title: pH-responsive polymeric micelles based on poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) for tumor-targeting and controlled delivery of doxorubicin and P-glycoprotein inhibitor.
abstract: The combination of a chemotherapeutic drug with a P-glycoprotein (P-gp) inhibitor has emerged as a promising strategy for treating multidrug resistance (MDR) cancer. To ensure that two drugs can be co-delivered to the tumor region and quickly released in tumor cells, tumor-targeted and pH-sensitive polymeric micelles were designed and prepared by combining cationic ring-opening polymerization of 2-ethyl-2-oxazoline (EOz) with anionic ring-opening polymerization of D,L-lactide (LA), and then encapsulating doxorubicin (DOX) and D-alpha-tocopheryl polyethylene glycol 1000 succinate (TPGS1000) into the micelles self-assembled by poly(2-ethyl-2-oxazoline)-poly(D,L-lactide) (PEOz-PLA) and DSPE-PEG-folate. PEOz-PLA exhibited a low critical micelle concentration and negligible cytotoxicity. The micelles enabled the rapid release of DOX when pH decreased from 7.4 to 5.0. The targeting ability of the micelles was demonstrated by in vitro flow cytometry in KBv cells and in vivo real time near-infrared fluorescence imaging in KBv tumor-bearing nude mice. The efficiency of MDR reversion for the micelles was testified by enhancement of intracellular DOX accumulation and cytotoxicity. The efficient drug delivery by the micelles was attributed to synergistic effects of folate-mediated targeting, pH-triggered drug release and TPGS1000-aroused P-gp inhibition. Therefore, the designed multifunctional polymeric micelles may have significant promise for therapeutic application of MDR cancer.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Dishi
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Jinwen
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Shujin
authors.initials: S
authors.lastname: Ma
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: yanliu@bjmu.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xinru
authors.initials: X
authors.lastname: Li
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D001672:Biocompatible Materials / Q000737:chemistry*; D002412:Cations; D004146:Dioxanes / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D006863:Hydrogen-Ion Concentration; D019344:Lactic Acid / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008823:Micelles; D008856:Microscopy, Fluorescence; D010080:Oxazoles / Q000737:chemistry; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D014810:Vitamin E / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001672:Biocompatible Materials; D002412:Cations; D004146:Dioxanes; D008823:Micelles; D010080:Oxazoles; D011091:Polyesters; D011108:Polymers; D014810:Vitamin E; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D004317:Doxorubicin; C091880:dilactide; C552862:2-ethyl-2-oxazoline; C014225:tocophersolan
keywords: Folate-targeted delivery; Multidrug resistance; P-glycoprotein inhibitor; Poly(2-ethyl-2-oxazoline)-poly(d,l-lactide); pH-responsive polymeric micelle