Doxorubicin-loaded redox-responsive micelles based on dextran and indomethacin for resistant breast cancer

• Main Authors: Zhou YF, Wang SH, Ying XH, Wang YF, Geng PW, Deng AP, Yu ZH
• Format: Article
• Language: English
• Published: Dove Medical Press 2017-08-01
• Series: International Journal of Nanomedicine
• Subjects: multidrug resistance; doxorubicin; indomethacin; redox-responsive; micelles
• Online Access: https://www.dovepress.com/doxorubicin-loaded-redox-responsive-micelles-based-on-dextran-and-indo-peer-reviewed-article-IJN

Yunfang Zhou,1,* Shuanghu Wang,1,* Xuhua Ying,2 Yifan Wang,2 Peiwu Geng,1 Aiping Deng,3 Zhihong Yu3 1The Laboratory of Clinical Pharmacy, The Sixth Affiliated Hospital of Wenzhou Medical University, The People’s Hospital of Lishui, Lishui, 2Cancer Institute of Integrative Medicine, Zhejiang Academy of Chinese Medicine, Hangzhou, 3Department of Pharmacy, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China *These authors contributed equally to this work Abstract: Multidrug resistance (MDR) against chemotherapeutic agents has become one of the major obstacles to successful cancer therapy and MDR-associated proteins (MRPs)-mediated drug efflux is the key factor for MDR. In this study, a redox-responsive polymer based on dextran (DEX) and indomethacin (IND), which could reduce MRPs-mediated efflux of chemotherapeutics, was synthesized, and the obtained polymer could spontaneously form stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 50 nm and effectively encapsulate doxorubicin (DOX); the micelles contain a disulfide bridge (cystamine, SS) between IND and DEX (DEX-SS-IND). In vitro drug release results indicated that DEX-SS-IND/DOX micelles could maintain good stability in a stimulated normal physiological environment and promptly depolymerized and released DOX in a reducing environment. After incubating DEX-SS-IND/DOX micelles with drug-resistant tumor (MCF-7/ADR) cells, the intracellular accumulation and retention of DOX were significantly increased under the synergistic effects of redox-responsive delivery and the inhibitory effect of IND on MRPs. In vitro cytotoxicity showed that DEX-SS-IND/DOX micelles exhibited higher cytotoxicity against MCF-7/ADR cells. Moreover, DEX-SS-IND/DOX micelles showed significantly enhanced inhibition of tumor in BALB/c nude mice bearing MCF-7/ADR tumors and reduced systemic toxicity. Overall, the cumulative evidence indicates that DEX-SS-IND/DOX micelles hold significant promise for overcoming MDR for cancer therapy. Keywords: multidrug resistance, doxorubicin, indomethacin, redox-responsive, micelles, breast cancer