title: Alpha-tocopheryl polyethylene glycol succinate-emulsified poly(lactic-co-glycolic acid) nanoparticles for reversal of multidrug resistance in vitro.
abstract: Multidrug resistance (MDR) is one of the factors in the failure of anticancer chemotherapy. In order to enhance the anticancer effect of P-glycoprotein (P-gp) substrates, inhibition of the P-gp efflux pump on MDR cells is a good tactic. We designed novel multifunctional drug-loaded alpha-tocopheryl polyethylene glycol succinate (TPGS)/poly(lactic-co-glycolic acid) (PLGA) nanoparticles (TPGS/PLGA/SN-38 NPs; SN-38 is 7-ethyl-10-hydroxy-camptothecin), with TPGS-emulsified PLGA NPs as the carrier and modulator of the P-gp efflux pump and SN-38 as the model drug. TPGS/PLGA/SN-38 NPs were prepared using a modified solvent extraction/evaporation method. Physicochemical characterizations of TPGS/PLGA/SN-38 NPs were in conformity with the principle of nano-drug delivery systems (nDDSs), including a diameter of about 200 nm, excellent spherical particles with a smooth surface, narrow size distribution, appropriate surface charge, and successful drug-loading into the NPs. The cytotoxicity of TPGS/PLGA/SN-38 NPs to MDR cells was increased by 3.56 times compared with that of free SN-38. Based on an intracellular accumulation study relative to the time-dependent uptake and efflux inhibition, we suggest novel mechanisms of MDR reversal of TPGS/PLGA NPs. Firstly, TPGS/PLGA/SN-38 NPs improved the uptake of the loaded drug by clathrin-mediated endocytosis in the form of unbroken NPs. Simultaneously, intracellular NPs escaped the recognition of P-gp by MDR cells. After SN-38 was released from TPGS/PLGA/SN-38 NPs in MDR cells, TPGS or/and PLGA may modulate the efflux microenvironment of the P-gp pump, such as mitochondria and the P-gp domain with an ATP-binding site. Finally, the controlled-release drug entered the nucleus of the MDR cell to induce cytotoxicity. The present study showed that TPGS-emulsified PLGA NPs could be functional carriers in nDDS for anticancer drugs that are also P-gp substrates. More importantly, to enhance the therapeutic effect of P-gp substrates, this work might provide a new insight into the design of pharmacologically inactive excipients that can serve as P-gp modulators instead of drugs that are P-gp inhibitors.
authors.affiliation: Jiangsu Key Laboratory for Supramolecular Medicinal Materials and Applications, College of Life Sciences, Nanjing Normal University, Nanjing 210046, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Miao
authors.initials: M
authors.lastname: Guo
authors.forename: Yu
authors.initials: Y
authors.lastname: Lu
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Ding
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Ron
authors.forename: Ya-Qing
authors.initials: YQ
authors.lastname: Liu
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Song
authors.forename: Shu-Qin
authors.initials: SQ
authors.lastname: Yu
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004655:Emulsions / Q000737:chemistry; D006801:Humans; D000077146:Irinotecan; D019344:Lactic Acid / Q000737:chemistry*; D008422:Materials Testing; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D053758:Nanoparticles; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D011092:Polyethylene Glycols / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004655:Emulsions; D053769:Nanocapsules; D014810:Vitamin E; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011092:Polyethylene Glycols; D000077146:Irinotecan; C014225:tocophersolan; D002166:Camptothecin