title: Pluronic-based functional polymeric mixed micelles for co-delivery of doxorubicin and paclitaxel to multidrug resistant tumor.
abstract: Although doxorubicin (DOX) and paclitaxel (PTX) are widely used in clinic as chemotherapeutics, both drug substances are found to be glycoprotein P (P-gp) substrates which are liable to develop the multidrug resistance (MDR). Additionally, the use of single chemotherapeutic drug has known limitations such as high toxicity profile due to the relatively high doses and limited regimen of clinical application. To this end, Pluronic P105-DOX conjugate was successfully designed and developed which can be further used as a hydrophobic core to entrap another anti-cancer drug PTX with Pluronic F127 to form the dual drug-loaded mixed micelles (PF-DP) in our study, which would offer great advantages over conventional micelles, including easy fabrication, high loading capacity, and co-delivery of hydrophilic DOX and hydrophobic PTX to achieve synergistic effect of these two drug substances. Results showed that PF-DP possessed a good polydispersity and sustained release profile for both DOX and PTX in vitro. Studies on cellular uptake demonstrated both anti-cancer drugs in PF-DP can effectively accumulate in MDR cancer cells. Furthermore, in vitro cytotoxicity, cell apoptosis and cell cycle arrest studies indicated that PF-DP had better antitumor efficacy in MDR cancer cells compared to those of single-drug loaded micelles. It was also found that PF-DP can suppress the growth of tumor cells more efficiently than single drug formulations at the equivalent drug concentrations, suggesting synergistic effect could be achieved. More importantly, a much stronger antitumor efficacy in MCF-7/ADR tumor-bearing mice was observed in PF-DP group than that of combined administration of free DOX and PTX. Collectively, the dual drug-loaded Pluronic-based functional mixed micelles developed in this study might be a potential nano-drug delivery system for MDR cancer chemotherapy.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China; Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: chenyz@ecust.edu.cn.
authors.forename: Yanzuo
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai 201203, China; CONRAD, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Arlington, VA 22209, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Yukun
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Gao
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Xianyi
authors.initials: X
authors.lastname: Sha
authors.affiliation: Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai 201203, China. Electronic address: xlfang@shmu.edu.cn.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Fang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical; D003692:Delayed-Action Preparations; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D017239:Paclitaxel / Q000008:administration & dosage* / Q000494:pharmacology; D020442:Poloxamer / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D008823:Micelles; D020442:Poloxamer; D004317:Doxorubicin; C519610:pluronic P105; D017239:Paclitaxel
keywords: Anti-cancer efficacy; Codelivery; Doxorubicin; Multidrug resistance; Paclitaxel; Polymeric micelle