title: Star-shape copolymer of lysine-linked di-tocopherol polyethylene glycol 2000 succinate for doxorubicin delivery with reversal of multidrug resistance.
abstract: A star-shape copolymer of nanostructure-forming material, P-glycoprotein (P-gp) reversible inhibitor and anticancer enhancer, lysine-linked di-tocopherol polyethylene glycol 2000 succinate (PLV(2K)), was synthesized to overcome multidrug resistance (MDR) in cancer chemotherapy. The critical micellar concentration of PLV(2K) was as low as 1.14 μg/mL, which can endow nanoassemblies good physical stability. Doxorubicin (DOX) was encapsulated into the hydrophobic core of PLV(2K) (PLV(2K)-DOX), with encapsulation efficiency as high as 94.5% and a particle size of 16.4 nm. DOX released from PLV(2K)-DOX nanomicelles was pH-dependent, which ensures micelles stable in blood circulation and releases DOX within tumor cells. Facilitated by the cytotoxicity and uncompetitive P-gp ATPase inhibition by PLV(2K), PLV(2K)-DOX showed greater cytotoxicity compared with DOX solution with increased intracellular accumulation in resistant MCF-7/Adr cells. PLV(2K)-DOX nanomicelles were uptaken into MCF-7/Adr cells via macropinocytosis and caveolae-mediated endocytosis, which further facilitate escapement of P-gp efflux. The anticancer efficacy in vivo was evaluated in 4T1-bearing mice and inhibition of tumor by PLV(2K)-DOX was more effective than TPGS-DOX and DOX solution. In summary, PLV(2K) copolymer has striking functions such as uncompetitive P-gp ATPase reversible inhibitor and anticancer efficacy, and could be a promising nanocarrier in improving the chemotherapy of hydrophobic anticancer drugs.
authors: Department of Biopharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang 110016, PR China.
authors: Jinling
authors: J
authors: Wang
authors: Jin
authors: J
authors: Sun
authors: Qin
authors: Q
authors: Chen
authors: Ying
authors: Y
authors: Gao
authors: Lin
authors: L
authors: Li
authors: Hui
authors: H
authors: Li
authors: Donglei
authors: D
authors: Leng
authors: Yongjun
authors: Y
authors: Wang
authors: Yinghua
authors: Y
authors: Sun
authors: Yongkui
authors: Y
authors: Jing
authors: Siling
authors: S
authors: Wang
authors: Zhonggui
authors: Z
authors: He
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors*; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry; D002152:Calorimetry, Differential Scanning; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D046529:Microscopy, Electron, Transmission; D053758:Nanoparticles / Q000737:chemistry; D010316:Particle Size; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000494:pharmacology*; D024505:Tocopherols / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D008823:Micelles; D011092:Polyethylene Glycols; D004317:Doxorubicin; D000251:Adenosine Triphosphatases; D024505:Tocopherols