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Current Drug Metabolism, 2014, 15, 632-649

Nanomedicine to Overcome Cancer Multidrug Resistance Xi Yang1, Cheng Yi1, Na Luo2 and Changyang Gong1,* 1

Department of Medical Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China; 2School of Medicine, Nankai University, Tianjin, 300071, China Abstract: Cancer is still considered to be one of the most severe diseases so far. Multidrug resistance (MDR) is a major obstacle against curative cancer chemotherapy. The over-expression of drug efflux pumps in cellular membrane plays a critical role in preventing cancer cells from conventional chemotherapy. Nanotechnology is emerging as a class of therapeutics for MDR. This review mainly focuses on some pivotal strategies to combat MDR, including the enhanced permeability and retention (EPR) effect, stealth nanoparticles to prolong circulation time, endosomal escape, active drug delivery, stimuli sensitive drug release, and targeted co-delivery of different compounds. While convinced challenges need combatting, large numbers of preclinical studies strongly suggest that nanomedicine formations have potential application for improving the treatment of MDR.

Keywords: Chemotherapy, drug delivery system, drug targeting, multidrug resistance, nanomedicine, tumor. INTRODUCTION Cancer is one of the most devastating mankind diseases which can cause increasing morbidity and mortality every year over the world [1]. In spite of the significant advances in the development of novel powerful anticancer drugs, efficiency of the treatment for various malignancies remains low, especially for primary advanced and metastatic tumors. A major impediment to successful chemotherapy of human cancers is the emergence of multidrug resistance (MDR), a state of simultaneous resilience against multiple chemically and mechanistically unrelated drugs [2-5]. This phenomenon is responsible for over 90% of treatment failure in patients with metastatic tumor [6-9]. Intrinsic or acquired resistance is one of the main obstacles associated with effective cancer treatment. Anticancer drug resistance may either be intrinsic (primary), i.e. existing since the beginning of chemotherapeutic treatment, or acquired (secondary), i.e. developed during the course of the treatment [5, 10, 11]. The evolution of such resistances requires to apply higher doses or frequency of dosing of the chemotherapeutic agents, thus increases the risk of severe adverse side effects or toxicity to healthy tissues [12, 13]. The biological background of MDR is complex and generally contains numerous mechanisms, which can be grouped into at least seven major categories: a) decreased drug influx; b) increased drug efflux via permeability glycoprotein (P-glycoprotein [P-gp]); c) altered drug metabolism and detoxification; d) secondary mutations in drug targets; e) activation of downstream or parallel signal transduction pathways; f) activation of DNA repair, and g) disruption of apoptosis combined with induction of antiapoptotic survival defense mechanisms [5, 9, 13-16] (Fig. 1). In contrast, the principal mechanism of MDR is actively transport of anticancer drugs out of tumor cells, thus increased drug efflux is predominantly mediated by ATP-driven extrusion pumps frequently of the ATP-binding cassette (ABC) superfamily. Members of the ABC superfamily include P-glycoprotein (P-gp/ACCB1) encoded by MDR-1, *Address correspondence to this author at the Department of Medical Oncology, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China; Tel: 86-28-85164063. Fax: 86-28-85164060; E-mail: [email protected]

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multidrug resistance proteins (MRP/ABCC) and breast cancer resistance protein (BCRP/ABCG2), which form a unique defense against numerous cytotoxic agents resulting in resistance to a multitude of structurally and mechanistically distinct antitumor agents [17, 18]. Typically, the most extensively studied paradigm multidrug transporter, mammalian P-gp, a broad-specificity transmembrane efflux pump for a wide variety of substrates, is considered to be the major event in establishment of MDR in cancer cells [19-22]. Although an enormous amount of researches are ongoing to reverse MDR, unfortunately, most will not be translatable to clinic. With the development of drug delivery technology, nanotechnology provides an innovative and promising alternative over conventional small molecule chemotherapeutics, overcoming or circumventing MDR by encapsulating, attaching, and conjugating drugs or therapeutic biological agents to nanocarriers. The emerging nanocarriers have confirmed desirable drug delivery characteristics such as solubilized hydrophobic agents, decreased drugs clearance, reduced non-specific cellular uptake, delivered multiple therapeutic payloads, targeted drug delivery, and controllable drug release [23]. Furthermore, the drug-loaded nanocarriers have recently demonstrated enhanced therapeutic efficacy and reduced adverse side effects or toxicity in combating MDR, compared with classical, non-targeted therapeutic drug combination modalities. Hence these advantages endow rapidly developing nanotechnology with the ability to address complicated and combined mechanisms of MDR and make nanotechnology a novel promising avenue for tackling and conquering chemoresistance. Nanocarriers applied to combat MDR containing liposomes, nanoparticles, micelles, dendrimers, nanogel, mesoporous silica particles, and polymer-drug conjugated, which have been developed to simultaneously encapsulate or attach multifunctional agents like anticancer drugs, antibodies or ligands targeting MDR cancer cells, nucleic acid, and inhibitors of P-gp to inhibit different contributors to MDR [5, 24-33]. Therefore, it is found that designing an advanced multifunctional nanocarrier should be a priority to combat MDR in cancer chemotherapy. The present review focuses on the advantages of modern advanced nanotechnology approaches to overcoming and suppressing of existing MDR. Herein, we summarize possible mechanisms of © 2014 Bentham Science Publishers

Current Drug Metabolism, 2014, Vol. 15, No. 6

Nanomedicine to Overcome Cancer Multidrug Resistance

ATP

ATP

Increased drug efflux

633

Decreased drug influx Drug

Caspase Activation of signal transduction pathways

Apoptosis Inhibited

Enzyme Altered drug metabolism and detoxification Drug Mutations in drug targets

Activation of DNA repair Fig. (1). Schematic the mechanisms of MDR. They can be grouped into at least seven major categories: decreased drug influx;, increased drug efflux via ATPdriven extrusion pumps, altered drug metabolism and detoxification, secondary mutations in drug targets, activation of downstream or parallel signal transduction pathways, activation of DNA repair, and apoptosis inhibited. Image was modified and adapted with permission from ref [5].

