cells. Curcumin was found to efficiently inhibit the P-gp drug efflux transporter, resulting in elevated intracellular paclitaxel retention, inhibition of cellular migration and cytotoxicity and enhanced reduction in tumor growth in a murine model .
Single-walled carbon nanotubes (SWCNTs) have been reported to efficiently overcome drug resistance in some experimental models. Li et al. demonstrated the co-delivery of anti-Pgp antibody and doxorubicin in SWCNTs in efforts to target and eliminate K562R leukemia stem cells. Their results clearly showed inhibition of tumor development and metastases . In an earlier study, Li et al. conjugated both ABCG2 and ABCB1 sequences onto pH-sensitive carbonate apatite nanoparticles for dual siRNA-mediated targeting of human breast cancer cell lines (MCF-7). This dual targeting approach sensitized the MCF-7 cells and enhanced toxicity by more than 50% when treated with cisplatin, paclitaxel and doxorubicin. While single siRNA targeting resensitized the cells, the dual siRNA targeting approach offered enhanced toxicity .
Nanomediated approaches to combat MDR not dependent on efflux pumps
Normal cells employ various repair mechanisms to avoid the replication of mutated DNA and to circumvent malignant transformation. If the damaged DNA is not repaired, the mutated cells are normally eliminated by apoptosis . MDR not dependent on efflux pumps can also develop in cancer cells via activation of anti-apoptotic cellular mechanisms including elevated expression of the B-cell lymphoma 2 (Bcl-2) gene and inhibition of pro-apoptotic signals, or via HIF-1α and NF-κB [160,161,162,163]. NF-κB is responsible for the transcriptional regulation of several genes involved in cell proliferation, migration, invasion, apoptosis escape processes and survival. Atypical regulation of NF-κB has been shown to be crucial for the development of MDR.
Nanomaterial-based approaches to combat tumor microenvironment-mediated MDR
The tumor microenvironment also plays an important role in MDR as well as cancer progression and development. Cancer cells and stromal cells embedded in the extracellular matrix play a crucial role in cancer cell invasion, metastasis and drug sensitivity . Cancer cells are known to utilize more aerobic glycolysis than oxidative phosphorylation due to high levels of glycolysis and poor transportation of metabolites from cells. Lactic acid accumulation makes the intracellular environment acidic by increasing proton concentrations. The significant difference in pH (acidic pH in the extracellular matrix and neutral to basic pH in the intracellular environment) also influences the effectiveness of chemotherapeutic agents by ionizing them, hindering their ability to cross cell membranes and reducing intracellular uptake via transporters, leading to MDR in cancer cells [165, 166]. The tumor microenvironment possesses inimitable characteristics, contributing actively to the development of MDR. Smart nanomaterials utilize the physiological characteristics of the tumor cells and respond according to the tumor microenvironment, thus offering more effective treatment than conventional chemotherapy. Smart engineered nanoparticles respond according to the cellular pH, for the release of chemotherapeutic drugs at the tumor site. Several pH-sensitive polymeric nanomaterials have been extensively studied in efforts to overcome acidic tumor microenvironment-mediated drug resistance. Bahadur et al. synthesized poly (2-)pyridine-2-yldisulfanyl)ethyl acrylate) (PDS) nanoparticles loaded with doxorubicin and decorated with a cRGD peptide and observed their stability and drug release in both acidic pH and redox potential conditions in colon cancer HCT-116 cells. Their results indicated that these nanoparticles are a promising nanotherapeutic system . Huo et al. employed a nanomicelle system for the co-delivery of the P-gp inhibitors disulfiram and paclitaxel in PEG-b-PLL/DMA with l-lysine side chains in efforts to reverse drug resistance. The nanomicelles tend to reverse surface charges depending on cellular pH conditions. Usually, nanomicelles have negative surface charge densities in neutral plasma circulations (pH 7.4) but they switch to a positive charge in an acidic tumor environment (pH 6.5–6.7). These positive surface charges facilitate their enhanced uptake into cells to overcome the drug resistance in MCF-7/ADR cells . Similarly, Mao and co-workers found that PDPA-b-P(FPMA-co-OEGMA) nanomicelles conjugated with doxorubicin have either a negative or positive surface charge depending upon the tumor microenvironment and are able to efficiently deliver drugs to HeLa cells .
The tumor microenvironment is also responsible for creating the hypoxic conditions that lead to MDR, as oxygen-deprived cells grow slowly and are less susceptible to conventional chemotherapeutic drugs. Oxidative stress leads to changes in the cancer microenvironment. Increased oxidative stress promotes tumor development and associated drug resistance . Targeting oxidative stress and the hypoxic microenvironment of tumors could also provide an opportunity to overcome MDR. Hypoxic conditions are associated with many cancers due to limited oxygen supply, which leads to overexpression of a transcription factor called HIF-1α. HIF-1α is the pivotal moderator of hypoxia-related responses that promote abnormal angiogenesis and MDR in several cancer subtypes . The hypoxic conditions also critically influence the expression of ABC drug transporters [21, 165, 171]. Several studies have demonstrated that HIF-1α inhibition in cancer cells significantly sensitizes the cells to chemotherapeutic drugs and also contributes as an antagonist of p53-mediated cell death. Nanoformulations can easily target the HIF-1α factor to resume apoptotic signalling and contribute to the reversal of drug resistance. Tian et al. investigated the role of polymeric nanomaterials that mimic the cancer cell membrane and could be conjugated with haemoglobin and doxorubicin for reversal of drug resistance. The haemoglobin has an oxygen-carrying capacity that suppresses the expression of the HIF-1α factor, further downregulating the MDR1 gene and enhancing cytotoxicity in MCF-7 and MCF-10A cell lines . Yang et al. demonstrated the application of silver nitrate nanoparticles (AgNPs) to target angiogenesis by downregulating VEGF and GLUT1 gene expression and inhibiting HIF-1α signaling in MCF-7 cells . Liu et al. evaluated the role of nanomicelles decorated with siRNA specific to silence the HIF-1α gene (siHIF) and doxorubicin in prostate cancer PC3 cells and in a xenograft mice model. Their findings indicated the inhibition of cell proliferation, disturbed angiogenesis and suppressed migration of cells in hypoxic conditions along with tumor growth inhibition in PC3 xenograft mice without elicitation of any immune reaction. siHIF-decorated nanomicelles downregulate MDR1 gene expression and also sensitize the cells to doxorubicin under a hypoxic environment . Lian et al. demonstrated the co-delivery of siHIF and cisplatin-conjugated chitosan-modified TPGS-b-(PCL-ran-PGA) nanoparticles in nasopharyngeal carcinoma for improved reversal of drug resistance in CNE-2 cells. The observations showed that silencing HIF-1α gene expression eventually inhibits P-gp expression, enhancing the sensitivity of cisplatin in multidrug-resistant cancer cells . Song et al. observed that perfluorocarbon nanocarriers supply oxygen targeted to the tumor hypoxic microenvironment in tumor-bearing nude mice for lung re-oxygenation and to overcome drug resistance . Alsaab et al. reported co-delivery of sorafenib and CA IX-C4.16 by TPGS nanoparticles in multidrug-resistant cancer cells to overcome hypoxia-mediated MDR. Sorafenib inhibited the p-AKT signaling pathway and upregulated the tumoricidal M1 macrophage by inducing caspase 3/7 apoptotic pathways in experimental human renal cell carcinoma A498/Evr resistant cells and RAW 264.7 macrophages .
Nanomedical approaches to combat MDR mediated by dysfunctional cell cycle regulation
Cell cycle regulation is essential for proper cell division and growth; it is maintained and regulated by cyclins and cyclin-dependent kinases (CDKs). Some chemotherapeutic drugs specifically target different stages of the cell cycle to arrest the cell growth of rapidly dividing cancer cells. The overexpression of CDKs in cancer cells can also account for resistance to conventional chemotherapy . A recent review published by Si et al. explains the crucial role of miRNA regulation in different types of cancer . Polymeric nanosystem-mediated delivery of miRNA modulates CDK expression to overcome drug resistance. Co-delivery of miRNA with CDK inhibitors has a synergistic effect that enhances inhibition of tumor development and reversal of drug resistance. For example, Hallaj et al. showed the role of folic acid-conjugated chitosan nanoparticles for co-delivery of anti-CD73 siRNA and dinaciclib to manage tumor growth and to reverse drug resistance in murine breast cancer 4T1 cells, murine colon cancer CT26 cells and in xenograft mice . Targeting the CDK4/6 cell cycle machinery using palbociclib and hydroxychloroquine-conjugated silica nanoparticles enhanced the biodistribution profile of chemotherapeutics and contributed to the reversal of MDR in pancreatic ductal adenocarcinoma in a xenograft mice model . Deng et al. demonstrated the co-delivery of mir-34a and doxorubicin in hyaluronic acid-functionalized chitosan nanoparticles to target apoptotic signaling pathways. Their results demonstrated the enhanced delivery of a nanoformulation into tumor cells and inhibition of Bcl-2 expression and Notch-1 signaling pathways in human breast cancer MDA-MB-231 cells and in nude BALB/c mice . Mittal et al. synthesized nanomicelles for co-delivery of gemcitabine and miRNA-205 in pancreatic cancer MIA PaCa-2R and CAPAN-1R cells and nude xenograft mice. Their results showed sustained drug release and miRNA-205-mediated suppression of tumor growth, activation of apoptosis-mediated signaling pathways and reversal of drug resistance . Because nanoparticles are able to cross the blood–brain barrier, a siRNA-conjugated liposomal nanoformulation was used to overcome drug resistance in glioma CSCs. The glioblastoma cells typically have elevated levels of O6-methylguanine DNA methyltransferase (MGMT), a DNA repair protein that facilitates acquired drug resistance. In another study, Kato et al. synthesized a novel liposomal nanoformulation known as LipoTrust conjugated with siRNA that is able to silence the gene responsible for MGMT and enhance the sensitivity of glioma cells to treatment. Treatment with the nanoformulation led to a reduction in tumor volume and inhibition of the activity of the MGMT enzyme in a majority of the cells and in a xenograft mouse model .
Nanomedical approaches to combat detoxification system-mediated MDR
Cytochrome P450 (CYP) superfamily enzymes oxidize fatty acids, steroids, and xenobiotics. They are involved in the clearance of various compounds from cells. In addition to carcinogenesis, CYP2 and CYP3 enzymes also contribute to MDR by activation or degradation of chemotherapeutic agents. There is a significant correlation between the upregulation of CYP enzymes and induction of the efflux transporters involved in the metabolism and detoxification of a wide spectrum of anticancer drugs, leading to MDR in cancer cells [184, 185]. For instance, the therapeutic effect of docetaxel was found to be constrained by CYP3A4/5 enzymes by oxidation to form pharmacologically inactive metabolites including t-butyl hydroxy docetaxel . Other anticancer drugs such as paclitaxel, vincristine, teniposide, vinblastine, etc., are substrates of both CYP3A4 and P-gp [187,188,189,190]. Glutathione S-transferases (GSTs) also function along with efflux transporters where substrates or pharmacologically inactive metabolites conjugated with GSH tend to be effluxed by MRP transporters from the body . A significant correlation has been established between CYP enzymes and drug efflux transporters. Hence, inhibition of CYP enzymes could also constitute an alternative therapy to overcome MDR . Nanomaterials can actively modulate the regulation of CYP enzymes, serving as an anticancer therapy. Minko et al. demonstrated that doxorubicin conjugated with an HPMA copolymer has the potential to reverse drug resistance by inhibiting the drug detoxification system, inducing apoptosis by enhancing DNA damage and also suppressing UDP and glutathione expression . Han and co-workers showed that inhibition of GST through ethacrynic acid-conjugated polymeric nanoparticles (MPEG-PLA-SS-ECA) could overcome the tumor cell detoxification system and associated drug resistance. Their findings demonstrate enhanced delivery of ethacrynic acid and inhibition of GST in cell lines. Two modifications were prepared for the purpose of disrupting the tumor detoxification system and overcoming drug resistance in oral squamous carcinoma SCC15/CBP and SCC15/PYM resistant cells, pingyangmycin (MPEG-PLA-SS-ECA/PYM) and carboplatin (MPEG-PLA-SS-ECA/CBP) . Niu et al. developed organosilicate nanoparticles for co-delivery of ethacrynic acid (EA) and cisplatin to inhibit GST and intracellular GSH detoxification. The EA treatment induced inhibition of GST and enhanced intracellular uptake of cisplatin, synergistically preventing cellular detoxification in A375/DDP cells and suppressing tumor development in a nude xenograft murine model . Wu et al. demonstrated the co-delivery of buthionine sulfoximine (a GSH inhibitor), celecoxib (a P-gp inhibitor) and doxorubicin in hybrid polymeric nanoparticles. They found that there was enhanced downregulation of GSH and P-gp expression and elevated intracellular doxorubicin retention in MCF-7/ADR cells. This nanomediated drug delivery platform exhibited the improved delivery of multiple target inhibitors and potent chemotherapeutic drugs to efficiently overcome MDR . Zhu et al. developed cisplatin-conjugated 2-dimensional (2-D)-titanium carbide nanomaterials and evaluated their potency in non-small lung carcinoma A549/DDP-resistant cells and nude xenograft mice. Their results showed that the 2D nanomaterials interfered with total glutathione (GSH/GSSG) levels, expression of glutamylcysteine synthetase and glutathione peroxidase in both resistant cell lines and a murine model. The titanium carbide 2D nanomaterials also revealed excellent biocompatibility in a murine model, enhanced intracellular accumulation of cisplatin and suppression of tumor growth . Wang et al. developed a glucosamine-grafted and doxorubicin-loaded hybrid nanosystem that interacted with GLUT1 receptors to enhance targeted receptor-mediated endocytosis in MCF-7 and MCF-7/ADR cells and tumor bearing nude xenograft mice. Due to elevated levels of GSH within cells, the pluronic L61 entity of the nanosystem induced intracellular ROS generation, release of cytochrome-c and also disruption of mitochondrial respiration. Intracellular doxorubicin accumulation was observed in cells that led to inhibition of cancer cell growth and tumor development, eventually facilitating the reversal of drug resistance . Wang and co-workers demonstrated a long-term effect of copper nanoparticles (CuNPs) on CYP450 enzymes in rat brains. Their findings proved that a higher dose of CuNPs induces oxidative stress via hydroxyl radicals and malondialdehyde in the brain and a simultaneous decrease in the cellular intrinsic antioxidant enzyme system (total superoxide dismutase, glutathione). CuNPs also led to a reduction in the protein expression of CYP450 2C11/3A1 and eventually a reversal of the associated drug resistance in male rats .
