title: Co-delivery of docetaxel and chloroquine via PEO-PPO-PCL/TPGS micelles for overcoming multidrug resistance.
abstract: The combination of two or more drug is a promising strategy to suppress the multidrug resistance (MDR) through different action mechanisms. Co-delivery drugs via polymeric micelle can minimize the amount of each drug and reduce toxic side effects. Here we co-encapsulate anticancer drug docetaxel (DTX) and autophagy inhibitor chloroquine (CQ) in complex micelles based on poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ϵ-caprolactone) (PEO-PPO-PCL) and D-α-tocopheryl poly(ethylene glycol) (TPGS) for enhancing anticancer effects. Two series copolymer with different length of hydrophobic chain were synthesized (PEO68-PPO34-PCL18 and PEO68-PPO34-PCL36) in our lab. The dual-drug micelles possessed nanosize and sustained release profile in vitro. Drug-loaded micelles have low hemolysis rate (<5%), indicating that they are safe for use in vivo. Studies on cellular uptake demonstrate that the micelles can effectively accumulate in cancer cells. Furthermore, in vitro cytotoxicity with different DTX/CQ mass ratio are studied and the sample with a DTX/CQ ratio of 0.8/0.2 is found to have the strongest synergism effect. The co-delivery micelles have obviously higher therapeutic effects against MCF-7 and MCF-7/ADR cells than either free drug or individually DTX-loaded micelles. The IC50 values of DTX/CQ-loaded PEO68-PPO34-PCL18/TPGS and PEO68-PPO34-PCL36/TPGS micelles are 134.16 and 194.74 fold smaller than that of free DTX after 48 h treatment with MCF-7/ADR cells, respectively. Therefore, the as-prepared co-delivery of DTX and CQ based on PEO-PPO-PCL/TPGS micelles can provide a promising combined therapeutic strategy for enhanced antitumor therapy.
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Chunhuan
authors.initials: C
authors.lastname: Shi
authors.affiliation: College of Science, China University of Petroleum, 66 West Changjiang Road, Qingdao, Shandong 266580, PR China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China.
authors.forename: Jiaxing
authors.initials: J
authors.lastname: Shi
authors.affiliation: College of Science, China University of Petroleum, 66 West Changjiang Road, Qingdao, Shandong 266580, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Science, Shandong University, 44 West Wenhua Road, Jinan, Shandong 250012, PR China. Electronic address: yuxialuan@sdu.edu.cn.
authors.forename: Yuxia
authors.initials: Y
authors.lastname: Luan
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D000077143:Docetaxel; D004338:Drug Combinations; D016503:Drug Delivery Systems; D065546:Drug Liberation; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008823:Micelles; D011091:Polyesters; D011092:Polyethylene Glycols; D043823:Taxoids / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology*; D014810:Vitamin E / Q000031:analogs & derivatives
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D008823:Micelles; D011091:Polyesters; D043823:Taxoids; C458722:polyethylene oxide-polycaprolactone copolymer; D014810:Vitamin E; D000077143:Docetaxel; C016240:polycaprolactone; D011092:Polyethylene Glycols; D002738:Chloroquine; C014225:tocophersolan
keywords: Chloroquine; Docetaxel; Micelles; Multidrug resistance