SCIENCE CHINA Chemistry • REVIEWS • · SPECIAL TOPIC · Cancer Nanotechnology
November 2010 Vol.53 No.11: 2226–2232 doi: 10.1007/s11426-010-4142-5
Overcoming multidrug resistance (MDR) in cancer by nanotechnology BU HuiHui, GAO Yu & LI YaPing* Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China Received May 17, 2010; accepted June 14, 2010
The emerging nanotechnology-based drug delivery holds tremendous potential to deliver chemotherapeutic drugs for treatment of multidrug resistance (MDR) cancer. This drug delivery system could improve the pharmacokinetic behavior of antitumor drugs, deliver chemotherapeutic drugs to target sites, control release of drugs, and reduce the systemic toxicity of drugs in MDR cancer. This review addresses the use of nanotechnology to overcome MDR classified on the bases of the fundamental mechanisms of MDR and various approaches to deliver drugs for treatment of MDR cancer. nanotechnology, nanoparticles, multidrug resistance, chemotherapeutic drugs, cancer, drug delivery system
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Introduction
There were over 21 million people diagnosed with cancer in 2008 according to the Global Cancer Report issued by the World Health Organization [1]. Although many efforts have been made for the treatment of cancer, cancer cells remain notorious during the chemotherapy in the clinic, and over 90% of cancer patients died from multidrug resistance (MDR) to different extents. MDR, which is defined as the resistance of tumor cells to a variety of chemotherapeutic agents with different targets and chemical structures, mediates a process of inactivating the drug or removing it from the target tumor cells [2], and becomes a substantial obstacle for the treatment of cancer. Nanotechnology has been widely used in physics, engineering, chemistry, biology and medicine. In pharmaceutics, nanoparticles, including but not limiting to micelles, liposomes, nanofibers, nanocells, nanotubes, nano-sized silicon chips, and self-assembling polymeric nanoconstructs, have been investigated for anticancer therapy [3–7]. These nanoparticle-based drug delivery systems offer numerous *Corresponding author (email:
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advantages including ease in surface modification, low toxicity, large surface area-to-volume ratio, the ability to target specific cells with targeting moieties, controlled release of drugs, protective encapsulation of drug molecules to enhance stability, delivery of multiple therapeutic agents in one formulation [8], and combination delivery of anti-cancer drugs and imaging contrast agents [9]. Besides, the unique size property of nanoparticles has sparked a considerable interest in cancer therapy as vehicles for targeted delivery of anticancer drugs. For example, nanoparticles could be constructed at a certain size for tumor passive targeting via the enhanced permeability and retention (EPR) effect which is a unique phenomenon of solid tumors [10]. It was reported that nanoparticles with size between 50 nm and 100 nm carrying a very slight positive charge could penetrate throughout tumors following systemic administration [11]. In view of these advantages, many studies are now committed to constructing multi-functional nanocarriers to overcome MDR (Figure 1). Increasingly, more reports have focused on investigating the molecular mechanisms of MDR. Hypotheses certified by various experiments have been suggested to explain the mechanism of MDR, mainly including (1) altering membrane transport protein to increase drug efflux, (2) enhancing chem.scichina.com
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Figure 1 Scheme of multi-functional nanoparticles.
DNA repair, (3) amending cell cycle regulation to block apoptosis, and (4) detoxification through increasing drug metabolism and decreasing drug activation (Figure 2). Although these categories represent the distinct mechanisms, the MDR phenotype is usually the synergistic result of a combination of several mechanisms. Nanotechnology can overcome MDR due to different mechanisms. This review outlines the recent development using nanotechnology to overcome MDR classified on the bases of the fundamental mechanisms of MDR.