Nanotechnology-based approaches to combat MDR mediated by apoptotic pathways
Downregulation of apoptotic pathways is often observed in cancer cells. Activation of certain signal transduction pathways is known to result in decreased apoptotic cell death in cancer cells . For example, upregulation of STAT family transcription factors plays a crucial role in cancer cell growth and metastasis, eventually leading to clinical MDR . Also, a dysfunctional TP53 gene results in attenuated apoptosis in multidrug-resistant cancer cells [162, 199]. Engineered nanomaterial that targets multiple molecular pathways is an ideal therapeutic platform to eliminate MDR. Prabha et al. studied the efficacy of wild-type p53 DNA loaded into PLGA nanoparticles to treat breast cancer, and evaluated their antiproliferative activity. They found the stable and sustained transfer of the wild-type p53 gene into cells with antiproliferative activity to overcome drug resistance . Choi et al. synthesized solid lipid nanoparticles for gene delivery to overcome drug resistance. Their results indicated efficient delivery of the p53 gene (plasmid DNA; pp53-EGFP) through nanoparticles in non-small cell lung carcinoma H1299 cells and in a xenograft murine model with improved biodistribution, inhibition of cell growth, suppression of tumor development and upregulated apoptotic pathways . Wang et al. utilized the co-delivery of Bcl-2-specific siRNA and paclitaxel through a liposomal nanoformulation with the aim of silencing Bcl-2-mediated signaling pathways and suppression of tumor growth in human breast cancer MDA-MB-231 cells and in a 4T1 mouse model to facilitate the reversal of drug resistance . Saad et al. also demonstrated the co-delivery of doxorubicin and siRNA specific to MRP1 and Bcl-2 mRNA via cationic liposomal nanoformulations to overcome drug resistance not related to drug efflux. Their results showed efficient drug accumulation, inhibition of efflux pumps via MRP1 gene expression and induction of cell death mechanisms in human lung cancer H69AR cells, MCF-7/AD breast cancer cells, HCT15 colon cancer cells and A2780/AD ovarian cancer cells . Chen et al. reported co-delivery of doxorubicin and Bcl-2 targeting siRNA via mesoporous silica nanoparticles resulting in enhanced cytotoxicity in human A2780/AD ovarian cancer cells. These nanoparticles bypassed efflux pumps and were internalized in perinuclear regions, thereby reversing drug resistance not dependent upon efflux pumps . In another study, Fan and co-workers investigated folic acid-conjugated chitosan nanomicelles for the co-delivery of pyrrolidinedithiocarbamate (PDTC) and doxorubicin to reverse drug resistance in HepG2 liver cancer drug-resistant cells. PDTC is a potent NF-κB inhibitor. After the nanomicelles were internalized within resistant cells, NF-κB signaling was blocked and intracellular doxorubicin delivery and retention were enhanced, further overcoming drug resistance .
Nanotechnology-based approaches to combat tumor cell heterogeneity and cancer stem cell-mediated MDR
Tumor heterogeneity is a distinct phenomenon that is a major impediment to the treatment of cancer. Clonal and subclonal mutations are mainly responsible for the heterogeneity of tumors. Heterogeneity also occurs due to the self-renewal and differentiation properties of tumors . Genetic and environmental factors are the main causes of tumor heterogeneity and progression. It has been observed that subclonal mutations are enhanced in patients who receive chemotherapy mainly because the clonal population is eliminated by chemotherapeutic drugs during the initial treatment . The emergence of resistant subclones that appear after the initial treatment instigates tumor expansion and eventually recurrence of tumors in the patients . Tumor heterogeneity influences chemotherapeutic sensitivity and stimulates MDR mechanisms. Researchers are actively exploiting various nanosystems designed to circumvent MDR mediated by tumor heterogeneity. Ling et al. investigated pH-sensitive magnetic iron oxide nanoparticles (PMNs) for the treatment of resistant heterogeneous tumors in-vivo. The PMNs were used for diagnosis of early stage resistant heterogeneous tumors. They allowed dual-modal tumor diagnosis via MRI and fluorescence imaging of tumors with diameters up to 3 mm. PMNs engineered to respond to pH conditions within the tumor could be an efficient treatment strategy to overcome MDR . Liu and co-workers applied the CRISPR/Cas9-based nanosystem nano-Cas9 ribonucleoprotein system (nanoRNP) to effectively combat tumor heterogeneity-mediated MDR. The nanoRNP conjugated with single guide RNAs (sgRNAs) specifically targeted and disrupted STAT3 and RUNX1 expression, thereby inhibiting the heterogenous tumor populations in glioblastoma U87MG cells and in a xenograft model .
Cancer stem cells (CSCs) are groups of cells (small subpopulations less than 1%) within a tumor that are characterized by stem-cell-like properties such as the ability to self-renew and to differentiate, leading to heterogeneity and acquired resistance to chemo- and/or radiotherapy . Most chemotherapeutic drugs target rapidly dividing cells and therefore do not affect dormant CSCs. Active DNA repair signaling contributes to acquired MDR mechanisms in CSCs. The Notch pathway, Wnt/β signaling and elevated expression of ABC drug efflux transporters allow increased survival, stability and the slow proliferation rate of CSCs . After initial chemotherapy, resistant CSCs repopulate the tumor by self-renewal and generate highly differentiated subpopulations. Cell surface markers such as CD133 and CD44 have exclusively been associated with the CSC phenotypic characteristics in different cancer types [211, 212]. Precise targeting of CSCs with drugs for their elimination is urgently needed to manage cancer relapse and recurrence. Elimination of CSCs via nanoformulations is one promising approach to overcoming MDR. Mamaeva et al. targeted the Notch signaling pathway, which is a potential regulator of CSCs and facilitates cancer progression. A nanomediated strategy to block the Notch pathway could work efficiently against CSCs. γ-secretase inhibitors (GSIs) conjugated with MSNs have demonstrated significant blocking of the Notch signaling pathway and reduction in tumor growth in in-vivo xenograft model after oral delivery of nanoparticles [28, 213].
Nanoconjugated gene silencing strategies have also been employed to target MDR-specific genes and inhibit CSC-mediated drug resistance. In one study, a lipid-based nanoformulation for co-delivery of paclitaxel and siRNA targeting CD133+ cells was evaluated to target the specific subsets of cells that are responsible for drug resistance and progression of colon cancer. The nanoformulation was evaluated in CHOK1 cells and gene silencing via siMDR1 was performed in CD133+ HT-29 colon cells which exhibited efficient MDR1 gene knockdown and enhanced intracellular retention of paclitaxel and associated antitumor potency in colon cancer CSCs .
Tissue transglutaminase (TG-2) is a multifunctional enzyme and another key regulator that has a crucial role in CSC-mediated cancer progression and drug resistance. Verma et al. targeted the TG2 enzyme via co-delivery of gemcitabine and a siRNA-conjugated liposomal nanoformulation in pancreatic ductal adenocarcinoma (PDAC) nude mice. Their results showed efficient downregulation of endogenous TG2 by siRNA, inhibiting the growth of PDAC and further enhancing therapeutic antitumor activity . Barth and co-workers synthesized indocyanine green (ICG)-conjugated calcium phosphosilicate nanoparticles (ICG-CPS NPs) for diagnostic imaging and drug delivery to CSC-mediated drug-resistant cancers. CD117 antigens are found abundantly on leukemia stem cells, so the ICG-CPS nanoparticles were decorated with anti-CD117 mAbs for direct targeting of NPs to CD117+ leukemia stem cells. The nanoformulation was found to mediate the elimination of specific leukemic cell populations responsible for drug resistance and disease progression in human samples as well as in a C3H/HeJ murine leukemia model .
Conclusion and future prospective
Nanomaterials offer an extraordinary platform to overcome the limitations imposed by different mechanisms involved in the development of MDR. Combining conventional treatments with current nanotechnology advances might be a promising therapeutic approach to eliminate multidrug-resistant cancer. Nanomaterials are able to block P-gp and ABCG2 pumps and/or bypass the transporters to reverse drug-efflux-mediated MDR. Furthermore, nanomaterials functionalized with different targeting ligands allow therapeutic drugs to reach tumor sites directly via blood circulation. pH-sensitive nanosystems can exploit hypoxic tumor microenvironments, thereby reducing the expression of pro-angiogenic factors via downregulating the expression of HIF-1α. Stimuli-responsive nanosystems take advantage of unique cellular properties including pH variation, redox potential as well as enzymatic activation to overcome the MDR phenomena. Thermal, magnetic and light-based nanosystems have recently been identified for efficient reversal of drug resistance. Antibody-functionalized metal nanosystems can actively target and recognize multidrug-resistant tumor cells. Nanoparticles functionalized with siRNA are able to reprogram the gene expression pattern of resistant cells. Furthermore, nanomaterials improve the therapeutic specificity and enhance the biodistribution and pharmacokinetics of chemotherapeutic drugs. There are currently many nano-based formulations in clinical trials, and some are now used in the clinic. The merits of nanosystems need to be further explored to effectively combat drug-resistant cancer.
Availability of data and materials
Amphiphilic drug-drug conjugate
Aerosol OT (sodium bis(2-ethylhexyl)) sulfosuccinate
- Fe3O4 :
Poly(ethylene glycol) monomethyl ether
Multiwalled carbon nanotubes
Poly butyl ether
- P(OEGMA 300):
Poly (oligo [ethylene glycol] methyl ether methacrylate
Poly (2-hydroxyethyl methacrylate)
Poly-juglanin-dithiodipropionic acid-b-poly ethylene glycol
Poly lactic acid
Reactive oxygen species
Superparamagnetic iron oxide nanoparticles
Trans-Activator of Transcription
Tocopheryl polyethylene glycol succinate
Tumor targeting Calcium ion nanogenerator
Pickup MW, Mouw JK, Weaver VM. The extracellular matrix modulates the hallmarks of cancer. EMBO Rep. 2014;15:1243–53.
Cancer. https://www.who.int/news-room/fact-sheets/detail/cancer. World Health Organization. Accessed 9 Aug 2022.
Megget K: Chemotherapy causes death in more than 25% of cancer patients. In PharmaTimes online. https://www.pharmatimes.com/news/chemotherapy_causes_death_in_more_than_25_of_cancer_patients_986391: PharmaTimes Media Limited; 2008. Accessed 9 Aug 2022.
Boyle JM, Kuryba A, Cowling TE, van der Meulen J, Fearnhead NS, Walker K, Braun MS, Aggarwal A. Survival outcomes associated with completion of adjuvant oxaliplatin-based chemotherapy for stage III colon cancer: a national population-based study. I J Cancer. 2022;150:335–46.
Überrück L, Nadiradze G, Yurttas C, Königsrainer A, Königsrainer I, Horvath P. In-hospital mortality and complication rates according to health insurance data in patients undergoing hyperthermic intraperitoneal chemotherapy for peritoneal surface malignancies in Germany. Annals Surgical Oncol. 2021;28:3823–30.
Maeda H, Khatami M. Analyses of repeated failures in cancer therapy for solid tumors: poor tumor-selective drug delivery, low therapeutic efficacy and unsustainable costs. Clin Transl Med. 2018;7:11–11.
Mansoori B, Mohammadi A, Davudian S, Shirjang S, Baradaran B. The different mechanisms of cancer drug resistance: a brief review. Adv Pharmaceut Bull. 2017;7:339–48.
Wang X, Zhang H, Chen X. Drug resistance and combating drug resistance in cancer. Cancer Drug Resist. 2019;2:141–60.
Housman G, Byler S, Heerboth S, Lapinska K, Longacre M, Snyder N, Sarkar S. Drug resistance in cancer: an overview. Cancers. 2014;6:1769–92.
Qin S, Jiang J, Lu Y, Nice EC, Huang C, Zhang J, He W. Emerging role of tumor cell plasticity in modifying therapeutic response. Signal Transduct Target Ther. 2020;5:228.
Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene. 2003;22:7468–85.
Zheng Y, Ma L, Sun Q. Clinically-relevant ABC transporter for anti-cancer drug resistance. Front Pharmacol. 2021;12:648407.
Rabik CA, Dolan ME. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev. 2007;33:9–23.
Muley H, Fadó R, Rodríguez-Rodríguez R, Casals N. Drug uptake-based chemoresistance in breast cancer treatment. Biochem Pharmacol. 2020;177: 113959.
Lusvarghi S, Robey RW, Gottesman MM, Ambudkar SV: Multidrug transporters: recent insights from cryo-electron microscopy-derived atomic structures and animal models. F1000Research 2020;9:F1000 Faculty Rev-1017.
Neophytou CM, Panagi M, Stylianopoulos T, Papageorgis P. The role of tumor microenvironment in cancer metastasis: molecular mechanisms and therapeutic opportunities. Cancers. 2021;13:2053.
Huang R, Zhou P-K. DNA damage repair: historical perspectives, mechanistic pathways and clinical translation for targeted cancer therapy. Signal Transduct Target Ther. 2021;6:254.
Rebucci M, Michiels C. Molecular aspects of cancer cell resistance to chemotherapy. Biochem Pharmacol. 2013;85:1219–26.
Li L-Y, Guan Y-D, Chen X-S, Yang J-M, Cheng Y. DNA repair pathways in cancer therapy and resistance. Front Pharmacol. 2021;11:629266.
Pinto L, Baidarjad H, Entz-Werlé N, Van Dyck E. Impact of chromatin dynamics and DNA repair on genomic stability and treatment resistance in pediatric high-grade gliomas. Cancers. 2021;13:5678.
Jing X, Yang F, Shao C, Wei K, Xie M, Shen H, Shu Y. Role of hypoxia in cancer therapy by regulating the tumor microenvironment. Mol Cancer. 2019;18:157.
Pistritto G, Trisciuoglio D, Ceci C, Garufi A, D’Orazi G. Apoptosis as anticancer mechanism: function and dysfunction of its modulators and targeted therapeutic strategies. Aging. 2016;8:603–19.
Møller MB, Gerdes A-M, Skjødt K, Mortensen LS, Pedersen NT. Disrupted p53 function as predictor of treatment failure and poor prognosis in B- and T-cell non-Hodgkin’s Lymphoma. Clin Cancer Res. 1999;5:1085.
Yu L, Yu T-T, Young KH. Cross-talk between Myc and p53 in B-cell lymphomas. Chronic Diseases Transl Med. 2019;5:139–54.
Akhdar H, Legendre C, Aninat C, More F. Anticancer drug metabolism: chemotherapy resistance and new therapeutic approaches. In: Paxton J, editor. Topics on drug metabolism. London: IntechOpen; 2012. https://doi.org/10.5772/30015.
Alrohaimi A, Alrohaimi B, Alruwais N, Aldmasi K. Interindividual variability of cytochromes P450 2B mediated oxidation in human liver. Pharmacogenetics. 2021;8:47.
Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 2018;15:81–94.
Vinogradov S, Wei X. Cancer stem cells and drug resistance: the potential of nanomedicine. Nanomedicine. 2012;7:597–615.
Phi LTH, Sari IN, Yang Y-G, Lee S-H, Jun N, Kim KS, Lee YK, Kwon HY. Cancer Stem Cells (CSCs) in Drug Resistance and their Therapeutic Implications in Cancer Treatment. Stem Cells Int. 2018;2018:5416923.
Mohammad IS, He W, Yin L. Understanding of human ATP binding cassette superfamily and novel multidrug resistance modulators to overcome MDR. Biomed Pharmacother. 2018;100:335–48.
Wang J-Q, Wu Z-X, Yang Y, Teng Q-X, Li Y-D, Lei Z-N, Jani KA, Kaushal N, Chen Z-S. ATP-binding cassette (ABC) transporters in cancer: a review of recent updates. J Evid Based Med. 2021;14:232–56.
Sharma P, Singh N, Sharma S. ATP binding cassette transporters and cancer: revisiting their controversial role. Pharmacogenomics. 2021;22:1211–35.
Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding cassette (ABC) transporter family. Hum Genomics. 2009;3:281–90.
Finch A, Pillans P. P-glycoprotein and its role in drug-drug interactions. Aust Prescr. 2014;37:137–9.
Lai J-I, Tseng Y-J, Chen M-H, Huang C-YF, Chang PM-H. Clinical perspective of FDA approved drugs with P-glycoprotein inhibition activities for potential cancer therapeutics. Front Oncol. 2020;10:561936–561936.
Liu XD, Zhang L, Xie L. Effect of P-glycoprotein inhibitors erythromycin and cyclosporin A on brain pharmacokinetics of nimodipine in rats. Eur J Drug Metab Pharmacokinet. 2003;28:309–13.
Srivalli KMR, Lakshmi PK. Overview of P-glycoprotein inhibitors: a rational outlook. Brazilian J Pharmaceut Sci. 2012;48:353–67.
Den Boer ML, Pieters R, Kazemier KM, Janka-Schaub GE, Henze G, Veerman AJP. The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia. Leukemia. 1998;12:912–20.
Shukla S, Ohnuma S, Ambudkar SV. Improving cancer chemotherapy with modulators of ABC drug transporters. Curr Drug Targets. 2011;12:621–30.
Dash RP, Jayachandra Babu R, Srinivas NR. Therapeutic potential and utility of elacridar with respect to P-glycoprotein Inhibition: an insight from the published in vitro, preclinical and clinical studies. Eur J Drug Metab Pharmacokinet. 2017;42:915–33.
Muthusamy G, Gunaseelan S, Prasad NR. Ferulic acid reverses P-glycoprotein-mediated multidrug resistance via inhibition of PI3K/Akt/NF-κB signaling pathway. J Nutr Biochem. 2019;63:62–71.
Ganesan M, Kanimozhi G, Pradhapsingh B, Khan HA, Alhomida AS, Ekhzaimy A, Brindha GR, Prasad NR. Phytochemicals reverse P-glycoprotein mediated multidrug resistance via signal transduction pathways. Biomed Pharmacother. 2021;139: 111632.
Chung SY, Sung MK, Kim NH, Jang JO, Go EJ, Lee HJ. Inhibition of P-glycoprotein by natural products in human breast cancer cells. Arch Pharmacal Res. 2005;28:823–8.
Dewanjee S, Dua TK, Bhattacharjee N, Das A, Gangopadhyay M, Khanra R, Joardar S, Riaz M, Feo VD, Zia-Ul-Haq M. Natural products as alternative choices for P-Glycoprotein (P-gp) inhibition. Molecules. 2017;22:871.
Roskoski R. Properties of FDA-approved small molecule protein kinase inhibitors: a 2020 update. Pharmacol Res. 2020;152: 104609.
Pottier C, Fresnais M, Gilon M, Jérusalem G, Longuespée R, Sounni NE. Tyrosine kinase inhibitors in cancer: breakthrough and challenges of targeted therapy. Cancers. 2020;12:731.
Bhullar KS, Lagarón NO, McGowan EM, Parmar I, Jha A, Hubbard BP, Rupasinghe HPV. Kinase-targeted cancer therapies: progress, challenges and future directions. Mol Cancer. 2018;17:48–48.
Shukla S, Patel A, Ambudkar SV. Mechanistic and pharmacological insights into modulation of ABC drug transporters by Tyrosine Kinase Inhibitors. In ABC Transporters-40 Years on. Springer; Drug Resist Updat. 2016: 227–272
Lemos C, Jansen G, Peters GJ. Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors. Br J Cancer. 2008;98:857–62.
Sims JT, Ganguly SS, Bennett H, Friend JW, Tepe J, Plattner R. Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1. PLoS ONE. 2013;8: e55509.
Guo X, To KKW, Chen Z, Wang X, Zhang J, Luo M, Wang F, Yan S, Fu L. Dacomitinib potentiates the efficacy of conventional chemotherapeutic agents via inhibiting the drug efflux function of ABCG2 in vitro and in vivo. J Exper Clin Cancer Res. 2018;37:31.
Narayanan S, Wu Z-X, Wang J-Q, Ma H, Acharekar N, Koya J, Yoganathan S, Fang S, Chen Z-S, Pan Y. The spleen tyrosine kinase inhibitor, entospletinib (GS-9973) restores chemosensitivity in lung cancer cells by modulating ABCG2-mediated multidrug resistance. Int J Biol Sci. 2021;17:2652–65.
Du W, Huang H, Sorrelle N, Brekken RA: Sitravatinib potentiates immune checkpoint blockade in refractory cancer models. JCI Insight 2018;3.
Kannaiyan R, Mahadevan D. A comprehensive review of protein kinase inhibitors for cancer therapy. Exp Rev Anticancer Ther. 2018;18:1249–70.
Huang L, Jiang S, Shi Y. Tyrosine kinase inhibitors for solid tumors in the past 20 years (2001–2020). J Hematol Oncol. 2020;13:143.
Grossman M, Adler E. Protein kinase inhibitors—selectivity or toxicity? In: Singh RK, editor. Protein kinases—promising targets for anticancer drug research. London: IntechOpen; 2021. https://doi.org/10.5772/intechopen.98640.
Paech F, Bouitbir J, Krähenbühl S: Hepatocellular Toxicity Associated with Tyrosine Kinase Inhibitors: Mitochondrial Damage and Inhibition of Glycolysis. Front Pharmacol 2017;8.
Logashenko EB, Vladimirova AV, Repkova MN, Venyaminova AG, Chernolovskaya EL, Vlassov VV. Silencing of MDR 1 gene in cancer cells by siRNA. Nucleoside nucleotide. Nucleic Acids. 2004;23:861–6.
Patutina OA, Mironova NL, Popova NA, Kaledin VI, Nikolin VP, Vlassov VV, Zenkova MA. The siRNA targeted to mdr1b and mdr1a mRNAs in vivosensitizes murine lymphosarcoma to chemotherapy. BMC Cancer. 2010;10:204.
Dönmez Y, Gündüz U. Reversal of multidrug resistance by small interfering RNA (siRNA) in doxorubicin-resistant MCF-7 breast cancer cells. Biomed Pharmacother. 2011;65:85–9.
Panzarini E, Dini L. Nanomaterial-induced autophagy: a new reversal MDR tool in cancer therapy? Mol Pharmaceut. 2014;11:2527–38.
Liu J-P, Wang T-T, Wang D-G, Dong A-J, Li Y-P, Yu H-J. Smart nanoparticles improve therapy for drug-resistant tumors by overcoming pathophysiological barriers. Acta Pharm Sinica. 2017;38:1–8.
Mi Y, Shao Z, Vang J, Kaidar-Person O, Wang AZ. Application of nanotechnology to cancer radiotherapy. Cancer Nanotechnol. 2016;7:11.
Xu L, Liu J, Xi J, Li Q, Chang B, Duan X, Wang G, Wang S, Wang Z, Wang L. Synergized multimodal therapy for safe and effective reversal of cancer multidrug resistance based on low-level photothermal and photodynamic effects. Small. 2018;14:1800785.
Amin ML. P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights. 2013;7:27–34.
Pires MM, Emmert D, Hrycyna CA, Chmielewski J. Inhibition of P-glycoprotein-mediated paclitaxel resistance by reversibly linked quinine homodimers. Mol Pharmacol. 2009;75:92–100.
Yao Y, Zhou Y, Liu L, Xu Y, Chen Q, Wang Y, Wu S, Deng Y, Zhang J, Shao A. Nanoparticle-based drug delivery in cancer therapy and its role in overcoming drug resistance. Front Mol Biosci. 2020;7:193.
Jin K-T, Lu Z-B, Chen J-Y, Liu Y-Y, Lan H-R, Dong H-Y, Yang F, Zhao Y-Y, Chen X-Y. Recent trends in nanocarrier-based targeted chemotherapy: selective delivery of anticancer drugs for effective lung, colon, cervical, and breast cancer treatment. J Nanomater. 2020;2020:9184284.
Delou JMA, Souza ASO, Souza LCM, Borges HL. Highlights in resistance mechanism pathways for combination therapy. Cells. 2019;8:1013.
Wu S, Fu L. Tyrosine kinase inhibitors enhanced the efficacy of conventional chemotherapeutic agent in multidrug resistant cancer cells. Mol Cancer. 2018;17:25.
Attia MF, Anton N, Wallyn J, Omran Z, Vandamme TF. An overview of active and passive targeting strategies to improve the nanocarriers efficiency to tumour sites. J Pharma Pharmacol. 2019;71:1185–98.
Shi Y, van der Meel R, Chen X, Lammers T. The EPR effect and beyond: strategies to improve tumor targeting and cancer nanomedicine treatment efficacy. Theranostics. 2020;10:7921–4.
Majidinia M, Mirza-Aghazadeh-Attari M, Rahimi M, Mihanfar A, Karimian A, Safa A, Yousefi B. Overcoming multidrug resistance in cancer: recent progress in nanotechnology and new horizons. IUBMB Life. 2020;72:855–71.
Chen S, Li Q, McClements DJ, Han Y, Dai L, Mao L, Gao Y. Co-delivery of curcumin and piperine in zein-carrageenan core-shell nanoparticles: formation, structure, stability and in vitro gastrointestinal digestion. Food Hydrocoll. 2020;99: 105334.