nanocarrier-based strategies to overcome cancer chemoresistance, including the enhanced permeability and retention (EPR) effect, stealth nanoparticles to prolong circulation time, endosomal escape, active drug delivery, stimuli sensitive drug release, and targeted codelivery of different compounds (e.g., genes, inhibitors of P-gp). In addressing each topic, we provide representative exemplification to emphasize the importance and illustrate their mechanism of action. PASSIVE TARGETING: THE EPR EFFECT A number of different nanocarriers depend on the tumor physiological characteristics for selectively drug accumulation, which is based on a mechanism known as the enhanced permeability and retention (EPR) effect, also called passive targeting [8, 9, 34-38]. The EPR effect in solid tumors was first introduced by Matsumura and Maeda in 1986 and described in greater detail and confirmed by Maeda et al. [39-41]. Their investigations suggested that the neovasculature in most solid tumors (hypervasculature) usually had an abnormal architecture compared with normal tissues and organs, containing defective endothelial cells with large fenestrations, irregular vascular alignment, lack of a smooth-muscle layer or the basement membrane, wide lumen and impaired functional receptors for angiotensin II (AT-II) [39, 42-45]. This anatomical defectiveness, along with functional abnormalities, leads to extensive leakage of blood plasma components into the tumor tissue, such as macromolecules, lipidic particles, nanoparticles [23, 46-49]. Further, the dysfunctional lymphatic drainage clearance, and the slow venous return in tumor tissue mean that macromolecules are retained in tumor sites, whereas extravasation into tumor interstitium continues [41, 50, 51]. This phenomenon, termed the EPR effect, also existing in multidrug resistant solid tumors. In a word, the result of EPR effect is a relatively higher accumulation of nanocarriers at the site of a tumor to conquer MDR. As mentioned above, the EPR effect is applicable for any biocompatible macromolecular compounds: complicated molecules such polymeric micelles and liposomes containing anticancer drugs

as nanocarriers above 40 kDa, even larger than 800 kDa, or the size of bacteria [44, 51-54]. The weight-dependent macromolecular is the threshold of renal clearance, which can prolong the blood halflife (thus, a much enhance t1/2), and make a higher AUC (area under the concentration-time curve) with the very slow clearance from the body [55]. Furthermore, these accumulated macromolecular anticancer drugs can prolong drug retention in tumors for a relatively long time (e.g., several days) [39-41, 52, 54, 56, 57]. In case of SMANCS/Lipiodol (SMANCS/Lpd) used for treating the primary hepatoma was clearly targeted to cancer tissue with great efficiency (the tumor/blood plasma ratio is greater than 2000) by arterially administration [35, 52, 56, 58, 59]. The SMANCS/Lpd was clearly operative for tumor-selective targeting via the EPR effect, serving as an effective anticancer macromolecular drug. Another family of macromolecular therapeutics targeted into numerous cancers via the EPR effect was based on hydrophilic N-(2-hydroxypropyl) methacrylamide (HPMA), to which a broad variety of anticancer drugs were attached. In addition, HPMA-based macromolecular chemotherapeutics are biocompatible, preferentially accumulate in tumors via the EPR effect, and possess a relatively higher anticancer efficacy than low molecular weight drugs [35, 60-62]. Interestingly, the EPR effect does not apply to low-molecular-weight anticancer drugs due to their rapid diffusion into the circulating blood by renal clearance. Meanwhile, these conventional small molecule chemotherapeutics may cause severe systemic side effects in normal tissues or organs because of their undesirable indiscriminatory distribution [44, 45, 55, 59, 63]. In general, their inabilities to accumulate selectively in tumor site and free diffusion of toxic anticancer agents in non-selective manner in the body make them disastrous to patients. More recently, polymer conjugates, micelle or liposomal drugs of anticancer agents, and antibody conjugates are based on the EPR effect, which is becoming a gold standard for macromolecular anticancer drugs designed [45, 64, 65]. What’s more, the most crucial mechanism for passive targeting of anticancer drugs to the sites of

634 Current Drug Metabolism, 2014, Vol. 15, No. 6

tumors-the EPR effect-would greatly increase therapeutic efficacy and reduce the associated risks, in contrast to conventional chemotherapy with low-molecular-weight drugs. STEALTH NANOPARTICLES TO PROLONG CIRCULATION TIME Although the EPR effect contributes to retain macromolecular drugs in tumor environment, nanocarriers must first remain in circulation long enough to initially reach the region of a tumor [8, 23, 34]. Once in the blood stream, nanoparticles can be easily recognized by the host immune system, and then rapidly cleared by the reticuloendothelial system (RES) organs like the kidney, liver, spleen, and lymph nodes [8, 36, 66-68]. Such higher RES uptake by monocytes and macrophages has thus far been an obstacle to any attempts at targeting to tumors. Herein, the need to improve chemotherapeutic agents’ accumulation in tumor site, especially for resistant tumors, and prolong circulation time while minimizing non-specific cellular uptake, which is greatly increased with stealth nanocarriers. One of the most preferred strategies adopted for stealth function was formulating the nanoparticles with polyethylene glycol (PEG) to the surface, owing to their enhanced hydrophilicity and flexibility [69, 70]. The termed PEGylation is used specifically for the decoration of a particle surface by entrapping, covalently grafting, and surface adsorbing of PEG chains [71-74]. The PEGylation surface prevents the nanocarrier recognition and interaction required for uptake and clearance by the RES resulting in an increase in the blood circulation half-life of the particles by several

orders of magnitude [23, 71]. Numerous lines of evidence indicated that PEG length and density on the stealth nanoparticles are key features, which will control the circulation times and accumulation in tumors [75-77]. The most suitable molecular weight of PEG has been reported between 1500-5000 Da to achieve the necessary stealth characteristics [78-81]. Also, it has been shown that as the molecular weight of PEG increases, the systemic half-life of a nanoparticle system increases, which may due in part to the increased chain flexibility of higher MW PEG polymers [82-84]. Similarly, the density of PEG on the surface of nanocarrier can also determine its shielding effects. It is found that a high density of PEG molecules is preferred for achieving optimum stealth properties, because no gaps or spaces on the particle surface are left uncovered [71, 85-87]. In this sense, PEGylation nanoparticle has become a significantly technological nanocarrier that can improve stealth properties unparalleled by any other surface coating and tailor their use in the biological environment. ENDOSOMAL ESCAPE Nanomedicine can not only overcome MDR through enhancing anticancer drugs accumulation at tumor regions (e.g., the EPR effect and stealth nanocarriers), but also can directly increase intracellular accumulation owing to endosomal escape. The termed endosomal escape in MDR cells is that stealth nanocarriers are taken up by endocytosis and cross the cellular membrane in an “invisible” form, which prevents the anticancer drugs from being recognized by the Pgp- and/or MRP-based drug efflux pumps [88] (Fig. 2). In

Multidrug resistant cell

Nano-drug

Free drug

Normal cell

Yang et al.