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family of trans-membrane proteins [12]. Overexpression of P-glycoprotein (P-gp, MDR1, also known as ABCB1), encoded by MDR-1 gene, which belongs to the family of ABC proteins, was the major mechanism of MDR [13]. P-gp is a 170 kDa protein consisting of two homologous halves, each containing six transmembrane domains (TMD) and a nucleotide binding domain (NBD), separated by a flexible linker polypeptide [14]. Vinca alkaloids, anthracyclines, epipodophyllotoxins and taxanes, which are significant in chemotherapeutic regimens, are all substrate of P-gp transporters [15]. A strategy that has been investigated to overcome efflux-mediated drug resistance is to inhibit the function of P-gp. Either using biological or chemical P-gp inhibitors [16] or down-regulation of MDR-1 gene expression [17] can inhibit the function of P-gp to reverse MDR and enhance the therapeutic efficacy. The nanoparticle-based drug delivery system is the most common and widely used approach to protect the drug from elimination in the microenvironment out of the tumor cells and increase intra-cellular drug accumulation. The multifunctional nanoparticle formulations could be designed to allow the drug to bypass efflux pump transporters [18] or combination delivery and drug efflux modulation simultaneously (Figure 3). Various formulations will be discussed to elucidate the application of nanoparticles to bypass or inhibit P-gp and overcome MDR. 2.1
2 Overcoming efflux of the membrane transport proteins One of the most significant forms of resistance against the current chemotherapeutic drugs is the change of membrane transport protein. With regard to the cancer cells, two approaches reducing the intracellular concentration of cytotoxic molecules are to reduce drug uptake and increase extrusion of the chemotherapeutic agents. They are both mediated by some of a family of energy-dependent transporters, known as ATP-binding cassette (ABC) proteins, the largest
Figure 2 Molecular mechanisms of multi-drug resistance in tumor cells.
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Bypassing the efflux action of P-gp
In P-gp overexpressed cancer cells, it is very difficult to maintain a high intracellular anticancer drug level for a reasonable length of time. Construction of the nanoparticlebased drug delivery system to bypass the efflux action of P-gp became one of the effective means to enhance the accumulation of drugs. A polymer-lipid hybrid nanoparticle (PLN) system loaded
Figure 3 Nanotechnology used in overcoming the efflux of membrane transport proteins for the treatment of multi-drug resistance.
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with Doxorubicin (Dox), a widely used anticancer drug and an established P-gp substrate, could significantly enhance Dox uptake and increase drug retention compared with free Dox (p < 0.05) [19]. Endocytosis inhibition revealed that phagocytosis was a significant pathway in the membrane permeability of nanoparticles. It was suggested that DoxPLNs could bypass the membrane-associated P-gp [19]. Additionally, the cancer suppressive activity of Dox treatment was improved only when it was an integral part of the nanoparticles, but not when it was separately added in the presence of blank PLNs or polymers [19]. Dox loaded poly (alkyl cyanoacrylate) (PACA) nanoparticles were also demonstrated to be able to enter cells by endocytosis without being recognized by P-gp [20, 21]. Modification of cell-specific antibodies or targeting ligands to the nanoparticle surface is an effective approach to bypass P-gp efflux though receptor-mediated endocytosis pathway [22–26]. For example, transferrin receptor-targeted liposomes encapsulated Dox could bypass P-gp mediated drug efflux in SBC-3/ADM multidrug resistance cells [27]. A pH-sensitive micelle (PHSM) composed of poly (L-histidine) (polyHis)/poly(ethylene glycol) (PEG) and poly(L-lactic acid) (pLLA)/PEG block copolymers with folate conjugation showed appropriate physicochemical properties for adequate release of the drug and the entry of the micelle occurred via receptor-mediated endocytosis [28]. Another Dox-loaded pH-sensitive micelle system conjugated with folic acid could effectively kill both sensitive (A2780) and Dox-resistant ovarian MDR cancer cells (A2780/Dox®) through an instantaneous high dose of Dox in cytosol, which resulted from active internalization, accelerated Dox release triggered by endosomal pH, and endosomal membrane disruption [29]. Nanoparticles modified with TAT (transactivator of transcription), which showed strong capability to translocate the nanoparticles into cells, provided a new strategy for solid tumor targeting. A micelle was developed with hided TAT during circulation and exposure of TAT at a slightly acidic tumor extracellular pH to facilitate internalization [30]. In order to enhance accumulation of anticancer drugs, the micelle core was engineered for quickly releasing Dox by disintegration in early endosomal pH of tumor cells [30]. 2.2 Co-delivery of anti-cancer drugs and P-gp inhibitors Nano-carriers with the ability to deliver two or more chemotherapy agents to the same target at the same time were ideal for co-administration. Many nano-formulations codelivery of anti-cancer drugs with P-gp inhibitors have been demonstrated to actively target MDR cells and increase the intra-cellular accumulation of chemotherapy agents for overcoming MDR. Poly(D,L-lactideco-glycolide acid) (PLGA) nanoparticles encapsulating both verapamil and vincristine were superior to free vincristine/verapamil combination in improving the drug accumulation in MCF-7/ADR cells [31].