Xiong K, Zhang Y, Wen Q, Luo J, Lu Y, Wu Z, Wang B, Chen Y, Zhao L, Fu S. Co-delivery of paclitaxel and curcumin by biodegradable polymeric nanoparticles for breast cancer chemotherapy. Int J Pharma. 2020;589: 119875.
Riganti C, Voena C, Kopecka J, Corsetto PA, Montorfano G, Enrico E, Costamagna C, Rizzo AM, Ghigo D, Bosia A. Liposome-encapsulated doxorubicin reverses drug resistance by inhibiting P-glycoprotein in human cancer cells. Mol Pharm. 2011;8:683–700.
Tang J, Ji H, Ren J, Li M, Zheng N, Wu L. Solid lipid nanoparticles with TPGS and Brij 78: a co-delivery vehicle of curcumin and piperine for reversing P-glycoprotein-mediated multidrug resistance in vitro. Oncol Lett. 2017;13:389–95.
Wu C, Gong M-Q, Liu B-Y, Zhuo R-X, Cheng S-X. Co-delivery of multiple drug resistance inhibitors by polymer/inorganic hybrid nanoparticles to effectively reverse cancer drug resistance. Colloids Surf B: Biointerfaces. 2017;149:250–9.
Lee S-M, Kim HJ, Kim SY, Kwon M-K, Kim S, Cho A, Yun M, Shin J-S, Yoo K-H. Drug-loaded gold plasmonic nanoparticles for treatment of multidrug resistance in cancer. Biomaterials. 2014;35:2272–82.
Cheng J, Wang J, Chen B, Xia G, Cai X, Liu R, Ren Y, Bao W, Wang X. A promising strategy for overcoming MDR in tumor by magnetic iron oxide nanoparticles co-loaded with daunorubicin and 5-bromotetrandrin. Int J Nanomed. 2011;6:2123.
Byeon Y, Lee J-W, Choi WS, Won JE, Kim GH, Kim MG, Wi TI, Lee JM, Kang TH, Jung ID, et al. CD44-targeting PLGA nanoparticles incorporating paclitaxel and FAK siRNA overcome chemoresistance in epithelial ovarian cancer. Cancer Res. 2018;78:6247.
Hallaj S, Heydarzadeh Asl S, Alian F, Farshid S, Eshaghi FS, Namdar A, Atyabi F, Masjedi A, Hallaj T, Ghorbani A, et al. Inhibition of CD73 using folate targeted nanoparticles carrying anti-CD73 siRNA potentiates anticancer efficacy of Dinaciclib. Life Sci. 2020;259: 118150.
Xu P-Y, Kankala RK, Pan Y-J, Yuan H, Wang S-B, Chen A-Z. Overcoming multidrug resistance through inhalable siRNA nanoparticles-decorated porous microparticles based on supercritical fluid technology. Int J Nanomed. 2018;13:4685–98.
Anselmo AC, Mitragotri S. Nanoparticles in the clinic: an update. Bioengineer Transl Med. 2019;4:e10143–e10143.
Miller DS. Regulation of ABC transporters at the blood-brain barrier. Clin Pharmacol Ther. 2015;97:395–403.
Begicevic R-R, Falasca M. ABC transporters in cancer stem cells: beyond chemoresistance. Int J Mol Sci. 2017;18:2362.
Teleanu DM, Chircov C, Grumezescu AM, Volceanov A, Teleanu RI. Blood-brain delivery methods using nanotechnology. Pharmaceutics. 2018;10:269.
Tang W, Fan W, Lau J, Deng L, Shen Z, Chen X. Emerging blood–brain-barrier-crossing nanotechnology for brain cancer theranostics. Chem Society Rev. 2019;48:2967–3014.
Gregory JV, Kadiyala P, Doherty R, Cadena M, Habeel S, Ruoslahti E, Lowenstein PR, Castro MG, Lahann J. Systemic brain tumor delivery of synthetic protein nanoparticles for glioblastoma therapy. Nat Commun. 2020;11:5687.
Ashrafzadeh MS, Akbarzadeh A, Heydarinasab A, Ardjmand M. In vivo glioblastoma therapy using targeted liposomal cisplatin. Int J Nanomed. 2020;15:7035–49.
Mfouo Tynga I, Abrahamse H. Nano-mediated photodynamic therapy for cancer: enhancement of cancer specificity and therapeutic effects. Nanomaterials. 2018;8:923.
Li R, Chen Z, Dai Z, Yu Y. Nanotechnology assisted photo- and sonodynamic therapy for overcoming drug resistance. Cancer Biol Med. 2021;18:388–400.
Liu Y, Cui J, Su M, Zhang D, Bai M: Overcoming chemoresistance using tumor mitochondria-targeted photodynamic therapy. In; 2019. Proc. SPIE: 6–12.
Guo D, Xu S, Huang Y, Jiang H, Yasen W, Wang N, Su Y, Qian J, Li J, Zhang C, Zhu X. Platinum(IV) complex-based two-in-one polyprodrug for a combinatorial chemo-photodynamic therapy. Biomaterials. 2018;177:67–77.
Li Z, Cai Y, Zhao Y, Yu H, Zhou H, Chen M. Polymeric mixed micelles loaded mitoxantrone for overcoming multidrug resistance in breast cancer via photodynamic therapy. Int J Nanomed. 2017;12:6595–604.
Li C, Zhang J, Zu Y-J, Nie S-F, Cao J, Wang Q, Nie S-P, Deng Z-Y, Xie M-Y, Wang S. Biocompatible and biodegradable nanoparticles for enhancement of anti-cancer activities of phytochemicals. Chin J Nat Med. 2015;13:641–52.
Sundar S, Kundu J, Kundu SC. Biopolymeric nanoparticles. Sci Technol Adv Material. 2010;11:014104–014104.
Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015;33:941–51.
Wei X, Song M, Li W, Huang J, Yang G, Wang Y. Multifunctional nanoplatforms co-delivering combinatorial dual-drug for eliminating cancer multidrug resistance. Theranostics. 2021;11:6334–54.
Famta P, Shah S, Chatterjee E, Singh H, Dey B, Guru SK, Singh SB, Srivastava S. Exploring new Horizons in overcoming P-glycoprotein-mediated multidrug-resistant breast cancer via nanoscale drug delivery platforms. Curr Res Pharmacol Drug Disc. 2021;2: 100054.
Kapse-Mistry S, Govender T, Srivastava R, Yergeri M. Nanodrug delivery in reversing multidrug resistance in cancer cells. Front Pharmacol. 2014;5:159–159.
Li B, Xu H, Li Z, Yao M, Xie M, Shen H, Shen S, Wang X, Jin Y. Bypassing multidrug resistance in human breast cancer cells with lipid/polymer particle assemblies. Int J Nanomed. 2012;7:187–97.
Das M, Sahoo SK. Folate decorated dual drug loaded nanoparticle: role of curcumin in enhancing therapeutic potential of nutlin-3a by reversing multidrug resistance. PLoS ONE. 2012;7:e32920–e32920.
Ventola CL. Progress in nanomedicine: approved and investigational nanodrugs. Pharm Ther. 2017;42:742–55.
Tang J, Zhang L, Gao H, Liu Y, Zhang Q, Ran R, Zhang Z, He Q. Co-delivery of doxorubicin and P-gp inhibitor by a reduction-sensitive liposome to overcome multidrug resistance, enhance anti-tumor efficiency and reduce toxicity. Drug Deliv. 2016;23:1130–43.
Huwyler J, Cerletti A, Fricker G, Eberle AN, Drewe J. By-passing of P-glycoprotein using immunoliposomes. J Drug Target. 2002;10:73–9.
Li N, Mai Y, Liu Q, Gou G, Yang J. Docetaxel-loaded D-α-tocopheryl polyethylene glycol-1000 succinate liposomes improve lung cancer chemotherapy and reverse multidrug resistance. Drug Deliv Transl Res. 2021;11:131–41.
Zhu YX, Jia HR, Duan QY, Liu X, Yang J, Liu Y, Wu FG. Photosensitizer-doped and plasma membrane-responsive liposomes for nuclear drug delivery and multidrug resistance reversal. ACS Appl Mater Interfaces. 2020;12:36882–94.
Olusanya TOB, Haj Ahmad RR, Ibegbu DM, Smith JR, Elkordy AA. Liposomal drug delivery systems and anticancer drugs. Molecules. 2018;23:907.
Gavas S, Quazi S, Karpiński TM. Nanoparticles for cancer therapy: current progress and challenges. Nanoscale Res Lett. 2021;16:173.
Lancet JE, Cortes JE, Hogge DE, Tallman MS, Kovacsovics TJ, Damon LE, Komrokji R, Solomon SR, Kolitz JE, Cooper M, et al. Phase 2 trial of CPX-351, a fixed 5:1 molar ratio of cytarabine/daunorubicin, vs cytarabine/daunorubicin in older adults with untreated AML. Blood. 2014;123:3239–46.
Lv L, Qiu K, Yu X, Chen C, Qin F, Shi Y, Ou J, Zhang T, Zhu H, Wu J, et al. Amphiphilic copolymeric micelles for doxorubicin and curcumin co-delivery to reverse multidrug resistance in breast cancer. J Biomed Nanotechnol. 2016;12:973–85.
Zhang C-G, Zhu W-J, Liu Y, Yuan Z-Q, Yang S-D, Chen W-L, Li J-Z, Zhou X-F, Liu C, Zhang X-N. Novel polymer micelle mediated co-delivery of doxorubicin and P-glycoprotein siRNA for reversal of multidrug resistance and synergistic tumor therapy. Sci Rep. 2016;6:23859.
Kim T-Y, Kim D-W, Chung J-Y, Shin SG, Kim S-C, Heo DS, Kim NK, Bang Y-J. Phase I and pharmacokinetic study of Genexol-PM, a cremophor-free, polymeric micelle-formulated paclitaxel, in patients with advanced malignancies. Clin Cancer Res. 2004;10:3708–16.
Jaiswal M, Dudhe R, Sharma PK. Nanoemulsion: an advanced mode of drug delivery system. 3 Biotech. 2015;5:123–7.
Nguyen T-T-L, Duong V-A, Maeng H-J. Pharmaceutical formulations with P-glycoprotein inhibitory effect as promising approaches for enhancing oral drug absorption and bioavailability. Pharmaceutics. 2021;13:1103.
Desai N. Nanoparticle albumin-bound anticancer agents. In: Crommelin DJA, de Vlieger JSB, editors. Non-biological complex drugs: the science and the regulatory landscape. Cham: Springer; 2015. p. 335–54.
Alkhatib MH, Bawadud RS, Gashlan HM. Incorporation of docetaxel and thymoquinone in borage nanoemulsion potentiates their antineoplastic activity in breast cancer cells. Sci Rep. 2020;10:18124.
Anbazhagan R, Muthusamy G, Krishnamoorthi R, Kumaresan S, Rajendra Prasad N, Lai J-Y, Yang J-M, Tsai H-C. PAMAM G4.5 dendrimers for targeted delivery of ferulic acid and paclitaxel to overcome P-glycoprotein-mediated multidrug resistance. Biotechnol Bioeng. 2021;118:1213–23.
Liu Y, Chiu GNC. Dual-functionalized PAMAM dendrimers with improved P-glycoprotein inhibition and tight junction modulating effect. Biomacromol. 2013;14:4226–35.
Stephen ZR, Kievit FM, Zhang M. Magnetite nanoparticles for medical MR imaging. Mater Today. 2011;14:330–8.
Saravanan M, Vahidi H, Medina Cruz D, Vernet-Crua A, Mostafavi E, Stelmach R, Webster TJ, Mahjoub MA, Rashedi M, Barabadi H. Emerging antineoplastic biogenic gold nanomaterials for breast cancer therapeutics: a systematic review. Int J Nanomed. 2020;15:3577–95.
Mostafavi E, Zarepour A, Barabadi H, Zarrabi A, Truong LB, Medina-Cruz D. Antineoplastic activity of biogenic silver and gold nanoparticles to combat leukemia: beginning a new era in cancer theragnostic. Biotechnol Rep. 2022;34: e00714.
Barabadi H, Hosseini O, Damavandi Kamali K, Jazayeri Shoushtari F, Rashedi M, Haghi-Aminjan H, Saravanan M. Emerging theranostic silver nanomaterials to combat lung cancer: a systematic review. J Clust Sci. 2020;31:1–10.
Barabadi H, Vahidi H, Damavandi Kamali K, Hosseini O, Mahjoub MA, Rashedi M, Jazayeri Shoushtari F, Saravanan M. Emerging theranostic gold nanomaterials to combat lung cancer: a systematic review. J Clust Sci. 2020;31:323–30.
Barabadi H, Vahidi H, Damavandi Kamali K, Rashedi M, Hosseini O, Saravanan M. Emerging theranostic gold nanomaterials to combat colorectal cancer: a systematic review. J Clust Sci. 2020;31:651–8.
Barabadi H, Vahidi H, Mahjoub MA, Kosar Z, Damavandi Kamali K, Ponmurugan K, Hosseini O, Rashedi M, Saravanan M. Emerging antineoplastic gold nanomaterials for cervical cancer therapeutics: a systematic review. J Clust Sci. 2020;31:1173–84.