Fig. (2). Concept for using stealth endocytosis to overcome multidrug resistance. Free drugs are often efficiently internalized by passive diffusion across the cellular membrane. In normal tumor cells, only a small number of drug molecules can diffuse out of the cell and most reach their target site. However, the expression of drug efflux pumps is highly upregulated in MDR tumor cells, leading to a large increase in the amount of free drugs pumping out of MDR tumor cells before the drugs reach the cytoplasm. The result is that very little drug reaches its target site. In case of nanomedicine formations, drug encased in nanocarriers are internalized by tumor cells in a stealth endocytosis process that cannot be sensed and immediately externalized by drug efflux pumps in MDR cellular membrane. Therefore, the overall amount of drug in nanocarriers delivered to the target site is expected to be higher for nano-drugs than for free drugs. Image was adapted with permission from ref [88].


contrast, free drug molecules are often internalized by passive diffusion across the cellular membrane. Subsequently, the drug efflux pumps on cell-surface can sense free drugs while they cross the cellular membrane, and prevent them from entering the cytoplasm [8, 23, 26]. Furthermore, several studies suggested that nanocarriers should be internalized through clathrin-dependent and clathrinindependent endocytosis relaying on the cell type and the composition of the cell surface resulting in accumulating anticancer drugs near the peri-nuclear region (or deep inside the cytoplasm) [36, 89, 90]. Consequently, nanocarriers have the potential to bypass multidrug resistance mechanisms to combat MDR cancers, as they enter cells via endocytosis. ACTIVE TARGETING Actively targeted drugs decorating nanotechnology to the tumor sites provide several distinct advantages over non-targeted drugs. The main advantages include a high accumulation of drugs within tumor rather than other healthy organs, reducing side effects of drugs and making the drugs better equipped to overcome cancers [91]. Most actively targeted nanocarriers can be designed to employ first the EPR effect to enter the neoplasm, and then tumor-targeting agents to be used to facilitate the uptake of carriers into target tumor cells [37]. This strategy depends on the ability of the therapeutic agents, which will specifically delivery to tumor environment, tumor cells, or specific organelles inside cancer cell. Furthermore, studies demonstrated that the alternative strategy to kill multidrug resistance cancer cells is to conjugate an antibody or a targeting ligand to nanocarriers (see Table 1). A number of mAb (A monoclonal antibody) in preparing targeted nanocarriers have approved for treating various MDR cancers, like ovarian, cervical, and breast MDR cancers. One of the most intriguing approaches in this field is that the mAb directed against extracellular epitopes of Pgp, which inhibit the in vitro efflux of anticancer drugs [105]. For instance, a study in this regard has been published by Limtrakul and colleagues, evaluating the cellular uptake capacity of anti-P-gp conjugated with two different nanoparticle formulations (e.g., NP1: poly (DL-lactic-coglycolic acid) (PLGA) nanoparticle and PEG; NP2: a modified poloxamer on PLGA nanoparticles), in multi-drug resistant (KB-V1) and drug sensitive (KB-3-1) cervical carcinoma cells [93]. It was found that the relatively higher cell uptake capability of targeted nanoparticles in KB-V1 cells than KB-3-1 cells, indicating that the two different targeted nanoparticles were internalized into MDR cells. In addition, another similar approach was reported by the same group, who used nanoparticles based on PLGA in the presence of modifiedpluronic F127 stabilizer co-delivering curcumin (Cur) and anti-P-gp (Cur–NPs–APgp) [94]. The specificity and cellular uptake of CurNPs and Cur-NPs-APgp were tested in cervical cancer cell lines KB-V1 and KB-3-1 (higher and lower expression of P-gp, respectively). As expected, Cur-NPs-APgp effectively targeted to P-gp on the cell surface membrane of KB-V1 cells, and improved the cellular uptake and cytotoxicity of Cur. Most successful and extensive researches chose folic acid (FA) as a targeting agent, because FA has several advantages such as lower molecular weight and immunogenicity than large antibodies, easily synthesis, and relatively high stability. Importantly, the folate receptors (FR) are often overexpressed in several types of malignant solid tumor, including uterine, ovarian, lung, breast, and head and neck cancers [106-111]. Conversely, normal tissues that lack FR are spared the toxicity of anticancer drugs, making FA an excellently tumor-targeting agent [111]. For example, FA was used as a targeting moiety for a ternary conjugate heparin-folic acid-


635

paclitaxel nanoparticles/paclitaxel load (HFT-T) towards FRpositive human head and neck cancer cell line KB-3-1 [112]. The resulting nanoparticle HFT-T, targeting FR-positive tumor, was a promising strategy to minimize adverse effects and remarkably improve antitumor efficacy of paclitaxel. Further interesting research has also been developed by Shin and co-workers, demonstrating that FR targeted HFT-T have the potential to overcome resistant human squamous cancer [29]. In vitro analyses suggested that the HFT-T nanoparticle was superior to free paclitaxel or nontargeted nanoparticle (HT-T) in inhibiting proliferation of drugresistant epidermal carcinoma cells (KB-8-5), partially owning to its enhanced intracellular uptake and prolonged retention. Moreover, HFT-T administration markedly retarded the in vivo growth of drug-resistant cancers in a xenograft model, indicating that the targeted HFT-T nanoparticle may be promising in combating P-gp related to drug resistance and enhancing therapeutic efficacy clinically. NANOMEDICINE FOR STIMULI-RESPONSIVE DELIVERY SYSTEM An effective approach to achieving located drug release in multidrug resistance cells is using stimuli-responsive delivery system. In this regard, considerable efforts have been devoted to improving the drug delivery efficiency and achieving the desired therapeutic efficacy employing a stimuli-sensitive nanocarrier because it could regulate and control drug release by stimuli. In addition, stimuli-responsive delivery formations can be classified into self-regulated and externally regulated delivery systems, relaying on a small change in internal (e.g., pH, redox property, enzyme levels) or external (e.g., heat, ultrasound, light, magnetic, electrical) stimuli [113-121] (Fig. 3). Therefore, more and more researches in nanomedicine confirmed that stimuli-coupled drug delivery could control the drug-releasing and accelerate tumor-specific drug accumulation to reach the therapeutic window [5, 8, 23, 122-126]. Among the common stimuli-responsive delivery systems, pHresponsiveness is one of the most widely studied [127]. As discussed earlier, the famous phenomenon of Warburg effect showed in the 1920s that tumor tissues metabolize approximately tenfold more glucose to locate in a given time than normal tissues as a result of the tumor microenvironment differs from the surrounding normal tissues [128, 129]. Furthermore, it has been demonstrated that the exact pH gradients of in extracellular (pH 6.8-7.2), endosomal (pH 5-6), and lysosomal (pH 4.5-5.5) environments, which were affirmed to be advantageous for tumor targeting and endosomal escape in pH-responsive DDS [130-132]. Herein pHresponsive nanocarriers could steadily deliver anticancer drugs at physiological pH to tumor sites, provide fast intracellular drug release through sensing pH descend localized within endosomal and/or lysosomal, and make the intracellular drug concentration reach a sufficiently therapeutic level to overcome MDR tumor cells [133-136]. For instance, polymers, mesoporous silica nanoparticles (MSNs), polymeric micelles, lipid conjugate, dendrimer, hydrogels and nanogels have been commonly reported as pH-responsive nanocarriers [71, 122, 137-144]. The development of inorganic nano-carriers like mesoporous silica nanoparticles (MSNs) has been designed as a drug reservoir for pH-responsive delivery application to achieve a controlled release on account of the electrostatic attraction between MSNs and encapsulated drugs. MSNs as pH-sensitive nanocarrier in nanobiomedical area serve many advantages including excellent biocompatibility, tunable pore sizes, high surface area and drug loading efficiency. Researches for Li’s group have developed doxorubicin/cetyl


