title: Synergistic effects of A-B-C-type amphiphilic copolymer on reversal of drug resistance in MCF-7/ADR breast carcinoma.
abstract: P-glycoprotein (P-gp) overexpression has become the most common cause of occurrence of multidrug resistance in clinical settings. We aimed to construct a micellar polymer carrier to sensitize drug-resistant tumors to doxorubicin (DOX). This A-B-C-type amphiphilic copolymer was prepared by the sequential linkage of β-cyclodextrin, hydrophobic poly(d,l-lactide), and hydrophilic poly(ethylene glycol). Upon incubation of the DOX-loaded micelles with DOX-resistant human breast carcinoma MCF-7/ADR cells, significantly enhanced cytotoxicity and apoptosis were achieved. A series of studies on the action mechanism showed that the polymer components such as β-cyclodextrin, hydrophobic poly(d,l-lactide) segment, and poly(ethylene glycol) coordinatively contributed to the improved intracellular ATP depletion and ATPase activity, increased intracellular uptake of P-gp substrates via competitive binding to P-gp, and decreased P-gp expression in MCF-7/ADR cells. More interestingly, a similar phenomenon was observed in the zebrafish xenograft model, resulting in ~64% inhibition of MCF-7/ADR tumor growth. These results implied that the polymeric micelles displayed great potentials as P-gp modulators to reverse DOX resistance in MCF-7/ADR breast carcinoma.
authors: Ministry of Education (MOE) Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou; Drug Clinical Trial Office, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou; College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors: Lu
authors: L
authors: Zhang
authors: College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
authors: Jiafei
authors: J
authors: Lu
authors: Ministry of Education (MOE) Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou.
authors: Liyan
authors: L
authors: Qiu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008823:Micelles; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000254:growth & development / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000737:chemistry
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D008823:Micelles; D011108:Polymers; D047392:beta-Cyclodextrins; D011092:Polyethylene Glycols; D004317:Doxorubicin; C031215:betadex
keywords: P-glycoprotein; doxorubicin; micelle; multidrug resistance; zebrafish