title: Systematic evaluation of multifunctional paclitaxel-loaded polymeric mixed micelles as a potential anticancer remedy to overcome multidrug resistance.
abstract: Multidrug resistance (MDR) of tumor cells is becoming the main reason for the failure of chemotherapy and P-glycoprotein (P-gp) mediated drug efflux has demonstrated to be the key factor for MDR. To address this issue, a novel pH-responsive mixed micelles drug delivery system composed of dextran-g-poly(lactide-co-glycolide)-g-histidine (HDP) and folate acid-D-α-tocopheryl polyethylene glycol 2000 (FA-TPGS2K) copolymers has been designed for the delivery of antitumor agent, paclitaxel (PTX) via FA-receptor mediated cell endocytosis, into PTX-resistant breast cancer MCF-7 cells (MCF-7/PTX). PTX-loaded FA-TPGS2K/HDP mixed micelles were characterized to have a small size distribution, high loading content and excellent pH-responsive drug release profiles. Compared with HDP micelles, FA-TPGS2K/HDP mixed micelles showed a higher cytotoxicity against MCF-7 and MCF-7/PTX cells due to the synergistic effect of FA-receptor mediated cell endocytosis, pH-responsive drug release and TPGS mediated P-gp inhibition. P-gp expression level, ATP content and mitochondrial membrane potential change have been measured, the results indicated blank FA-TPGS2K/HDP mixed micelles could inhibit the P-gp activity by reducing the mitochondrial membrane potential and depleting ATP content but not down-regulating the P-gp expression. In vivo antitumor activities demonstrated FA-TPGS2K/HDP mixed micelles could reach higher antitumor activity compared with HDP micelles for MCF-7/PTX tumor cells. Histological assay also indicated that FA-TPGS2K/HDP mixed micelles showed strongly apoptosis inducing effect, anti-proliferation effect and anti-angiogenesis effect. All these evidences demonstrated this pH-sensitive FA-TPGS2K/HDP micelle-based drug delivery system is a promising approach for overcoming MDR.
  
  
  
  In this work, a novel FA-TPGS2K copolymer has been synthesized and used it to construct mixed micelles with HDP copolymer to overcome MDR effect. Furthermore, a series in vitro and in vivo evaluations have been made, which supported enough evidences for the efficient delivery of antitumor drug to MDR cells.
authors.affiliation: Department of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: zjl1160@163.com.
authors.forename: Jiulong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Oncology Department, Affiliated Hongqi Hospital of Mudanjiang Medical College, Mudanjiang 157000, PR China.
authors.forename: Xiufeng
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Xiaoyi
authors.initials: X
authors.lastname: Yin
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Xiu
authors.initials: X
authors.lastname: Xin
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Mingxi
authors.initials: M
authors.lastname: Qiao
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Pharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, PR China. Electronic address: raura3687yd@163.com.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D003911:Dextrans / Q000737:chemistry; D065546:Drug Liberation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004705:Endocytosis / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D006639:Histidine / Q000737:chemistry; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D008856:Microscopy, Fluorescence; D017239:Paclitaxel / Q000494:pharmacology*; D010316:Particle Size; D011091:Polyesters / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D003911:Dextrans; D008823:Micelles; D011091:Polyesters; D011108:Polymers; C419144:dextran-polylactide hydrogel; D006639:Histidine; D017239:Paclitaxel
keywords: Multidrug resistance (MDR); Polymeric micelles; Systematic evaluation; pH-Sensitive