Table 1. Active targeting agents Antibody

Yang et al.

Selected examples of nanovehicles for active targeting to overcome anticancer drug resistance.

Main nanovehicle component(s)

Payload type

In vitro

In vivo

Results

Ref.

UIC2-targeted N-(2-

Doxorubicin or Meso

Pgp-expressing human ovarian carcinoma cell line A2780/AD

-

Improved cytotoxicity

[92]

Cervical cancer cell lines KB-V1

-

Improved cytotox-

[93, 94]

hydroxypropyl) methacrylamide chlorin e6 mono(N-2(HPMA) copolymer/drug conju- aminoethylamide) gates Poly (DL-lactide-co-glycolide)

Curcumin

(PLGA) nanoparticles and

(higher expression of P-gp) and

modified pluronic F127 and

KB-3-1 (lower expression of P-gp)

conjugated anti-P-glycoprotein (P-gp) (NPs-APgp) Poly(lactic-co-glycolic acid)

PE38KDEL

HER2 overexpressing breast

(PLGA) nanoparticles -

cancer cells

antiHER2 Fab’ bioconjugates (PE-NP-HER) Immunoliposomes (ILs) deco-

Doxorubicin

rated with anti-EGFR antibodies (anti-EGFR ILs) Immunoliposome carrying anti-

Imatinib

Folate-receptor targeted nanopar-

HER2 overexpress- Improved cytotoxing tumor xenograft model

Paclitaxel

ticle (Heparin-folat-paclitaxel HFT)

MDA-MB-231

Improved

human cancer cells (HT-29 and MDA-MB-231)

Vb100 xenograft model

cytotoxicity and

Philadelphia chromosomepositive

-

inhibited tumor growth Improved

Folate receptor –overexpressing

KB-8-5 xenograft

Improved

human epidermal carcinoma cell

model

cytotoxicity and

Poly(D,L-lactide-co-

Lonidamine and

EGFR overexpressing human

MDA-MB-231

Improved

paclitaxel

breast cancer cell lines (SKOV3

tumors

cytotoxicity and

cells, MDA-MB-231 cells, and OVCAR5 cells)

Poly(ethylene oxide)-block-

Doxorubicin

435/LCC6

PCL) integrin targeting ligand RGD4C (RGD4C-PEO-b-PCL)

WT

RGD peptide (arginine-glycine-

siRNA or Doxorubi- DOX-resistant human breast cancer

aspartic acid)-modified

(wide type) and MDA-

435/LCC6 MDR (P-gp overexpress)

cin

MCF7/A cells

[29]

[98, 99]

inhibited tumor growth Less toxic

Human melanoma cell lines MDA- SCID mice bearing

poly(-caprolactone) (PEO-b-

[97]

inhibited tumor growth

glycolide)/poly(ethylene glyreceptor targeting peptide (PLGA/PEG/EGFR-peptide)

[96]

cytotoxicity

lines KB-3-1 (sensitive) and KB-85 (drug-resistance)

col)/epidermal growth factor

[95]

icity and inhibited tumor growth

EGFR-overexpressing pairs of

acute lymphoblastic leukemia (Ph+ ALL)

CD19 antibody (CD19liposomes). Ligands

icity and cellular uptake

MDA-435/LCC6 WT

and MDA-

435/LCC6 MDR tumors

Improved inhibited tumor growth

Mouse model of

Improved

MCF7/A tumor

cytotoxicity and

liposomes (RGD-modified liposomes)

[100, 101]

cytotoxicity and

[102, 103]

inhibited tumor growth

CD44 targeted hyaluronic acid

Cisplatin

Human non-small cell lung cancer

Nude mice bearing

Enhanced tumor

(HA) nanoparticle (NP)

siRNA

A549 and small cell caner H69; the

human lung cancers

targeting capabil-

corresponding resistant cell lines (A549DDP and H69AR)

ity; the safe and efficient MDR treatment

[104]



637

A Thermo-responsive Ultrasound-responsive Light-responsive Magnetic-responsive Electrical-responsive

External Internal stimulus stimulus

B

pH-responsive Reduction-responsive Enzyme-responsive

Endo/lysosomes pH 4.5 _ 6 / Enzymes Blood

GSH Tumor tissue pH 6.5

Magnetic field

Tumor cell

GSSG

Enzymes

Drug release

Heat; Light; Ultrasound

Fig. (3). (A) Stimuli-sensitive delivery formations may be classified into self-regulated and externally regulated delivery systems relaying on a small change in internal (e.g., pH, redox property, enzyme levels) or external (e.g., heat, ultrasound, light, magnetic, electrical) stimuli. (B) General scheme of the mechanisms of stimuli-responsive delivery systems. Image (B) was adapted with permission from ref [5].

