title: Polyphosphazene vesicles for co-delivery of doxorubicin and chloroquine with enhanced anticancer efficacy by drug resistance reversal.
abstract: The conventional chemotherapeutic agent doxorubicin hydrochloride (DOX·HCl) is often accompanied by drug resistance which has severely hindered its clinical application. By taking advantage of the self-assembled behavior of amphiphilic polyphosphazenes, we constructed novel polymersomes loading DOX·HCl or desalted DOX with chloroquine phosphate (CQ) as a drug resistance-reversal agent at 1:1 or 2:1 weight ratios via a one-step common dialysis method. The cytotoxicity evaluation of this dual drug-loaded polymersome was performed on DOX-resistant MCF-7/Adr breast cancer and HL60/Adr leukemia cells. Simultaneously, to simulate in vivo cancerous tissue, 3D tumor spheroid was constructed for tissue penetration and anti-cancer effect evaluation. As a result, PEP-DHC-1 containing DOX·HCl and CQ at 1:1 weight ratio exhibited the strongest toxicity. Furthermore, the in vivo tumor inhibition study carried out on a zebrafish xenograft model also validated that PEP-DHC-1 made the outstanding contribution to improve the sensitivity of MCF-7/Adr breast cancer to chemotherapeutics. These findings suggest that this DOX·HCl and CQ co-delivery system based on PEP polymersomes might be promising for drug resistance reversal of cancer therapy and consequently enhanced anti-cancer efficacy.
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xu
authors.affiliation: College of Pharmaceutical Sciences, Zhejiang University, 866 Yu-Hang-Tang Road, Hangzhou 310058, China.
authors.forename: Xiumei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Ministry of Education (MOE) Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, 38 Zheda Road, Hangzhou 310027, China; Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. Electronic address: lyqiu@zju.edu.cn.
authors.forename: Liyan
authors.initials: L
authors.lastname: Qiu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy; D002738:Chloroquine / Q000008:administration & dosage*; D004317:Doxorubicin / Q000008:administration & dosage*; D016503:Drug Delivery Systems / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000502:physiology; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D061986:MCF-7 Cells; D009943:Organophosphorus Compounds / Q000008:administration & dosage*; D011108:Polymers / Q000008:administration & dosage*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods; D015027:Zebrafish
chemical_list: D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D011108:Polymers; C108974:poly(phosphazene); D004317:Doxorubicin; D002738:Chloroquine
keywords: Chloroquine; Combination cancer therapy; Doxorubicin; Drug resistance; Polymersomes; Polyphosphazene