Chen B-A, Mao P-P, Cheng J, Gao F, Xia G-H, Xu W-L, Shen H-L, Ding J-H, Gao C, Sun Q, et al. Reversal of multidrug resistance by magnetic Fe3O4 nanoparticle copolymerizating daunorubicin and MDR1 shRNA expression vector in leukemia cells. Int J Nanomed. 2010;5:437–44.
Jiang Z, Chen B-A, Xia G-H, Wu Q, Zhang Y, Hong T-Y, Zhang W, Cheng J, Gao F, Liu L-J, et al. The reversal effect of magnetic Fe3O4 nanoparticles loaded with cisplatin on SKOV3/DDP ovarian carcinoma cells. Int J Nanomed. 2009;4:107–14.
Singh A, Dilnawaz F, Sahoo SK. Long circulating lectin conjugated paclitaxel loaded magnetic nanoparticles: a new theranostic avenue for leukemia therapy. PLoS ONE. 2011;6: e26803.
Wu B, Torres-Duarte C, Cole BJ, Cherr GN. Copper oxide and zinc oxide nanomaterials act as inhibitors of multidrug resistance transport in sea urchin embryos: their role as chemosensitizers. Environ Sci Technol. 2015;49:5760–70.
Norouzi M, Yathindranath V, Thliveris JA, Kopec BM, Siahaan TJ, Miller DW. Doxorubicin-loaded iron oxide nanoparticles for glioblastoma therapy: a combinational approach for enhanced delivery of nanoparticles. Sci Rep. 2020;10:11292.
Jiang Y, Wang Z, Duan W, Liu L, Si M, Chen X, Fang C-J. The critical size of gold nanoparticles for overcoming P-gp mediated multidrug resistance. Nanoscale. 2020;12:16451–61.
Rathinaraj P, Muthusamy G, Prasad NR, Gunaseelan S, Kim B, Zhu S. Folate–gold–bilirubin nanoconjugate induces apoptotic death in multidrug-resistant oral carcinoma cells. Eur J Drug Metab Pharmacokinet. 2020;45:285–96.
Dreaden EC, Raji IO, Austin LA, Fathi S, Mwakwari SC, Humphries WH, Kang B, Oyelere AK, El-Sayed MA. P-glycoprotein-dependent trafficking of nanoparticle-drug conjugates. Small. 2014;10:1719–23.
Qi L, Pan T, Ou L, Ye Z, Yu C, Bao B, Wu Z, Cao D, Dai L. Biocompatible nucleus-targeted graphene quantum dots for selective killing of cancer cells via DNA damage. Commun Biol. 2021;4:214.
Ruzycka-Ayoush M, Kowalik P, Kowalczyk A, Bujak P, Nowicka AM, Wojewodzka M, Kruszewski M, Grudzinski IP. Quantum dots as targeted doxorubicin drug delivery nanosystems in human lung cancer cells. Cancer Nanotechnol. 2021;12:8.
Son KH, Hong JH, Lee JW. Carbon nanotubes as cancer therapeutic carriers and mediators. Int J Nanomed. 2016;11:5163–85.
Sun Y, Zhang J, Yin H, Yin J. MicroRNA-mediated suppression of P-glycoprotein by quantum dots in lung cancer cells. J Appl Toxicol. 2020;40:525–34.
Luo C, Li Y, Guo L, Zhang F, Liu H, Zhang J, Zheng J, Zhang J, Guo S. Graphene quantum dots downregulate multiple multidrug-resistant genes via interacting with their C-rich Promoters. Adv Healthc Mater. 2017;6:1700328.
Liu M, Fu M, Yang X, Jia G, Shi X, Ji J, Liu X, Zhai G. Paclitaxel and quercetin co-loaded functional mesoporous silica nanoparticles overcoming multidrug resistance in breast cancer. Colloids Surf B Biointerfaces. 2020;196: 111284.
Zhao P, Li L, Zhou S, Qiu L, Qian Z, Liu X, Cao X, Zhang H. TPGS functionalized mesoporous silica nanoparticles for anticancer drug delivery to overcome multidrug resistance. Mater Sci Eng C Mater Biol Appl. 2018;84:108–17.
Dong X, Mumper RJ. Nanomedicinal strategies to treat multidrug-resistant tumors: current progress. Nanomedicine. 2010;5:597–615.
Nanayakkara AK, Follit CA, Chen G, Williams NS, Vogel PD, Wise JG. Targeted inhibitors of P-glycoprotein increase chemotherapeutic-induced mortality of multidrug resistant tumor cells. Sci Rep. 2018;8:967.
Kou L, Sun R, Bhutia YD, Yao Q, Chen R. Emerging advances in P-glycoprotein inhibitory nanomaterials for drug delivery. Expert Opin Drug Deliv. 2018;15:869–79.
Abouzeid AH, Patel NR, Torchilin VP. Polyethylene glycol-phosphatidylethanolamine (PEG-PE)/vitamin E micelles for co-delivery of paclitaxel and curcumin to overcome multi-drug resistance in ovarian cancer. Int J Pharm. 2014;464:178–84.
Shafiei-Irannejad V, Samadi N, Salehi R, Yousefi B, Rahimi M, Akbarzadeh A, Zarghami N. Reversion of multidrug resistance by co-encapsulation of doxorubicin and metformin in poly(lactide-co-glycolide)-d-α-tocopheryl polyethylene glycol 1000 succinate nanoparticles. Pharm Res. 2018;35:119.
Wong HL, Bendayan R, Rauth AM, Xue HY, Babakhanian K, Wu XY. A mechanistic study of enhanced doxorubicin uptake and retention in multidrug resistant breast cancer cells using a polymer-lipid hybrid nanoparticle system. J Pharmacol Exp Ther. 2006;317:1372.
Joshi U, Filipczak N, Khan MM, Attia SA, Torchilin V. Hypoxia-sensitive micellar nanoparticles for co-delivery of siRNA and chemotherapeutics to overcome multi-drug resistance in tumor cells. Int J Pharm. 2020;590: 119915.
Lamprecht A, Benoit J-P. Etoposide nanocarriers suppress glioma cell growth by intracellular drug delivery and simultaneous P-glycoprotein inhibition. J Control Release. 2006;112:208–13.
Fan X, Cheng H, Wang X, Ye E, Loh XJ, Wu Y-L, Li Z. Thermoresponsive supramolecular chemotherapy by “V”-shaped armed β-cyclodextrin star polymer to overcome drug resistance. Adv Healthc Mater. 2018;7:1701143.
Cheng H, Fan X, Wang X, Ye E, Loh XJ, Li Z, Wu Y-L. Hierarchically self-assembled supramolecular host-guest delivery system for drug resistant cancer therapy. Biomacromol. 2018;19:1926–38.
Han W, Shi L, Ren L, Zhou L, Li T, Qiao Y, Wang H. A nanomedicine approach enables co-delivery of cyclosporin A and gefitinib to potentiate the therapeutic efficacy in drug-resistant lung cancer. Signal Transduct Target Ther. 2018;3:16.
Chow Edward K, Zhang X-Q, Chen M, Lam R, Robinson E, Huang H, Schaffer D, Osawa E, Goga A, Ho D. Nanodiamond therapeutic delivery agents mediate enhanced chemoresistant tumor treatment. Sci Transl Med. 2011;3:73ra21-73ra21.
Liu J, Zhu C, Xu L, Wang D, Liu W, Zhang K, Zhang Z, Shi J. Nanoenabled intracellular calcium bursting for safe and efficient reversal of drug resistance in tumor cells. Nano Lett. 2020;20:8102–11.
Zhao M-D, Li J-Q, Chen F-Y, Dong W, Wen L-J, Fei W-D, Zhang X, Yang P-L, Zhang X-M, Zheng C-H. Co-delivery of curcumin and paclitaxel by “core-shell” targeting amphiphilic copolymer to reverse resistance in the treatment of ovarian cancer. Int J Nanomed. 2019;14:9453–67.
Li R, Wu R, Zhao L, Wu M, Yang L, Zou H. P-Glycoprotein antibody functionalized carbon nanotube overcomes the multidrug resistance of human leukemia cells. ACS Nano. 2010;4:1399–408.
Li YT, Chua MJ, Kunnath AP, Chowdhury EH. Reversing multidrug resistance in breast cancer cells by silencing ABC transporter genes with nanoparticle-facilitated delivery of target siRNAs. Int J Nanomed. 2012;7:2473–81.
Chatterjee N, Walker GC. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen. 2017;58:235–63.
Bentires-Alj M, Barbu V, Fillet M, Chariot A, Relic B, Jacobs N, Gielen J, Merville M-P, Bours V. NF-κB transcription factor induces drug resistance through MDR1 expression in cancer cells. Oncogene. 2003;22:90–7.
Campbell KJ, Tait SWG. Targeting BCL-2 regulated apoptosis in cancer. Open Biol. 2018;8: 180002.
Liu R, Chen Y, Liu G, Li C, Song Y, Cao Z, Li W, Hu J, Lu C, Liu Y. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Disc. 2020;11:797.
Neophytou CM, Trougakos IP, Erin N, Papageorgis P. Apoptosis deregulation and the development of cancer multi-drug resistance. Cancers. 2021;13:4363.
Cho Y, Kim YK. Cancer stem cells as a potential target to overcome multidrug resistance. Front Oncol. 2020;10:764.
Chiche J, Brahimi-Horn MC, Pouysségur J. Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. J Cell Mol Med. 2010;14:771–94.
Swietach P. What is pH regulation, and why do cancer cells need it? Cancer Metastasis Rev. 2019;38:5–15.
Remant Bahadur KC, Thapa B, Xu P. pH and redox dual responsive nanoparticle for nuclear targeted drug delivery. Mol Pharm. 2012;9:2719–29.
Huo Q, Zhu J, Niu Y, Shi H, Gong Y, Li Y, Song H, Liu Y. pH-triggered surface charge-switchable polymer micelles for the co-delivery of paclitaxel/disulfiram and overcoming multidrug resistance in cancer. Int J Nanomed. 2017;12:8631–47.
Mao J, Li Y, Wu T, Yuan C, Zeng B, Xu Y, Dai L. A Simple dual-pH responsive prodrug-based polymeric micelles for drug delivery. ACS Appl Mater Interfaces. 2016;8:17109–17.
Cort A, Ozben T, Saso L, De Luca C, Korkina L. Redox control of multidrug resistance and its possible modulation by antioxidants. Oxid Med Cell Longev. 2016;2016:4251912.
Al Tameemi W, Dale TP, Al-Jumaily RMK, Forsyth NR. Hypoxia-modified cancer cell metabolism. Front Cell Dev Biol. 2019;7:4.
Tian H, Luo Z, Liu L, Zheng M, Chen Z, Ma A, Liang R, Han Z, Lu C, Cai L. Cancer cell membrane-biomimetic oxygen nanocarrier for breaking hypoxia-induced chemoresistance. Adv Funct Mater. 2017;27:1703197.
Yang T, Yao Q, Cao F, Liu Q, Liu B, Wang X-H. Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis. Int J Nanomed. 2016;11:6679–92.
Liu X-Q, Xiong M-H, Shu X-T, Tang R-Z, Wang J. Therapeutic delivery of siRNA silencing HIF-1 alpha with micellar nanoparticles inhibits hypoxic tumor growth. Mol Pharm. 2012;9:2863–74.
Lian D, Chen Y, Xu G, Zeng X, Li Z, Li Z, Zhou Y, Mei L, Li X. Delivery of siRNA targeting HIF-1α loaded chitosan modified d-α-tocopheryl polyethylene glycol 1000 succinate-b-poly(ε-caprolactone-ran-glycolide) nanoparticles into nasopharyngeal carcinoma cell to improve the therapeutic efficacy of cisplatin. RSC Adv. 2016;6:37740–9.
Song X, Feng L, Liang C, Yang K, Liu Z. Ultrasound triggered tumor oxygenation with oxygen-shuttle nanoperfluorocarbon to overcome hypoxia-associated resistance in cancer therapies. Nano Lett. 2016;16:6145–53.
Alsaab HO, Sau S, Alzhrani RM, Cheriyan VT, Polin LA, Vaishampayan U, Rishi AK, Iyer AK. Tumor hypoxia directed multimodal nanotherapy for overcoming drug resistance in renal cell carcinoma and reprogramming macrophages. Biomaterials. 2018;183:280–94.
Sun Y, Liu Y, Ma X, Hu H. The influence of cell cycle regulation on chemotherapy. Int J Mol Sci. 2021;22:6923.
Si W, Shen J, Zheng H, Fan W. The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenet. 2019;11:25.
Ji Y, Liu X, Li J, Xie X, Huang M, Jiang J, Liao Y-P, Donahue T, Meng H. Use of ratiometrically designed nanocarrier targeting CDK4/6 and autophagy pathways for effective pancreatic cancer treatment. Nat Commun. 2020;11:4249.
Deng X, Cao M, Zhang J, Hu K, Yin Z, Zhou Z, Xiao X, Yang Y, Sheng W, Wu Y, Zeng Y. Hyaluronic acid-chitosan nanoparticles for co-delivery of MiR-34a and doxorubicin in therapy against triple negative breast cancer. Biomaterials. 2014;35:4333–44.