trimethyl ammonium bromide (DOX/CTAB) micelles-co-loaded MSN and DOX-loaded hollow MSN to construct a pH-responsive multi-drug delivery system [145, 146]. Consequently, it is found that the nanocarriers had a highly precise pH-responsive drug release through ion exchanging interaction between H+/H3O+ and positively charged drugs, exhibiting high intracellular drug concentration led to stronger anticancer activity against MCF7/ADR cells. Recently, an interesting example in pH-sensitive field has also been reported by Li’s group, who used polymeric micelles based on poly (styrene-co-maleicanhydride) (SMA) derivative with adipic dihydrazide (ADH) through an acid-cleavable hydrazone bond conjugating doxorubicin (SMA-ADH-DOX, SAD) and encapsulating disulfiram (DSF) [147]. The results showed that the pH-responsive polymeric micelles system was very effective in inhibiting the growth of drug-resistant breast cancer xenografts. In a word, the enhanced growth inhibition by smart DSF-loaded SAD micelles (DSM) was due to the fact that loaded DSF was released fast to combat the activity of P-gp and restore apoptotic signaling pathways, while conjugated DOX was released in a sustained and pHdependent manner and highly accumulated in MCF-7/ADR cells to exert the therapeutic action. NANOTECHNOLOGY FOR TARGETING GENE/DRUG COMBINATION TO OVERCOME MDR In recent years, gene-specific therapeutics such as small interfering RNA (siRNA), small hairpin (shRNA), antisense oligonucleotides (AON), and plasmid DNA (pDNA), have attracted more attention in cancer multidrug resistance [148-151]. The majority of the studies in this area focus on the delivery of siRNAs, which provide the opportunity of knocking down genes involved in multidrug

resistance. However, a major challenge in intracellular delivery of siRNA still remains, because a siRNA is a negatively charged and water-soluble macromolecule. That is, the delivery system for tumor-targeted siRNA delivery in vivo should be designed to combat hurdles including ribonuclease (RNase) degradation, low cellular uptake, endosomal trapping, and rapid clearance of siRNA from the circulation [131, 152-156]. Therefore, nontoxic and nonimmunogenic carriers are required to deliver siRNA to its target validation, which will greatly improve its clinical application of these agents. Current researches in nanomedicine are driven by the desire to create a methodology to effectively co-delivery of traditional chemotherapy with newly emerging siRNA-based therapy and to improve the therapies of MDR cancers with synergistic or combined effects. Various nanocarrier platforms like cationic liposomes or polymers, mesoporous silica nanoparticles, lipoplex and polyplex, which have been developed to simultaneous administration of chemotherapy with siRNA to reverse MDR. Further, in MDR tumors therapy, siRNA has been used to knock down of MDR-related proteins by silencing the expression of drug efflux pumps (e.g., Pgp or MDR1; BCRP or ABCG2; MRP1), antiangiogenesis proteins (e.g., vascular endothelial growth factor, VEGF), antiapoptotic proteins (e.g., Bcell lymphoma-2, Bcl-2), oncogenes (e.g., c-Myc), and regulators of cell cycle (e.g., polo-like kinase1, Plk1) and transcription (e.g., signal transducer and activator of transcription 3, STAT3) (see Table 2). Numerous researches in this field demonstrated that coloaded nanocarriers could be able to protect siRNA, co-transport siRNA and drugs to the cancer sites, induce minimal toxicity or immune response, and enhance the anticancer activity of drugs. Researchers form Nel’s group have reported mesoporous silica nanoparticles (MSNP) based nano-carrier systems for the co-delivery


Table 2.

Nucleic acid MDR1/ Pgp

Yang et al.

Selected examples of siRNA-drug combinations in cancer multidrug resistance. The table is adapted and reproduced with permission from ref [150]. Drug

Nanovehicle

In vitro

In vivo

Results

Ref.

Vinblastine, doxorubicin, paclitaxel, hydroxyurea

OligofectamineTM

The MDR human breast cancer MCF-7/AdrR and MCF-7/BC-19 and human ovarian carcinoma A2780 and A2780Dx5

-

Suppressed P-gp expression Improved cytotoxicity

[157]

Cyclosporine A, digoxin, vinblastine, and vincristine

LipofectamineTM 2000

Human colon adenocarcinoma (Caco-2) cells

-

Reduced efflux ratio

[158]

Doxorubicin

Lipid-modified dextran-based polymeric nanoparticles

Multi-drug resistant osteosarcoma cell lines (KHOSR2 and U-2OSR2)

-

Suppressed P-gp expression

[159]

Doxorubicin

Lipid-modified dextran derivatives

Multi-drug resistant osteosarcoma cell lines (KHOSR2) and ovarian cancer cell lines (SKOV-3TR)

-

Suppressed P-gp expression

[160]

Doxorubicin, Paclitaxel

PLL, stearic acid-substituted PLL (PLL-StA); PEI, oleic acidsubstituted PEI (PEI-OA), and Lipofectamine 2000

Multidrug-resistant MDA435/LCC6 (MDR1) cells

-

Improved cytotoxicity Improved doxorubicin uptake

[161]

Doxil™

Cationic polymers polyethylenimine (PEI) and stearic acidsubstituted poly-L-lysine (PLLStA)

Multidrug-resistant MDA435/LCC6 (MDR1) cells

Multidrug-resistant MDA435/LCC6 (MDR1) cells xenografts in NODSCID mouse

Suppressed P-gp expression Improved tumor growth inhibition

[162]

Doxorubicin

Poly(ethylene oxide)-blockpoly(-caprolactone) (PEO-bPCL) block copolymers attaching two ligands: integrin Rv3specific ligand (RGD4C); cellpenetrating peptide TAT

Multidrug-resistant MDA-MB-435/LCC6 MDR1 cells

-

Suppressed P-gp expression Improved cytotoxicity

[163]

Athymic mice bearing MDA-MB435/LCC6MDR1resistant tumors for optical imaging

Improved cytotoxicity Improved targeting delivery

[100]

Paclitaxel

Poly(D,L-lactide-co-glycolide) nanoparticles functionalized with biotin

Drug-resistance primary mammary adenocarcinoma (JC) cells

BALB/c mice bearing JC tumors

Improved cytotoxicity Improved tumor growth inhibition

[164]

Doxorubicin

Mesoporous silica nanoparticles (MSNP)

Drug-resistant cancer cell line (KB-V1 cells)

-

Improved cytotoxicity Suppressed P-gp expression

[165]

Doxorubicin

Multifunctional mesoporous silica nanoparticle (MSNP) functionalized by a polyethyleneiminepolyethylene glycol (PEI-PEG) copolymer

MDR breast cancer cell line (MCF-7/MDR)

MCF-7/MDR tumor-bearing mice


[33]

Doxorubicin

Phospholipid (dioleoylphosphatidylethanolamine) and polyethylenimine DOPE-PEI complexes

MDR breast cancer cell line (MCF-7/MDR)

-

Improved cytotoxicity Improved doxorubicin uptake

[166]



639

Table (2) contd….

Nucleic acid

Drug

Nanovehicle

In vitro

In vivo

Results

Ref.

