title: Enhanced effect of pH-sensitive mixed copolymer micelles for overcoming multidrug resistance of doxorubicin.
abstract: P-glycoprotein (P-gp) mediated drug efflux has been recognized as a key factor contributing to the multidrug resistance (MDR) in tumor cells. To address this issue, a new pH-sensitive mixed copolymer micelles system composed of hyaluronic acid-g-poly(l-histidine) (HA-PHis) and d-α-tocopheryl polyethylene glycol 2000 (TPGS2k) copolymers was developed to co-deliver doxorubicin (DOX) and TPGS2k into drug-resistant breast cancer MCF-7 cells (MCF-7/ADR). The DOX-loaded HA-PHis/TPGS2k mixed micelles (HPHM/TPGS2k) were characterized to have a unimodal size distribution, high DOX loading content and a pH dependent drug release profile due to the protonation of poly(l-histidine). As compared to HA-PHis micelles (HPHM), the HPHM/TPGS2k showed higher and comparable cytotoxicity against MCF-7/ADR cells and MCF-7 cells, respectively. The enhanced MDR reversal effect was attributed to the higher amount of cellular uptake of HPHM/TPGS2k in MCF-7/ADR cells than HPHM, arising from the inhibition of P-gp mediated drug efflux by TPGS2k. The measurements of P-gp expression level and mitochondrial membrane potential indicate that the blank HPHM/TPGS2k inhibited P-gp activity by reducing mitochondrial membrane potential and depletion of ATP but without inhibition of P-gp expression. In vivo study of micelles in tumor-bearing mice indicate that HPHM/TPGS2k could reach the tumor site more effectively than HPHM. The pH-sensitive mixed micelles system has been demonstrated to be a promising approach for overcoming the MDR.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Jiangnan University, No. 1800, Lihu Road, Wuxi 214122, PR China.
authors.forename: Lipeng
authors.initials: L
authors.lastname: Qiu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China.
authors.forename: Mingxi
authors.initials: M
authors.lastname: Qiao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, No. 199, Renai Road, Suzhou 215123, PR China.
authors.forename: Chenmin
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China.
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Long
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, No. 199, Renai Road, Suzhou 215123, PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, No. 199, Renai Road, Suzhou 215123, PR China.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, No. 199, Renai Road, Suzhou 215123, PR China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No.103, Wenhua Road, Shenyang 110016, PR China. Electronic address: chendawei@syphu.edu.cn.
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D003692:Delayed-Action Preparations / Q000737:chemistry / Q000494:pharmacology*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006639:Histidine / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006820:Hyaluronic Acid / Q000737:chemistry / Q000494:pharmacology; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D008823:Micelles; D014810:Vitamin E; C033223:polyhistidine; D011092:Polyethylene Glycols; D006639:Histidine; D004317:Doxorubicin; D006820:Hyaluronic Acid; C014225:tocophersolan
keywords: Copolymer micelles; Hyaluronic acid; Multidrug resistance; P-glycoprotein; d-α-tocopheryl polyethylene glycol succinate; pH-sensitive