Mittal A, Chitkara D, Behrman SW, Mahato RI. Efficacy of gemcitabine conjugated and miRNA-205 complexed micelles for treatment of advanced pancreatic cancer. Biomaterials. 2014;35:7077–87.
Kato T, Natsume A, Toda H, Iwamizu H, Sugita T, Hachisu R, Watanabe R, Yuki K, Motomura K, Bankiewicz K, Wakabayashi T. Efficient delivery of liposome-mediated MGMT-siRNA reinforces the cytotoxity of temozolomide in GBM-initiating cells. Gene Ther. 2010;17:1363–71.
McDonnell AM, Dang CH. Basic review of the cytochrome p450 system. J Adv Pract Oncol. 2013;4:263–8.
Lynch T, Price AL. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76:391–6.
Tran A, Jullien V, Alexandre J, Rey E, Rabillon F, Girre V, Dieras V, Pons G, Goldwasser F, Tréluyer JM. Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms. Clin Pharmacol Ther. 2006;79:570–80.
Hendrikx JJMA, Lagas JS, Rosing H, Schellens JHM, Beijnen JH, Schinkel AH. P-glycoprotein and cytochrome P450 3A act together in restricting the oral bioavailability of paclitaxel. Int J Cancer. 2013;132:2439–47.
Smith NF, Mani S, Schuetz EG, Yasuda K, Sissung TM, Bates SE, Figg WD, Sparreboom A. Induction of CYP3A4 by vinblastine: role of the nuclear receptor NR1I2. Ann Pharmacother. 2010;44:1709–17.
Wacher VJ, Silverman JA, Zhang Y, Benet LZ. Role of P-glycoprotein and cytochrome P450 3A in limiting oral absorption of peptides and peptidomimetics. J Pharma Sci. 1998;87:1322–30.
Wu J, Lin N, Li F, Zhang G, He S, Zhu Y, Ou R, Li N, Liu S, Feng L, et al. Induction of P-glycoprotein expression and activity by Aconitum alkaloids: implication for clinical drug–drug interactions. Sci Rep. 2016;6:25343.
Pal D, Kwatra D, Minocha M, Paturi DK, Budda B, Mitra AK. Efflux transporters- and cytochrome P-450-mediated interactions between drugs of abuse and antiretrovirals. Life Sci. 2011;88:959–71.
Minko T, Kopečková P, Kopeček J. Comparison of the anticancer effect of free and HPMA copolymer-bound adriamycin in human ovarian carcinoma cells. Pharm Res. 1999;16:986–96.
Han B, Wang Y, Wang L, Shang Z, Wang S, Pei J. Preparation of GST inhibitor nanoparticle drug delivery system and its reversal effect on the multidrug resistance in oral carcinoma. Nanomaterials. 2015;5:1571–87.
Niu B, Zhou Y, Liao K, Wen T, Lao S, Quan G, Pan X, Wu C. “Pincer Movement”: reversing cisplatin resistance based on simultaneous glutathione depletion and glutathione S-transferases inhibition by redox-responsive degradable organosilica hybrid nanoparticles. Acta Pharm Sin B. 2021;12(4):2074–88.
Zhu Y, Sui B, Liu X, Sun J. The reversal of drug resistance by two-dimensional titanium carbide Ti2C (2D Ti2C) in non-small-cell lung cancer via the depletion of intracellular antioxidant reserves. Thorac Cancer. 2021;12:3340–55.
Wang X, Yang L, Fang Q, Xu J, Cheng X, Xue Y, Tang R. GLUT1-targeting and GSH-responsive DOX/L61 nanodrug particles for enhancing MDR breast cancer therapy. Part Syst Charact. 2020;37:2000165.
Wang Y, Tang H, Xu M, Luo J, Zhao L, Shi F, Ye G, Lv C, Li Y. Effect of copper nanoparticles on brain cytochrome P450 enzymes in rats. Mol Med Rep. 2019;20:771–8.
Lee H-J, Zhuang G, Cao Y, Du P, Kim H-J, Settleman J. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell. 2014;26:207–21.
Hientz K, Mohr A, Bhakta-Guha D, Efferth T. The role of p53 in cancer drug resistance and targeted chemotherapy. Oncotarget. 2017;8:8921–46.
Prabha S, Labhasetwar V. Nanoparticle-mediated wild-type p53 gene delivery results in sustained antiproliferative activity in breast cancer cells. Mol Pharm. 2004;1:211–9.
Choi SH, Jin S-E, Lee M-K, Lim S-J, Park J-S, Kim B-G, Ahn WS, Kim C-K. Novel cationic solid lipid nanoparticles enhanced p53 gene transfer to lung cancer cells. Eur J Pharm Biopharm. 2008;68:545–54.
Wang Y, Gao S, Ye W-H, Yoon HS, Yang Y-Y. Co-delivery of drugs and DNA from cationic core–shell nanoparticles self-assembled from a biodegradable copolymer. Nat Mater. 2006;5:791–6.
Saad M, Garbuzenko OB, Minko T. Co-delivery of siRNA and an anticancer drug for treatment of multidrug-resistant cancer. Nanomedicine. 2008;3:761–76.
Chen AM, Zhang M, Wei D, Stueber D, Taratula O, Minko T, He H. Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells. Small. 2009;5:2673–7.
Fan L, Li F, Zhang H, Wang Y, Cheng C, Li X, Gu C-H, Yang Q, Wu H, Zhang S. 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.
Lim Z-F, Ma PC. Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy. J Hematol Oncol. 2019;12:134.
Wilting RH, Dannenberg J-H. Epigenetic mechanisms in tumorigenesis, tumor cell heterogeneity and drug resistance. Drug Resist Updat. 2012;15:21–38.
Dexter DL, Leith JT. Tumor heterogeneity and drug resistance. J Clin Oncol. 1986;4:244–57.
Ling D, Park W, Park S-J, Lu Y, Kim KS, Hackett MJ, Kim BH, Yim H, Jeon YS, Na K, Hyeon T. Multifunctional tumor pH-sensitive self-assembled nanoparticles for bimodal imaging and treatment of resistant heterogeneous tumors. J Am Chem Soc. 2014;136:5647–55.
Liu Q, Cai J, Zheng Y, Tan Y, Wang Y, Zhang Z, Zheng C, Zhao Y, Liu C, An Y, et al. NanoRNP overcomes tumor heterogeneity in cancer treatment. Nano Lett. 2019;19:7662–72.
Nagata T, Sakakura C, Komiyama S, Miyashita A, Nishio M, Murayama Y, Komatsu S, Shiozaki A, Kuriu Y, Ikoma H, et al. Expression of cancer stem cell markers CD133 and CD44 in locoregional recurrence of rectal cancer. Anticancer Res. 2011;31:495.
Wang C, Xie J, Guo J, Manning HC, Gore JC, Guo N. Evaluation of CD44 and CD133 as cancer stem cell markers for colorectal cancer. Oncol Rep. 2012;28:1301–8.
Mamaeva V, Rosenholm JM, Bate-Eya LT, Bergman L, Peuhu E, Duchanoy A, Fortelius LE, Landor S, Toivola DM, Lindén M, Sahlgren C. Mesoporous silica nanoparticles as drug delivery systems for targeted inhibition of Notch signaling in cancer. Mol Ther. 2011;19:1538–46.
Liu C, Zhao G, Liu J, Ma N, Chivukula P, Perelman L, Okada K, Chen Z, Gough D, Yu L. Novel biodegradable lipid nano complex for siRNA delivery significantly improving the chemosensitivity of human colon cancer stem cells to paclitaxel. J Control Release. 2009;140:277–83.
Verma A, Guha S, Diagaradjane P, Kunnumakkara AB, Sanguino AM, Lopez-Berestein G, Sood AK, Aggarwal BB, Krishnan S, Gelovani JG. Therapeutic significance of elevated tissue transglutaminase expression in pancreatic cancer. Clin Cancer Res. 2008;14:2476–83.
Barth BM, Altinoğlu E, Shanmugavelandy SS, Kaiser JM, Crespo-Gonzalez D, DiVittore NA, McGovern C, Goff TM, Keasey NR, Adair JH, et al. Targeted indocyanine-green-loaded calcium phosphosilicate nanoparticles for in vivo photodynamic therapy of leukemia. ACS Nano. 2011;5:5325–37.
Yhee JY, Song S, Lee SJ, Park S-G, Kim K-S, Kim MG, Son S, Koo H, Kwon IC, Jeong JH, et al. Cancer-targeted MDR-1 siRNA delivery using self-cross-linked glycol chitosan nanoparticles to overcome drug resistance. J Control Release. 2015;198:1–9.
Alkholief M. Optimization of Lecithin-Chitosan nanoparticles for simultaneous encapsulation of doxorubicin and piperine. J Drug Deliv Sci Technol. 2019;52:204–14.
Guo M, Rong W-T, Hou J, Wang D-F, Lu Y, Wang Y, Yu S-Q, Xu Q. Mechanisms of chitosan-coated poly(lactic-co-glycolic acid) nanoparticles for improving oral absorption of 7-ethyl-10-hydroxycamptothecin. Nanotechnology. 2013;24: 245101.
Malmo J, Sandvig A, Vårum KM, Strand SP. Nanoparticle mediated P-glycoprotein silencing for improved drug delivery across the blood-brain barrier: a siRNA-chitosan approach. PLoS ONE. 2013;8:e54182–e54182.
Zatsepin TS, Kotelevtsev YV, Koteliansky V. Lipid nanoparticles for targeted siRNA delivery—going from bench to bedside. Int J Nanomed. 2016;11:3077–86.
Shah P, Chavda K, Vyas B, Patel S. Formulation development of linagliptin solid lipid nanoparticles for oral bioavailability enhancement: role of P-gp inhibition. Drug Deliv Transl Res. 2021;11:1166–85.
Tong WY, Alnakhli M, Bhardwaj R, Apostolou S, Sinha S, Fraser C, Kuchel T, Kuss B, Voelcker NH. Delivery of siRNA in vitro and in vivo using PEI-capped porous silicon nanoparticles to silence MRP1 and inhibit proliferation in glioblastoma. J Nanobiotech. 2018;16:38.
Igaz N, Bélteky P, Kovács D, Papp C, Rónavári A, Szabó D, Gácser A, Kónya Z, Kiricsi M. Functionalized mesoporous silica nanoparticles for drug-delivery to multidrug-resistant cancer cells. Int J Nanomed. 2022;17:3079.
Charbe NB, Amnerkar ND, Ramesh B, Tambuwala MM, Bakshi HA, Aljabali AAA, Khadse SC, Satheeshkumar R, Satija S, Metha M, et al. Small interfering RNA for cancer treatment: overcoming hurdles in delivery. Acta Pharm Sin B. 2020;10:2075–109.
Li F, Zhou X, Zhou H, Jia J, Li L, Zhai S, Yan B. Reducing both Pgp overexpression and drug efflux with anti-cancer gold-paclitaxel nanoconjugates. PLoS ONE. 2016;11: e0160042.
Deng R, Ji B, Yu H, Bao W, Yang Z, Yu Y, Cui Y, Du Y, Song M, Liu S, et al. Multifunctional gold nanoparticles overcome MicroRNA regulatory network mediated-multidrug resistant leukemia. Sci Rep. 2019;9:5348.
Guo W, Chen Z, Feng X, Shen G, Huang H, Liang Y, Zhao B, Li G, Hu Y. Graphene oxide (GO)-based nanosheets with combined chemo/photothermal/photodynamic therapy to overcome gastric cancer (GC) paclitaxel resistance by reducing mitochondria-derived adenosine-triphosphate (ATP). J Nanobiotech. 2021;19:146.
Wang S-B, Ma Y-Y, Chen X-Y, Zhao Y-Y, Mou X-Z. Ceramide-graphene oxide nanoparticles enhance cytotoxicity and decrease HCC xenograft development: a novel approach for targeted cancer therapy. Front Pharmacol. 2019;10:69–69.
Mello FVC, de Moraes GN, Maia RC, Kyeremateng J, Iram SH, Santos-Oliveira R. The effect of nanosystems on ATP-binding cassette transporters: understanding the influence of nanosystems on multidrug resistance protein-1 and P-glycoprotein. Int J Mol Sci. 2020;21:2630.
Chen W-H, Lecaros RLG, Tseng Y-C, Huang L, Hsu Y-C. Nanoparticle delivery of HIF1α siRNA combined with photodynamic therapy as a potential treatment strategy for head-and-neck cancer. Cancer Lett. 2015;359:65–74.
Zhao X, Li F, Li Y, Wang H, Ren H, Chen J, Nie G, Hao J. Co-delivery of HIF1α siRNA and gemcitabine via biocompatible lipid-polymer hybrid nanoparticles for effective treatment of pancreatic cancer. Biomaterials. 2015;46:13–25.
Davis A, Morris KV, Shevchenko G. Hypoxia-directed tumor targeting of CRISPR-Cas9 and HSV-TK suicide gene therapy using lipid nanoparticles. Mol Ther Methods Clin Dev. 2022;25:158–69.