STAT3

Doxorubicin Paclitaxel

Lipid-substituted polymers linoleic acid-substituted (PEILA) polymer

Drug resistant MDAMB-435 breast cancer cells

-

Improved cytotoxicity Suppressed STAT3 expression

[167]

Plk1

Paclitaxel

Poly(ethylene glycol)-b-poly(caprolactone)-b-poly(2aminoethyl ethylene phosphate)

Multidrug-resistant MDA-MB-435s tumor cell line

MDA-MB-435s xenograft murine model


[168]

-

Poly(ethylene glycol)-bpoly(d,l-lactide) (PEG-PLA) nanoparticles

HepG2 and MDA-MB435s cancer cells

Orthotopic murine liver cancer model and MDA-MB435s murine xenograft model


[169]

Paclitaxel

PDMAEMA–PCL–PDMAEMA triblock copolymers

Human breast cancer cell MDA-MB-435GFP and human prostate carcinoma cell PC3 cells

-

Improved cellular uptake

[170]

Doxorubicin

Polyethylenimine (PEI) -stearic acid (SA) PEI-SA micelles

Human hepatoma Huh7 cells

Huh-7

Improved tumor growth inhibition

[171]

VEGF

cancer cells bearing in male C.B17/ICR SCID mice

VEGF/cMyc

Doxorubicin

Cationic liposome-polycationDNA (LPD) and anionic liposome-polycation-DNA (LPD-II)

Multidrug-resistant ovarian cancer cell line NCI/ADR-RES cells and drug-sensitive line OVCAR-8

NCI/ADR-RES tumor-bearing mice


[172]

c-Myc

Doxorubicin

PEGylated LPD (liposomepolycationDNA) with NGR (aspargine–glycine–arginine) peptide (LPD-PEG-NGR)

Human fibrosarcoma HT-1080 cells

HT-1080 tumorbearing mice


[173]

Bcl-2

Doxorubicin

Mesoporous Silica Nanoparticles

Multidrug-resistant A2780/AD human ovarian cancer cells

-

Limited adverse side effects Improved cytotoxicity

[156]

Doxorubicin

Polyplex: poly(-caprolactone) (PCL) and linear poly(ethylene imine) (PEI) (PEI-PCL) Folate (FA)- poly(ethylene glycol)blockpoly(glutamic acid) (FAPEG-PGA)

Rat glioma C6 cells

In situ rat C6 glioma model

Suppressed BCL-2 gene expression Improved tumor growth inhibition

[174]

MRP1 /Bcl-2

Doxorubicin

Cationic liposomes

Human MDR A2780/AD ovarian and MCF-7/AD breast cancer cells

-


[175]

BCRP

Methotrexate

Lipid-substituted polymers

BCRP-transfected Madin–Darby Canine Kidney (MDCK) cell

-


[176]

MDR1/B CRP /MRP1

-

Poly(ethylene oxide)poly(propylene oxide) block copolymers (poloxamines)

Human hepatoma cell line (Huh7)

-

Down-regulation of MDR1 and ABCG2 genes MRP1 gene was not affected

[177]


of a chemotherapeutic agent doxorubicin (Dox) and P-gp siRNA to drug-resistant cancer lines (KB-V1 cells and MDF-7/AD cells) [33, 165]. These results demonstrated that the dual delivery of Dox and siRNA in MDR cells was capable of increasing the intracellular and intranuclear drug concentration, owing to effective silencing of P-gp mRNA and significant suppression of the pump mediated resistance in vitro. Following the establishment of a MCF-7/ADR xenograft tumor model in nude mice, it was indicated that polyethyleneimine/polyethylene glycol (PEI-PCL) functionalized MSNP could provide protected delivery of stably bound Dox and P-gp siRNA to the tumor sites, and achieve an 8% enhanced permeability and retention effect at the targeted sites. Therefore, the dual delivery system resulted in synergistic inhibition of tumor growth in mice models compared free Dox or the inorganic nanoparticles loaded either with siRNA or drug alone. Another interesting study in this regard has been reported by Minko’s group, who prepared cationic liposomes for the codelivery of doxorubicin as a chemotherapeutic drug, and two different siRNAs targeted against proteins responsible for pump and nonpump mediated cellular resistance (e.g., MRP-1 and Bcl-2 siRNAs) in MDR small cell lung cancer (H69AR cells) [8, 123, 175, 178]. The study confirmed that the effective co-delivery of Dox and siRNAs can not only promote cell-death induction but also can suppress cellular resistance in MDR cells, which could not be achieved by MRP1-siRNA, Bcl2-siRNA and/or Dox. SIMULTANEOUS DELIVERY OF EFFLUX INHIBITORS AND ANTICANCER DRUGS In addition, a promising strategy for overcoming effluxmediated drug resistance is to co-administer P-gp inhibitors along with anticancer drugs [179]. The first generation P-gp inhibitors, like verapamil, quinine, cyclosporine A, were ineffective or unacceptable toxicity at the doses required weakening P-gp function [180, 181]. Then, the further researches were carried out the second-generation agents (e.g., PSC833, VX-710), which had better tolerability but induced unexpected pharmacokinetic interactions limiting the drug clearance and metabolism of chemotherapy [182, 183]. Subsequently, the third-generation modulators (elacridar, tariquidar, zosuquidar, laniquidar, and ONT-093) were designed specifically for high affinity to P-gp and low pharmacokinetic interaction [184-186]. Although the clinical advantages of the first- and second- generation P-gp modulators are in question, the inhibitors used today are much improved and the clinical trials with the third generation are ongoing [186-188]. However, safety concerns have limited the clinical benefits of P-gp inhibitors because the efflux pumps highly express in healthy tissues and important pharmacological barriers, serving as a guardian against endogenous and xenobiotic compounds in the body. Another relevant factor shows that some P-gp modulators are lower solubility in aqueous solutions, which can strongly influence the bioavailability and efficacy of these agents in vivo [189]. Numerous studies that have been extensively evaluated made the use of nanomedicines in combination with P-gp inhibitors to overcome MDR (see Table 3). As demonstrated in these studies, the simultaneous administration of a P-gp inhibitor and an anticancer drug with a DDS could reduce side effects and improve the solubility and the consequent pharmacological profile [178, 190]. Moreover, the nanocarriers have attractive properties for reducing drug efflux, and reverting MDR phenotype. Therefore, many groups have turned their attention to co-deliver anticancer agents with P-gp inhibitors [23]. As an example for the former, researchers from Torchilin’s group have confirmed that nanocarriers co-loaded with P-gp inhibi-

Yang et al.

