Abstract
Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance (MDR) which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp), multidrug resistance-associated proteins (MRP1, MRP2), and breast cancer resistance protein (BCRP). Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective, and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells, or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses, and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading, or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1α gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-κB. “Theragnostics” combining a cytotoxic agent, targeting moiety, chemosensitizing agent, and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome MDR in cancer cell.
Highlights
Cancer is a heterogeneous disease and use of multiple drugs simultaneously can result in drug resistance which is either intrinsic or acquired known as multidrug resistance (MDR)
These efflux pumps belong to ATP-binding cassette (ABC) family and include (a) permeability glycoprotein (P-gp) known as multidrug resistance protein 1 (MDR1) or cluster of differentiation 243 (CD243) a ATP-binding cassette sub-family B member 1 encoded in human by ABCB1 gene (b) Multidrug Resistance Associated Protein 1 (MRP1) a ATP-binding cassette sub-family C member 1 encoded in human by ABCC1 gene, Multidrug Resistance Associated Protein 2 (MRP2) called as canalicular multispecific organic anion transporter 1 a ATP-binding cassette sub-family C member 2 encoded in human by ABCC2 gene (c) breast cancer resistance protein (BCRP) known as cluster of differentiation (CDw338) a member of white sub-family and ATP-binding cassette G member 2 encoded in human by ABCG2 gene (Ozben, 2006)
Wang et al (2010) observed 35% reduction in tumor growth, inhibition of P-gp and mdr1 gene levels in KB-A-1 cells implanted in Balb/c-nu/nu mice targeted by folic acid conjugated antisense oligodeoxynucleotides-hydroxypropyl-chitosan nanoparticles compared to bare antisense oligodeoxynucleotides to overcome tumor drug resistance
Summary
Sonali Kapse-Mistry 1, Thirumala Govender 2, Rohit Srivastava 3 and Mayur Yergeri 4*. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp), multidrug resistance-associated proteins (MRP1, MRP2), and breast cancer resistance protein (BCRP). Nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective, and promising platforms for treatment of drug resistant cancer cells. “Theragnostics” combining a cytotoxic agent, targeting moiety, chemosensitizing agent, and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR.
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