Ashrafizadeh M, Hushmandi K, Rahmani Moghadam E, Zarrin V, Hosseinzadeh Kashani S, Bokaie S, Najafi M, Tavakol S, Mohammadinejad R, Nabavi N, et al. Progress in delivery of siRNA-based therapeutics employing nano-vehicles for treatment of prostate cancer. Bioengineering. 2020;7:91.
Izadi S, Moslehi A, Kheiry H, Karoon Kiani F, Ahmadi A, Masjedi A, Ghani S, Rafiee B, Karpisheh V, Hajizadeh F, et al. Codelivery of HIF-1α siRNA and dinaciclib by carboxylated graphene oxide-trimethyl chitosan-hyaluronate nanoparticles significantly suppresses cancer cell progression. Pharm Res. 2020;37:196.
Gong X, Wang H, Li R, Tan K, Wei J, Wang J, Hong C, Shang J, Liu X, Liu J, Wang F. A smart multiantenna gene theranostic system based on the programmed assembly of hypoxia-related siRNAs. Nat Commun. 2021;12:3953.
Karpisheh V, Fakkari Afjadi J, Nabi Afjadi M, Haeri MS, Abdpoor Sough TS, Heydarzadeh Asl S, Edalati M, Atyabi F, Masjedi A, Hajizadeh F, et al. Inhibition of HIF-1α/EP4 axis by hyaluronate-trimethyl chitosan-SPION nanoparticles markedly suppresses the growth and development of cancer cells. Int J Biol Macromol. 2021;167:1006–19.
Budi HS, Izadi S, Timoshin A, Asl SH, Beyzai B, Ghaderpour A, Alian F, Eshaghi FS, Mousavi SM, Rafiee B, et al. Blockade of HIF-1α and STAT3 by hyaluronate-conjugated TAT-chitosan-SPION nanoparticles loaded with siRNA molecules prevents tumor growth. Nanomedicine. 2021;34: 102373.
Armiñán A, Mendes L, Carrola J, Movellan J, Vicent MJ, Duarte IF. HIF-1α inhibition by diethylstilbestrol and its polyacetal conjugate in hypoxic prostate tumour cells: insights from NMR metabolomics. J Drug Target. 2017;25:845–55.
Yang S, Han Y, Bao B, Hu C, Li Z. Boosting the anti-tumor performance of disulfiram against glioblastoma by using ultrasmall nanoparticles and HIF-1α inhibitor. Compos B Eng. 2022;243: 110117.
Basoglu H, Goncu B, Akbas F. Magnetic nanoparticle-mediated gene therapy to induce Fas apoptosis pathway in breast cancer. Cancer Gene Ther. 2018;25:141–7.
Bala Tannan N, Manzari MT, Herviou L, Da Silva FM, Hagen C, Kiguchi H, Manova-Todorova K, Seshan V, de Stanchina E, Heller DA, Younes A. Tumor-targeted nanoparticles improve the therapeutic index of BCL2 and MCL1 dual inhibition. Blood. 2021;137:2057–69.
Zhang X, Wang M, Feng J, Qin B, Zhang C, Zhu C, Liu W, Wang Y, Liu W, Huang L, et al. Multifunctional nanoparticles co-loaded with Adriamycin and MDR-targeting siRNAs for treatment of chemotherapy-resistant esophageal cancer. J Nanobiotech. 2022;20:166.
Choi KY, Correa S, Min J, Li J, Roy S, Laccetti KH, Dreaden E, Kong S, Heo R, Roh YH, et al. Binary targeting of siRNA to hematologic cancer cells in vivo using layer-by-layer nanoparticles. Adv Funct Mater. 2019;29:1900018.
Kucuksayan E, Bozkurt F, Yilmaz MT, Sircan-Kucuksayan A, Hanikoglu A, Ozben T. A new combination strategy to enhance apoptosis in cancer cells by using nanoparticles as biocompatible drug delivery carriers. Sci Rep. 2021;11:13027.
Das M, Sahoo SK. Folate decorated dual drug loaded nanoparticle: role of curcumin in enhancing therapeutic potential of nutlin-3a by reversing multidrug resistance. PLoS ONE. 2012;7: e32920.
Xiang Y, Liu C, Chen L, Li L, Huang Y. Active targeting nanoparticle self-assembled from cisplatin-palbociclib amphiphiles ensures optimal drug ratio for combinatorial chemotherapy. Adv Ther. 2021;4:2000261.
Lim C, Dismuke T, Malawsky D, Ramsey JD, Hwang D, Godfrey VL, Kabanov AV, Gershon TR, Sokolsky-Papkov M. Enhancing CDK4/6 inhibitor therapy for medulloblastoma using nanoparticle delivery and scRNA-seq–guided combination with sapanisertib. Sci Adv. 2022;8(4):eabl5838.
Chen KTJ, Militao GGC, Anantha M, Witzigmann D, Leung AWY, Bally MB. Development and characterization of a novel flavopiridol formulation for treatment of acute myeloid leukemia. J Control Release. 2021;333:246–57.
Abe S, Kubota T, Otani Y, Furukawa T, Watanabe M, Kumai K, Kitajima M. UCN-01 (7-Hydroxystaurosporine) enhances 5-fluorouracil cytotoxicity through down-regulation of thymidylate synthetase messenger RNA. Jpn J Cancer Res. 2000;91:1192–8.
Jain A, Jain R, Jain S, Khatik R, Veer Kohli D. Minicapsules encapsulating nanoparticles for targeting, apoptosis induction and treatment of colon cancer. Artif Cells Nanomed Biotechnol. 2019;47:1085–93.
Liu Y, Zhu Y-H, Mao C-Q, Dou S, Shen S, Tan Z-B, Wang J. Triple negative breast cancer therapy with CDK1 siRNA delivered by cationic lipid assisted PEG-PLA nanoparticles. J Control Release. 2014;192:114–21.
He GZ, Lin WJ. Peptide-functionalized nanoparticles-encapsulated cyclin-dependent kinases inhibitor seliciclib in transferrin receptor overexpressed cancer cells. Nanomaterials. 2021;11:772.
Kuroda S, Tam J, Roth JA, Sokolov K, Ramesh R. EGFR-targeted plasmonic magnetic nanoparticles suppress lung tumor growth by abrogating G2/M cell-cycle arrest and inducing DNA damage. Int J Nanomed. 2014;9:3825–39.
Yoo J, Jang S-Y, Park C, Lee D, Kwon S, Koo H. Lowering glutathione level by buthionine sulfoximine enhances in vivo photodynamic therapy using chlorin e6-loaded nanoparticles. Dyes Pigm. 2020;176:108207.
Iyer R, Nguyen T, Padanilam D, Xu C, Saha D, Nguyen KT, Hong Y. Glutathione-responsive biodegradable polyurethane nanoparticles for lung cancer treatment. J Control Release. 2020;321:363–71.
Liu M, Li W, Xu R, Jiang X, Liu A. Hollow gold nanoparticles loaded with L-buthionine-sulfoximine as a novel nanomedicine for in vitro cancer cell therapy. J Nanomater. 2021;2021:3595470.
Ling X, Tu J, Wang J, Shajii A, Kong N, Feng C, Zhang Y, Yu M, Xie T, Bharwani Z, et al. Glutathione-responsive prodrug nanoparticles for effective drug delivery and cancer therapy. ACS Nano. 2019;13:357–70.
Yang Q, Xiao H, Cai J, Xie Z, Wang Z, Jing X. Nanoparticle mediated delivery of a GST inhibitor ethacrynic acid for sensitizing platinum based chemotherapy. RSC Adv. 2014;4:61124–32.
Wang Y, Challa P, Epstein DL, Yuan F. Controlled release of ethacrynic acid from poly(lactide-co-glycolide) films for glaucoma treatment. Biomaterials. 2004;25:4279–85.
Kaushal N, Chen Z-S, Lin S. Double-coated poly(butyl cyanoacrylate) nanoparticles as a potential carrier for overcoming P-Gp- and BCRP-mediated multidrug resistance in cancer cells. Front Nanotechnol. 2021;3:80.
Esim O, Sarper M, Ozkan CK, Oren S, Baykal B, Savaser A, Ozkan Y. Effect simultaneous delivery with P-glycoprotein inhibitor and nanoparticle administration of doxorubicin on cellular uptake and in vitro anticancer activity. Saudi Pharm J. 2020;28:465–72.
Zhang B, Huang X, Wang H, Gou S. Promoting antitumor efficacy by suppressing hypoxia via nano self-assembly of two irinotecan-based dual drug conjugates having a HIF-1α inhibitor. J Mater Chem B. 2019;7:5352–62.
Li L, He S, Yu L, Elshazly EH, Wang H, Chen K, Zhang S, Ke L, Gong R. Codelivery of DOX and siRNA by folate-biotin-quaternized starch nanoparticles for promoting synergistic suppression of human lung cancer cells. Drug Deliv. 2019;26:499–508.
Liu Y, Zhou Z, Lin X, Xiong X, Zhou R, Zhou M, Huang Y. Enhanced reactive oxygen species generation by mitochondria targeting of anticancer drug to overcome tumor multidrug resistance. Biomacromol. 2019;20:3755–66.
Son J, Yang SM, Yi G, Roh YJ, Park H, Park JM, Choi M-G, Koo H. Folate-modified PLGA nanoparticles for tumor-targeted delivery of pheophorbide a in vivo. Biochem Biophys Res Commun. 2018;498:523–8.
Zhao P, Yin W, Wu A, Tang Y, Wang J, Pan Z, Lin T, Zhang M, Chen B, Duan Y, Huang Y. Dual-targeting to cancer cells and M2 macrophages via biomimetic delivery of mannosylated albumin nanoparticles for drug-resistant cancer therapy. Adv Funct Mater. 2017;27:1700403.
Zeng Y, Yang Z, Li H, Hao Y, Liu C, Zhu L, Liu J, Lu B, Li R. Multifunctional nanographene oxide for targeted gene-mediated thermochemotherapy of drug-resistant tumour. Sci Rep. 2017;7:43506.
Wen Z-M, Jie J, Zhang Y, Liu H, Peng L-P. A self-assembled polyjuglanin nanoparticle loaded with doxorubicin and anti-Kras siRNA for attenuating multidrug resistance in human lung cancer. Biochem Biophys Res Commun. 2017;493:1430–7.
Zhao Y, Huan M-L, Liu M, Cheng Y, Sun Y, Cui H, Liu D-Z, Mei Q-B, Zhou S-Y. Doxorubicin and resveratrol co-delivery nanoparticle to overcome doxorubicin resistance. Sci Rep. 2016;6:35267.
Tang X, Liang Y, Feng X, Zhang R, Jin X, Sun L. Co-delivery of docetaxel and Poloxamer 235 by PLGA–TPGS nanoparticles for breast cancer treatment. Mater Sci Eng C Mater Biol Appl. 2015;49:348–55.
Yu X, Yang G, Shi Y, Su C, Liu M, Feng B, Zhao L. Intracellular targeted co-delivery of shMDR1 and gefitinib with chitosan nanoparticles for overcoming multidrug resistance. Int J Nanomed. 2015;10:7045.
Guo Y, Chu M, Tan S, Zhao S, Liu H, Otieno BO, Yang X, Xu C, Zhang Z. Chitosan-g-TPGS nanoparticles for anticancer drug delivery and overcoming multidrug resistance. Mol Pharm. 2014;11:59–70.
Kim H-O, Kim E, An Y, Choi J, Jang E, Choi EB, Kukreja A, Kim M-H, Kang B, Kim D-J, et al. A Biodegradable polymersome containing Bcl-xL siRNA and doxorubicin as a dual delivery vehicle for a synergistic anticancer effect. Macromol Biosci. 2013;13:745–54.
Duan J, Mansour HM, Zhang Y, Deng X, Chen Y, Wang J, Pan Y, Zhao J. Reversion of multidrug resistance by co-encapsulation of doxorubicin and curcumin in chitosan/poly(butyl cyanoacrylate) nanoparticles. Int J Pharm. 2012;426:193–201.
Lei T, Srinivasan S, Tang Y, Manchanda R, Nagesetti A, Fernandez-Fernandez A, McGoron AJ. Comparing cellular uptake and cytotoxicity of targeted drug carriers in cancer cell lines with different drug resistance mechanisms. Nanomedicine. 2011;7:324–32.
Misra R, Sahoo SK. Coformulation of doxorubicin and curcumin in poly(d, l-lactide-co-glycolide) nanoparticles suppresses the development of multidrug resistance in K562 cells. Mol Pharm. 2011;8:852–66.
Khdair A, Chen D, Patil Y, Ma L, Dou QP, Shekhar MPV, Panyam J. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance. J Control Release. 2010;141:137–44.
Ling G, Zhang P, Zhang W, Sun J, Meng X, Qin Y, Deng Y, He Z. Development of novel self-assembled DS-PLGA hybrid nanoparticles for improving oral bioavailability of vincristine sulfate by P-gp inhibition. J Control Release. 2010;148:241–8.
Dickerson EB, Blackburn WH, Smith MH, Kapa LB, Lyon LA, McDonald JF. Chemosensitization of cancer cells by siRNA using targeted nanogel delivery. BMC Cancer. 2010;10:10.
Wang J, Tao X, Zhang Y, Wei D, Ren Y. Reversion of multidrug resistance by tumor targeted delivery of antisense oligodeoxynucleotides in hydroxypropyl-chitosan nanoparticles. Biomaterials. 2010;31:4426–33.