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The simultaneous delivery of anticancer drugs and chemosensitizers to the same cellular location was critical for the therapeutic effectiveness of this anticancer drug-chemosensitizer combination [32]. Significant tumor growth inhibition was observed on the mouse MDR model following the treatment with biotin-functionalized nanoparticles encapsulating both paclitaxel and tariquidar, a third generation P-gp inhibitors, while paclitaxel itself at the same dose showed no effect [33]. These results suggested that the use of optimized, dual agent nanoparticles co-delivery of P-gp inhibitors and anticancer drugs was a very promising approach to overcome MDR. 2.3
Down-regulating the expression of P-gp
Another approach to obstruct drug efflux is down-regulation of P-gp expression. Over-expression of the MDR-1 gene which encodes P-gp is one of the causes of MDR. RNA interference is a powerful approach to down-regulate gene expression in cells [34, 35]. For cancer therapy, siRNA has been used to suppress tumor growth by silencing various oncogenes [36–38], as well as down-regulate the expression of P-gp by silencing MDR-1 gene [39–41]. To overcome the low efficiency of delivery of siRNA and anticancer drugs, novel poly(ethylene oxide)-modified poly(beta-amino ester) (PEO-PbAE) and PEO-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles were formulated to efficiently encapsulate MDR-1 silencing siRNA and paclitaxel (PTX), respectively [42]. The combination of MDR-1 gene silencing and nanoparticle-mediated delivery significantly induced the cytotoxic activity of PTX in SKOV3TR cells, which was similar to what was observed in drug sensitive SKOV3 cells [42]. The calcium channel antagonist or P-gp antibody were also used to down-regulate the expression of MDR-1 gene or P-gp. The combination of magnetic nanoparticle composed of Fe3O4 (MNPs-Fe3O4) and BrTet significantly increased the intracellular daunorubicin (DNR) accumulation in K562/A02 cell line, and down-regulated the level of MDR-1 gene and expression of P-gp [43]. The antibody of P-gp (anti-P-gp) functionalized water-soluble single-walled carbon nanotubes (Ap-SWNTs) loaded with Dox demonstrated the effective loading and controllable release performance for Dox toward the target K562R cells by exposing to near-infrared radiation (NIR) [44]. Taken together, drug-loaded nanoparticles could indeed multiply intra-cellular drug accumulation and enhance the cytotoxicity of the chemotherapeutic drug.