tor and antineoplastic agent could enhance the effectiveness of chemotherapy against resistance tumor cells. First, Patel et al. tested co-delivery of tariquidar (XR9576) with paclitaxel into SKOV-3 and SKOV-3TR cells to reverse MDR using longcirculating liposomes [204]. As shown in (Fig. 4), the IC50 values for tariquidar- and paclitaxel-co-loaded liposomes were 17.68 nM and 34 nM in SKOV-3 cells and SKOV-3TR cells, respectively. Meanwhile, these results indicated that the co-encapsulation have produced an equivalent toxicity in both cell lines but about 80-fold lower than the IC50 of free paclitaxel in SKOV-3TR cells (2743 nM). What’s more, Sarisozen et al. have recently worked on the Polyethylene glycol/phosphatidyl ethanolamine (PEG-PE-based) micelles as carriers for the simultaneous co-administration of elacridar (GG918) or cyclosporine A and paclitaxel against MDCKIIMDR1 cells [198, 202]. The obtained results showed that micelles co-loading of P-gp inhibitor and anticancer drug have potential application in overcoming drug resistance. Other interesting studies were reported by Panyam’s group, who used co-administration of verapamil and paclitaxel in poly (lactic-co-glycolic acid) (PLGA) NPs, acting as more effective means of reversing drug-resistant NCI-ADR/RES cells in vitro [197]. Similarly, the same research team demonstrated that PLGA NPs co-delivery of paclitaxel and tatriquidar were effective in inducing significantly higher cytotoxicity and greater inhibition of tumor growth in drug resistant cell lines JC and NCI/ADR (Fig. 4) [203]. In line with previous preclinical studies, the results certified that it’s feasible to inhibit P-gp by this synergistic and promising strategy (see Table 3). As a result of in vivo data, a phase I clinical study in patients with a histologically documented resistant or recurrent malignancies investigated the effects of valspodar on PEGylated liposomal doxorubicin (PEG-LD) toxicity and pharmacokinetics [206]. Treatment with PEG-LD 25 mg/m2 every two weeks coadministrated with valspodar resulted in a moderate prolongation of total doxorubicin clearance and half-life, suggesting that there is a weak pharmacokinetic interaction between valspodar and PEG-LD (Doxil®). In summary, the encouraging studies demonstrated that dual-loaded nanocarriers could always cause minimal tissue drug toxicity, and achieve the most improved pharmacokinetic profiles and the highest reversal efficacy and the long-term suppression of cancerous tumors. CONCLUSIONS Development of resistance to multiple drugs is a key reason for the failure of the traditional chemotherapy in many cancers. As described above, tumor MDR can be intrinsic or acquired through exposure to chemotherapeutic compounds. Because of several intricate mechanisms of cancer-cell resistance, higher drug doses and more frequent administrations are needed to achieve effective treatment, or they may lead to unexpected adverse side effects with clinical inconvenience. However, innovative nanomedicines provide a powerful and versatile drug delivery option to conquer MDR. Numerous favorable characteristics including the EPR effect, stealth nanoparticles to prolong circulation time, endosomal escape, active drug delivery, stimuli sensitive drug release, and targeted codelivery of different agents have made drug-load nanocarriers highly promising in overcoming cancer drug resistance. OUTLOOK Although there are numerous positive features of therapeutic nanocarriers for MDR cancers, there are also several issues of concern: a) the pharmacokinetics of agents delivered by nanocarriers



Table 3.

Drug class Frist generation

Characteristics and results of in vitro and in vivo studies using the novel combination of nanocarriers and P-gp modulators to overcome multidrug resistance. The table is adapted and reproduced with permission from ref [179]. MDR

MDR

Modulator

Substrate

Verapamil

Doxorubicin

Nanocarrier

In vitro

In vivo

Results

Ref.

Stealth liposomes

-

Pharmacokinetics in normal rats

Improved pharmacokinetic profile

[191]

Multidrug resistant rat prostate cancer Mat-LyLu-B2 (MLLB2) cells

-


[192]

Verapamil

Doxorubicin

Transferrin-conjugated liposomes

Chronic myelogenous leukemia (K562/DOX) cells

-


[193]

Verapamil

Vincristine

Poly(D,L-lactide-co-glycolide acid) (PLGA) nanoparticles

Human breast cancer (MCF7/ADR) cells

-


[194]

Human hepatocellular carcinoma (BEL7402/5-FU) cells

-


[195]


-


[196]

-


[197]

Verapamil

Paclitaxel

Deoxycholic acid- Ocarboxymethylated chitosanfolic acid conjugates and （DOMCFA）micelles

Poly(D,L-lactide-co-glycolide acid) NCI-ADR/RES (Human breast (PLGA) nanoparticles cancer MCF-7/ADR) Cyclosporin A Doxorubicin

Second generation

Polyalkylcyanoa-crylate (PACA) nanoparticles

Doxorubicin-resistant leukemia (P388/ADR) cells

-


[47]

Cyclosporin A

Paclitaxel

Polyethylene glycol/phosphatidyl ethanolamine (PEG-PE-based) micelles Targeted (anticancer mAb 2C5-modified) polymeric lipid-core PEG-PE-based micelles

Madin–Darby Canine Kidney (MDCKII-MDR1)

-


[198]

Tamoxifen

Topotecan

Wheat germ agglutinin-conjugated liposomes

Murine glial tumor (C6) cells Transport across BBB (brain microvascular endothelial cells/rat astrocytes)— (BMVECs/RAs)

C6 tumorbearing Sprague Dawley rats

Improved cytotoxicity Improved transport and targeting of C6 cells Longer survival of animals

[199]

Valspodar (PSC-833)

Doxorubicin

MDA435/LC Improved cytotoxicity Improved pharmaC6/MDR1 cokinetic profile solid tumor xenograft models

[200]

PEG containing distearoylglyceroHuman breast carcinoma phosphocholine (DSPC)/Chol (MDA435/LCC6/MDR1) cells liposome Clonogenic assay in MDA435/LCC6/MDR1 cells

Third generation

641

Elacridar

Doxorubicin Polymer–lipid hybrid nanoparticles Human breast carcinoma (PLN) (MDA435/LCC6/MDR1) cells Clonogenic assay in MDA435/LCC6/MDR1 cells

Elacridar

Paclitaxel

Tariquidar

Paclitaxel

-

Improved doxorubicin uptake Long-term cancer growth suppression

[201]

-


[202]

Poly(D,L-lactide-co-glycolide acid) Murine mammary adenocarciJC tumorImproved cytotoxicity Improved tumor (PLGA) nanoparticles noma (JC) and human ovarian bearing female growth inhibition Biotin-poly(D,L-lactide-coadenocarcinoma (NCI/ADR- BALB/c mice glycolide acid) (PLGA) nanopartiRES) cells cles

[203]

Polyethylene glycol/phosphatidyl ethanolamine (PEG-PE-based) micelles

Madin–Darby Canine Kidney (MDCKII-MDR1)


Yang et al.

