Abstract
Chemotherapy remains one of the most commonly used strategies in cancer treatment but suffers from damages to healthy tissues and organs. How to precisely co-deliver two or more drugs with different mechanisms of action to the tumors for synergistic function is a challenge for chemotherapy. Herein, Oleanolic acid (OA)-conjugated Hyaluronic acid self-assembled nano-micelles loaded with Doxorubicin (DOX) (HSO NPs/DOX) were constructed for CD44 positive cancer targeted codelivery of DOX and OA. HSO NPs/DOX exhibited reduction triggered drug release under high concentration of glutathione, more efficient uptake by 4T1 breast cancer cells than free DOX leading to higher cytotoxicity, pro-apoptotic, and migration inhibitory activities against 4T1 cells. The ex vivo biodistribution experiment demonstrated more HSO NPs/DOX were accumulated in the tumor tissues than free DOX and less in the non-tumor tissues after injections in 4T1 tumor bearing mice. More importantly, synergistic anti-tumor effects of DOX and OA were obtained using HSO NPs/DOX in 4T1 breast tumor-bearing mice and toxicity of DOX to liver and heart were circumvented through regulating the Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Silent Information Regulator 1 (Sirt1) expressions. Taken together, HSO NPs/DOX may become a promising codelivery system for chemotherapeutics in cancer therapy.
Published Version
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