3 Interruption of DNA repair pathway in cancer cells DNA repair is a complex biological process, which plays a fundamental role in the maintenance of genomic integrity,
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and is also used by tumor cells for surviving from DNA damage induced by chemotherapeutic drugs. Many DNAdamaging agents, such as the alkylating agents, resemble nucleotides and nucleotide precursors or cofactors, and ionizing radiation and radiomimetic agents are commonly used in cancer therapy. They could obstruct replication fork progression and result in replication-associated or replicationindependent DNA double-strand breaks (DSBs). However, there are several efficient DNA repair pathways such as non-homologous end joining to repair direct DSBs [45], homologous recombination (HR) to repair replication-associated DSBs [46], removing alkylations on the O6 position of guanine by O-6-methylguanine-DNA methyltransferase (MGMT) and reverting 1-methyladenine and 3-methylcytosine back to adenine or cytosine by the DNA dioxygenases [47]. All of the associated DNA repair pathways were thought to be the fundaments of MDR in cancer cells, and the efficacy of anticancer drugs was highly impacted by the intra-cellular DNA repair capacity. Therefore, the inhibition of specific DNA repair pathways was demonstrated to be one of the effective ways to improve the efficacy of DNA-damaging chemotherapeutic drugs [48]. Recently, several strategies involving formulations with DNA repair inhibitors and anticancer agents were developed to overcome MDR induced by DNA repair pathways. One of the strategies was to use DNA repair inhibitors co-administration with DNA-damaging anticancer agents. For example, co-administration of O6-benzylguanine and an alkylating agent could significantly reduce the doses of the toxic chemotherapy agent than conventional methods [49]. However, the co-administration lacks selectivity for malignant tissues, and no improvement in the therapeutic index was observed in clinical trials [50]. Other nanoparticles without DNA repair inhibitor were reported to increase DNA damage by interrupting DNA repair pathways [51]. The most significant was undoubtedly the metal associated nanoparticles [52, 53]. Platinum nanoparticles (Pt-NPs) which entered the cells through diffusion could increase DNA damage, accumulation of cells at the S-phase of the cell cycle and apoptosis [54]. Another silver nanoparticle (Ag-NP) induced DNA damage in the human alveolar cell line [55]. Titanium dioxide (TiO2) nanoparticles could induce genotoxicity, oxidative DNA damage, and inflammation in a mouse model [56].
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Repairing the apoptosis pathway
Apoptosis is genetically encoded and highly regulated cell death which plays a vital role in physiological processes such as embryogenesis and immunological reaction [57]. It can be triggered by intrinsic or extrinsic signals. Intrinsic apoptotic signals caused by cellular damage include DNA damage, growth factor withdrawal, activation of p53 (p53 dependent), or pro-apoptotic Bcl-2 homology (BH) 3 pro-
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teins (p53 independent) which subsequently activate a series of caspases (such as caspases 3 and 7), and finally result in apoptosis [58]. The extrinsic apoptosis pathway can be activated through the activation of death receptors (TNF-related apoptosis-inducing ligand receptor, TRAIL-R), and induces apoptosis also through caspases 3 and 7 [59]. Fundamentally, nearly all anti-tumor approaches including anticancer drugs, c-irradiation, suicide genes, and immunotherapy kill tumor cells through inducing cell apoptosis [59–65]. A growing body of evidence suggests that in multidrug resistant cancer cells, the drug-induced apoptosis pathway is blocked because of the change of related enzymes and proteins. Therefore, apoptosis resistance can be overcome by down-regulating the expression of anti-apoptotic molecules or re-sensitizing apoptosis-inducing molecules [66]. Upregulation of TRAIL [67], and downregulation of Bcl-2, Bcl-XL and Bcl-W have been demonstrated valid in cancer therapy [68]. Novel nano-formulations have been used in reverting the apoptosis pathway in resistant cancer cells. One of the main approaches is using RNA interference that can specifically silence target genes, which encode the apoptosis proteins. Nano-formulations which simultaneously deliver siRNA with the conventional anticancer drug to resistant cancer cells are applied to enhance chemotherapeutic efficacy. Mesoporous silica nanoparticles (MSNs) were used for co-delivery of Dox, which induced an antiapoptotic cellular defense when prescribed alone, and Bcl-2 siRNA, as a suppressor of cellular antiapoptic defense for efficient cancer therapy [69]. The siRNA was efficiently transported into cytoplasm, and Dox was