Table (3) contd….

Drug class

MDR Substrate

Tariquidar

Nanocarrier

In vitro

In vivo

Results

Ref.

Paclitaxel

Stealth liposomes

Paclitaxel-resistant human ovarian adenocarcinoma (SK-OV-3TR) cells

-


[204]

Disulfiram

Doxorubicin

Poly(styrene-co-maleic anhydride) (SMA) derivative / adipic dihydrazide (ADH) / doxorubicin SMAADH-DOX (SAD) conjugate


Mice bearing Improved cytotoxicity Improved pharmaMCF-7/ADR cokinetic tumor Profile Improved tumor growth inhibition

[147]

Pluronic®P85

Doxorubicin

Poly (L-histidine)-poly (D,Llactide)-polyethyleneglycol-poly (D,L-lactide)-poly (L-histidine) (PHis-PLA-PEG-PLA-PHis) and Pluronic®F127


Female Improved cytotoxicity Improved tumor BALB/c mice growth inhibition bearing MCF7/ADR tumor

[205]

C

Extracellular

Efflux of hydrophobic substrates Cell membrane

ATP

Intracellular

Pgp

a

1000

100

SKOV-3 SKOV-3TR

10

PCL alone

PCL liposomes

XRPCL liposomes

PX-SOL PX-TAR-SOL TAR-SOL

0

3

10

30

50

100

300 500 700 1000

Paclitaxel dose (nM) 140 100 80

PX-NP

60

PX-TAR-NP

40

PX-SOL

20

PX-TAR-SOL

0

1

PX-TAR-NP

40

120

*

% Survival

IC50 for Pacliaxel at 48 hrs (nM)

D

*

PX-NP

60

0

Drugs

10000

80

20

Hydrophobic

B

120 100

% Survival

Other

A

MDR Modulator

TAR-SOL

0

3

10

30

50

100

300 500 700 1000

Paclitaxel dose (nM)

Fig. (4). Overcoming MDR using nanomedicines and Pgp inhibitors. (A) Schematic depiction of a Pgp efflux pump located within the cellular membrane effluxing hydrophobic substrates. (B) IC50 for paclitaxel in SKOV-3 and SKOV-3TR cells. Cells were treated with free paclitaxel (PCL alone), paclitaxel liposomes (PCL liposomes) and tariquidar- paclitaxel combination liposomes (XRPCL liposomes) at various concentrations. (C) JC and (D) NCI/ADR-RES Cells were incubated with treatments and the cell viability was determined using MTS assay. Legend: PX-NP-Nanoparticles containing paclitaxel, PXTARNP-Nanoparticles containing paclitaxel and tariquidar, PX-SOL-Paclitaxel insolution, PX-TAR-SOL-Paclitaxel and tariquidar in solution, and TAR-SOLTariquidar in solution. Reprinted with permission from [178, 203-204].



through MDR tumor tissue; b) simultaneously inhibit both pump and non-pump mechanisms; c) anti-MDR nanomedicines applied in the clinical cancer treatment; d) the complication of manufacturing the multifunctional nanocarriers at large scale with appropriate quality. Overall, it seems that continuous research efforts on antiMDR nanomedicines should drive their successful development, and the continuing emergence of a new class of multiple resistance anticancer therapies.

DSF

=

Disulfiram

siRNA

=

Interfering RNA

shRNA

=

Small hairpin

AON

=

Antisense oligonucleotides

643

pDNA

=

Plasmid DNA

RNase

=

Ribonuclease

VEGF

=

Vascular endothelial cell growth factor

DECLARATION OF INTEREST STATEMENT

Bcl-2

=

B-cell lymphoma-2

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Plk1

=

Polo-like kinase1

STAT3

=

Signal transducer and activator of transcription 3

ACKNOWLEDGEMENTS This work was financially supported by National Natural Science Foundation of China (81201724) and Sichuan Support Project of Science and Technology (2013SZ0018).

PEI-PCL

=

Polyethyleneimine/polyethylene glycol

PLL-StA

=

Poly-L-lysine-stearic acid-substituted

PEO-b-PCL

=

Poly(ethylene oxide)-block-poly (-caprolactone)

PEG-PE

=

Polyethylene glycol/phosphatidyl ethanolamine

GG918

=

Elacridar

LIST OF ABBREVIATIONS Abbreviations

=

Meaning

MDR

=

Multidrug resistance

The EPR effect

=

The enhanced permeability and retention effect

PEG-LD

=

PEGylated liposomal doxorubicin

DOMC-FA

=

Deoxycholic acid- Ocarboxymethylated chitosanfolic acid conjugates micelles

The ABC superfamily =

The ATP-binding cassette superfamily

P-gp

=

P-glycoprotein

MRP

=

Multidrug resistance protein

PACA

=

Polyalkylcyanoa-crylate

BCRP

=

Breast cancer resistance protein

PLN

=

Polymer–lipid hybrid nanoparticles

AT- II

=

Angiotensin II

AUC

=

Area under the concentration-time curve

PHis-PLA-PEGPLA-PHis

=

Poly (L-histidine)-poly (D,L-lactide)polyethyleneglycol-poly (D,L-lactide)poly (L-histidine)

SMANCS/Lpd

=

SMANCS/Lipiodol

HPMA

=

Hydrophilic N-(2-hydroxypropyl) methacrylamide

RES

=

Reticuloendothelial system

PEG

=

Polyethylene glycol

MW

=

Molecular weight

mAb

=

A monoclonal antibody

PLGA

=

Poly (DL-lactic-coglycolic acid)

Cur

=

Curcumin

FA

=

Folic acid

FR

=

Folate receptors

HFT-T

=

Heparin-folic acid-paclitaxel nanoparticle/paclitaxel

HER2

=

Human epidermal growth for receptor2

ILs

=

Immunoliposomes

EGFR

=

Epidermal growth factor receptor

RGD

=

Arginine-glycine-aspartic acid

DDS

=

Drug delivery system

MSNs/MSNP

=

Mesoporous silica nanoparticles

DOX

=

Doxorubicin

DOX/CTAB

=

Doxorubicin/cetyl trimethyl ammonium bromide

SMA

=

Poly (styrene-co-maleicanhydride)

ADH

=

Adipic dihydrazide

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Received: January 29, 2014

Revised: May 12, 2014

Accepted: May 12, 2014

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