Patil YB, Swaminathan SK, Sadhukha T, Ma L, Panyam J. The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance. Biomaterials. 2010;31:358–65.
Patil Y, Sadhukha T, Ma L, Panyam J. Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance. J Control Release. 2009;136:21–9.
Song XR, Cai Z, Zheng Y, He G, Cui FY, Gong DQ, Hou SX, Xiong SJ, Lei XJ, Wei YQ. Reversion of multidrug resistance by co-encapsulation of vincristine and verapamil in PLGA nanoparticles. Eur J Pharm Sci. 2009;37:300–5.
Yadav S, van Vlerken LE, Little SR, Amiji MM. Evaluations of combination MDR-1 gene silencing and paclitaxel administration in biodegradable polymeric nanoparticle formulations to overcome multidrug resistance in cancer cells. Cancer Chemother Pharmacol. 2009;63:711–22.
van Vlerken LE, Duan Z, Little SR, Seiden MV, Amiji MM. Biodistribution and pharmacokinetic analysis of Paclitaxel and ceramide administered in multifunctional polymer-blend nanoparticles in drug resistant breast cancer model. Mol Pharm. 2008;5:516–26.
Devalapally H, Duan Z, Seiden MV, Amiji MM. Paclitaxel and ceramide co-administration in biodegradable polymeric nanoparticulate delivery system to overcome drug resistance in ovarian cancer. Int J Cancer. 2007;121:1830–8.
Mahira S, Kommineni N, Husain GM, Khan W. Cabazitaxel and silibinin co-encapsulated cationic liposomes for CD44 targeted delivery: a new insight into nanomedicine based combinational chemotherapy for prostate cancer. Biomed Pharmacother. 2019;110:803–17.
Chen M, Song F, Liu Y, Tian J, Liu C, Li R, Zhang Q. A dual pH-sensitive liposomal system with charge-reversal and NO generation for overcoming multidrug resistance in cancer. Nanoscale. 2019;11:3814–26.
Li X, Wu X, Yang H, Li L, Ye Z, Rao Y. A nuclear targeted Dox-aptamer loaded liposome delivery platform for the circumvention of drug resistance in breast cancer. Biomed Pharmacother. 2019;117: 109072.
Chen Y, Bathula SR, Li J, Huang L. Multifunctional nanoparticles delivering small interfering RNA and doxorubicin overcome drug resistance in cancer. J Biol Chem. 2010;285:22639–50.
Wu J, Lu Y, Lee A, Pan X, Yang X, Zhao X, Lee RJ. Reversal of multidrug resistance by transferrin-conjugated liposomes co-encapsulating doxorubicin and verapamil. J Pharm Pharm Sci. 2007;10:350–7.
Thierry AR, Vigé D, Coughlin SS, Belli JA, Dritschilo A, Rahman A. Modulation of doxorubicin resistance in multidrug-resistant cells by liposomes. FASEB J. 1993;7:572–9.
Rahman A, Husain SR, Siddiqui J, Verma M, Agresti M, Center M, Safa AR, Glazer RI. Liposome-mediated modulation of multidrug resistance in human HL-60 leukemia cells. J Natl Cancer Inst. 1992;84:1909–15.
Fathy Abd-Ellatef G-E, Gazzano E, Chirio D, Hamed AR, Belisario DC, Zuddas C, Peira E, Rolando B, Kopecka J, Assem Said Marie M, et al. Curcumin-loaded solid lipid nanoparticles bypass P-Glycoprotein mediated doxorubicin resistance in triple negative breast cancer cells. Pharmaceutics. 2020;12:96.
El-Menshawe SF, Sayed OM, Abou Taleb HA, Saweris MA, Zaher DM, Omar HA. The use of new quinazolinone derivative and doxorubicin loaded solid lipid nanoparticles in reversing drug resistance in experimental cancer cell lines: a systematic study. J Drug Deliv Sci Technol. 2020;56: 101569.
Xu W, Bae EJ, Lee M-K. Enhanced anticancer activity and intracellular uptake of paclitaxel-containing solid lipid nanoparticles in multidrug-resistant breast cancer cells. Int J Nanomed. 2018;13:7549–63.
Li X, Jia X, Niu H. Nanostructured lipid carriers co-delivering lapachone and doxorubicin for overcoming multidrug resistance in breast cancer therapy. Int J Nanomed. 2018;13:4107–19.
Tang J, Ji H, Ren J, Li M, Zheng N, Wu L. Solid lipid nanoparticles with TPGS and Brij 78: a co-delivery vehicle of curcumin and piperine for reversing P-glyciprotein-mediated multidrug resistance in vitro. Oncol Lett. 2017;13(1):388–95.
Baek J-S, Cho C-W. A multifunctional lipid nanoparticle for co-delivery of paclitaxel and curcumin for targeted delivery and enhanced cytotoxicity in multidrug resistant breast cancer cells. Oncotarget. 2017;8(18):30369–82.
Dong X, Wang W, Qu H, Han D, Zheng J, Sun G. Targeted delivery of doxorubicin and vincristine to lymph cancer: evaluation of novel nanostructured lipid carriers in vitro and in vivo. Drug Deliv. 2016;23:1374–8.
Chen H-H, Huang W-C, Chiang W-H, Liu T-I, Shen M-Y, Hsu Y-H, Lin S-C, Chiu H-C. pH-Responsive therapeutic solid lipid nanoparticles for reducing P-glycoprotein-mediated drug efflux of multidrug resistant cancer cells. Int J Nanomed. 2015;10:5035.
Li L, Liu T, Liao J-X, Zhang Z-Y, Song D-B, Wang G-H. Dual-responsive TPGS crosslinked nanocarriers to overcome multidrug resistance. J Mater Chem B. 2020;8:8383–94.
Sun L, Wei H, Zhang X, Meng C, Kang G, Ma W, Ma L, Wang B, Yu C. Synthesis of polymeric micelles with dual-functional sheddable PEG stealth for enhanced tumor-targeted drug delivery. Polym Chem. 2020;11:4469–76.
Gao L, Dong B, Zhang J, Chen Y, Qiao H, Liu Z, Chen E, Dong Y, Cao C, Huang D, Chen W. Functional biodegradable nitric oxide donor-containing polycarbonate-based micelles for reduction-triggered drug release and overcoming multidrug resistance. ACS Macro Lett. 2019;8:1552–8.
Suo X, Eldridge BN, Zhang H, Mao C, Min Y, Sun Y, Singh R, Ming X. P-Glycoprotein-targeted photothermal therapy of drug-resistant cancer cells using antibody-conjugated carbon nanotubes. ACS Appl Mater Interfaces. 2018;10:33464–73.
Zhou M, Zhang X, Xie J, Qi R, Lu H, Leporatti S, Chen J, Hu Y. pH-Sensitive Poly(β-amino ester)s Nanocarriers Facilitate the Inhibition of Drug Resistance in Breast Cancer Cells. Nanomaterials. 2018;8:952.
Butt AM, Amin MCIM, Katas H, Abdul Murad NA, Jamal R, Kesharwani P. Doxorubicin and siRNA codelivery via chitosan-coated pH-responsive mixed micellar polyplexes for enhanced cancer therapy in multidrug-resistant tumors. Mol Pharm. 2016;13:4179–90.
Sheu M-T, Jhan H-J, Su C-Y, Chen L-C, Chang C-E, Liu D-Z, Ho H-O. Codelivery of doxorubicin-containing thermosensitive hydrogels incorporated with docetaxel-loaded mixed micelles enhances local cancer therapy. Colloids Surf B Biointerfaces. 2016;143:260–70.
Wang J, Li L, Du Y, Sun J, Han X, Luo C, Ai X, Zhang Q, Wang Y, Fu Q, et al. Improved oral absorption of doxorubicin by amphiphilic copolymer of lysine-linked ditocopherol polyethylene Glycol 2000 succinate: in vitro characterization and in vivo evaluation. Mol Pharm. 2015;12:463–473.
Jin X, Zhou B, Xue L, San W. Soluplus® micelles as a potential drug delivery system for reversal of resistant tumor. Biomed Pharmacother. 2015;69:388–95.
Rapoport N, Marin A, Luo Y, Prestwich GD, Muniruzzaman M. Intracellular uptake and trafficking of Pluronic micelles in drug-sensitive and MDR cells: effect on the intracellular drug localization. J Pharm Sci. 2002;91:157–70.
Chen S, Zhang J, Wu L, Wu H, Dai M. Paeonol nanoemulsion for enhanced oral bioavailability: optimization and mechanism. Nanomedicine. 2018;13:269–82.
Patel NR, Piroyan A, Ganta S, Morse AB, Candiloro KM, Solon AL, Nack AH, Galati CA, Bora C, Maglaty MA, et al. In vitro and in vivo evaluation of a novel folate-targeted theranostic nanoemulsion of docetaxel for imaging and improved anticancer activity against ovarian cancers. Cancer Biol Ther. 2018;19:554–64.
Wei T, Chen C, Liu J, Liu C, Posocco P, Liu X, Cheng Q, Huo S, Liang Z, Fermeglia M, et al. Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance. Proceed Natl Acad Sci. 2015;112:2978.
Choudhury H, Gorain B, Karmakar S, Biswas E, Dey G, Barik R, Mandal M, Pal TK. Improvement of cellular uptake, in vitro antitumor activity and sustained release profile with increased bioavailability from a nanoemulsion platform. Int J Pharm. 2014;460:131–43.
Ganta S, Amiji M. Coadministration of paclitaxel and curcumin in nanoemulsion formulations to overcome multidrug resistance in tumor cells. Mol Pharm. 2009;6:928–39.
Soma CE, Dubernet C, Bentolila D, Benita S, Couvreur P. Reversion of multidrug resistance by co-encapsulation of doxorubicin and cyclosporin A in polyalkylcyanoacrylate nanoparticles. Biomaterials. 2000;21:1–7.
Zhu H, Cao G, Fu Y, Fang C, Chu Q, Li X, Wu Y, Han G. ATP-responsive hollow nanocapsules for DOX/GOx delivery to enable tumor inhibition with suppressed P-glycoprotein. Nano Res. 2021;14:222.
Yalcin S, Gündüz U. Synthesis and biological activity of siRNA and Etoposide with magnetic nanoparticles on drug resistance model MCF-7 Cells: molecular docking study with MRP1 enzyme. Nanomed J. 2021;8:98–105.
Hu Y, Lv T, Ma Y, Xu J, Zhang Y, Hou Y, Huang Z, Ding Y. Nanoscale coordination polymers for synergistic NO and chemodynamic therapy of liver cancer. Nano Lett. 2019;19:2731–8.
Pan J, Mendes LP, Yao M, Filipczak N, Garai S, Thakur GA, Sarisozen C, Torchilin VP. Polyamidoamine dendrimers-based nanomedicine for combination therapy with siRNA and chemotherapeutics to overcome multidrug resistance. Euro J Pharm Biopharm. 2019;136:18–28.
Gopisetty MK, Kovács D, Igaz N, Rónavári A, Bélteky P, Rázga Z, Venglovecz V, Csoboz B, Boros IM, Kónya Z, Kiricsi M. Endoplasmic reticulum stress: major player in size-dependent inhibition of P-glycoprotein by silver nanoparticles in multidrug-resistant breast cancer cells. J Nanobiotechnol. 2019;17:9–9.
Wang Y, Wang F, Liu Y, Xu S, Shen Y, Feng N, Guo S. Glutathione detonated and pH responsive nano-clusters of Au nanorods with a high dose of DOX for treatment of multidrug resistant cancer. Acta Biomater. 2018;75:334–45.
Ricci M, Miola M, Multari C, Borroni E, Canuto RA, Congiusta N, Vernè E, Follenzi A, Muzio G. PPARs are mediators of anti-cancer properties of superparamagnetic iron oxide nanoparticles (SPIONs) functionalized with conjugated linoleic acid. Chem Biol Interact. 2018;292:9–14.
Rastegar R, Akbari Javar H, Khoobi M, Dehghan Kelishadi P, Hossein Yousefi G, Doosti M, Hossien Ghahremani M, Shariftabrizi A, Imanparast F, Gholibeglu E, Gholami M. Evaluation of a novel biocompatible magnetic nanomedicine based on beta-cyclodextrin, loaded doxorubicin-curcumin for overcoming chemoresistance in breast cancer. Artif Cells Nanomed Biotechol. 2018;46:207–16.
Song L, Jiang Q, Liu J, Li N, Liu Q, Dai L, Gao Y, Liu W, Liu D, Ding B. DNA origami/gold nanorod hybrid nanostructures for the circumvention of drug resistance. Nanoscale. 2017;9:7750–4.
Vishwakarma SK, Sharmila P, Bardia A, Chandrakala L, Raju N, Sravani G, Sastry BVS, Habeeb MA, Khan AA, Dhayal M. Use of biocompatible sorafenib-gold nanoconjugates for reversal of drug resistance in human hepatoblatoma cells. Sci Rep. 2017;7:8539.
Wang RH, Bai J, Deng J, Fang CJ, Chen X. TAT-modified gold nanoparticle carrier with enhanced anticancer activity and size effect on overcoming multidrug resistance. ACS Appl Mater Interfaces. 2017;9:5828–37.