primarily localized in the perinuclear region and in nuclei with weak signals in the region close to cell membranes [69]. The phenomenon suggested that this delivery system probably entered cancer cells through endocytosis and could bypass the efflux pump proteins which abounded on the plasma membrane [69]. A synergistic effect could also be achieved when paclitaxelloaded nanoparticle/siRNA complexes were used [70]. Some materials which are nanoparticles themselves or could self-assemble into nanoparticles have been demonstrated to be available in enhancing the pro-apoptotic activity and preventing the activation of the anti-apoptotic cellular defense in vitro [71]. For example, pluronic and magnetic nanoparticles of Fe3O4 (MNPs-Fe3O4) were both applied to enhance the chemosensitivity of MDR cells. It was found that p53, p21 and Bax were up-regulated, whereas Bcl-2 and procaspase 9 were down-regulated in the cells treated with conjugated linoleic acid-coupled Pluronic F127 [72]. Daunorubicin-loaded MNPs-Fe3O4 could also overcome MDR in vivo with decreasing transcriptions of MDR-1 and Bcl-2 genes, and increasing transcription and expression of Bax and caspase-3 [73]. Ceramide is a second messenger signaling molecule involved in differentiation, proliferation, immune response and apoptosis, which is used as an apoptotic modulator with
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therapeutic potential. The enzyme glucosylceramide synthase (GCS), converting ceramide to a nonfunctional moiety glucosylceramide, is overexpressed in many MDR tumors and is associated with cell survival in the presence of chemotherapy agents. Encapsulating ceramide and other anticancer agents into nano-formulation is another strategy to repair the apoptosis pathway. Poly(ethylene oxide)-modified poly(epsilon-caprolactone) (PEO-PCL) nanoparticles encapsulating and co-delivering of ceramide and paclitaxel could greatly improve the chemosensitivity of MDR ovarian cancer cells [74].
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Overcoming MDR with multiple mechanisms
The mechanisms of MDR are very complex, and one MDR phenotype is usually the synergistic result of a combination of a few mechanisms. As a result, many formulations based on nanotechnology were designed to target more than one MDR mechanisms. The lipid-modified dextran nanoparticles loaded with Dox showed a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via P-gp independent pathway, and also showed increased apoptosis in osteosarcoma cells as compared with Dox alone [3]. The P-gp drug efflux function can be significantly inhibited by using folic acid modified micelles which enfold a potent MDR modulator, FG020326 [75]. The apparent effect of the polymeric micelles was credited to integrating the targeting effect of folic acid and inhibiting effect of FG020326. Similar effects were found by using gene delivering antisense oligonucleotides (ASO) targeted to MDR-1 and Bcl-2 mRNA as suppressors of pump and nonpump resistance in one formulation [76]. Encapsulation of Dox and ASO into liposomes showed suppression of both pump and nonpump resistance and the in vitro or in vivo apoptosis induced by Dox was dramatically enhanced [76]. Liposomes could be successfully used for cytoplasmic and nuclear delivery of anticancer drugs and antisense oligonucleotides [76]. The encapsulated Dox was more effective compared with its free form, and the liposomal ASO could effectively inhibit the expression of targeted mRNA and proteins, while free ASO in solution did not display such ability [76]. Co-administration of siRNA targeted to MRP1 and Bcl-2 and Dox in one multifunctional nanocarrier-based delivery system (NDS) also suppressed cellular resistance in MDR lung cancer cells [77].
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tion mechanisms of nanoparticles are still significant work. In addition, there are still many unsolved problems such as toxicology of nanomaterials in human, instability of nanoparticles in circulation, inadequate tissue distribution and reproducibility of batches of the formulations. With the progress of mechanistic studies and clinical evaluations of nanotechnology-based drug delivery systems in overcoming MDR, we expect fascinating new development in MDR cancer treatment in the near future. The National Basic Research Program of China (2010CB934000), the National Natural Science Foundation of China (30925041), and Shanghai Nanomedicine Program (0852nm05700) are gratefully acknowledged for financial support.
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Nanoparticles are potential drug delivery systems in MDR treatment, and the slight variation in nanoparticle formulations can lead to significant difference in the therapeutic effects. Therefore, developing new materials and clarifying the ac-
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