Zwitterionic Polymer Micelles with Dual Conjugation of Doxorubicin and Curcumin: Synergistically Enhanced Efficacy against Multidrug-Resistant Tumor Cells

• Published in: Langmuir 2020-03, Vol.36 (9), p.2383-2395
• Main Authors: Zhao, Guangfu, Sun, Yan, Dong, Xiaoyan
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Betaine - chemistry; Curcumin - chemistry; Curcumin - metabolism; Curcumin - pharmacology; Curcumin - toxicity; Doxorubicin - chemistry; Doxorubicin - metabolism; Doxorubicin - pharmacology; Doxorubicin - toxicity; Drug Carriers - chemistry; Drug Liberation; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Drug Synergism; Humans; MCF-7 Cells; Methacrylates - chemistry; Micelles; Polymethacrylic Acids - chemistry
• ISSN: 0743-7463; 1520-5827
• DOI: 10.1021/acs.langmuir.9b03722

This paper reports a novel redox-sensitive micellar system for the co-delivery of doxorubicin (Dox) and a chemosensitizer (curcumin, Cur) to overcome the multidrug resistance (MDR) in cancer cells. Dox and Cur were co-conjugated onto a zwitterionic polymer, poly­(carboxybetaine) (pCB), to form Cur-pCB-Dox that self-assembled into stable micelles (164.2 ± 4.8 nm). Single-drug conjugates (pCB-Dox and pCB-Cur) were prepared for comparisons. Compared to the high half-maximal inhibitory concentration (IC50) of Dox (437.2 μg/mL), the IC50 value of pCB-Dox (14.1 μg/mL) was only 1/33 that of Dox. Confocal laser scanning microscopy and flow cytometry revealed the greatly enhanced cell uptake of the conjugate due to the enhanced permeability and retention effect of tumor cells on the micellar conjugate. Co-delivery of pCB-Dox with pCB-Cur further reduced the IC50 value by 37% (8.9 μg/mL). More importantly, Cur-pCB-Dox exhibited the strongest cytotoxicity against MCF-7/Adr cells (IC50, 5.87 μg/mL) because the co-delivered Dox and Cur on one carrier specifically transported into the same cells, which inhibited the efflux of Dox by Cur, led to a higher intracellular Dox concentration and made the drugs exert synergistic effects at the targeting regions. The results proved the zwitterionic micelles as promising drug co-delivery vehicles for fighting against MDR.