Nitric Oxide Releasing d-伪-Tocopheryl Polyethylene Glycol Succinate for Enhancing Antitumor Activity of Doxorubicin

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• 作者：Qingle Song ; Songwei Tan ; Xiangting Zhuang ; Yuanyuan Guo ; Yongdan Zhao ; Tingting Wu ; Qi Ye ; Luqin Si ; Zhiping Zhang
• 刊名：Molecular Pharmaceutics
• 出版年：2014
• 出版时间：November 3, 2014
• 年：2014
• 卷：11
• 期：11
• 页码：4118-4129
• 全文大小：708K
• ISSN：1543-8392

文摘

Nitric oxide (NO) has attracted much attention for its antitumor activity and synergistic effects when codelivered with anticancer agents. However, due to its chemical instability and short half-life, delivering gaseous NO directly to tumors is still challenging. Herein, we synthesized a NO releasing polymer, nitrate functionalized d-伪-tocopheryl polyethylene glycol succinate (TNO₃). TNO₃ was able to self-assemble into stable micelles in physiological conditions, accumulate in tumors, and release 鈭?0% of NO content in cancer cells for 96 h. It further exhibited significant cancer cell cytotoxicity and apoptosis compared with nitroglycerine (GTN). Notably, TNO₃ could also serve as an enhancer for the common chemotherapeutic drug doxorubicin (DOX). Codelivering TNO₃ with DOX to hepatocarcinoma HepG2 cancer cells strengthened the cellular uptake of DOX and enabled the synergistic effect between NO and DOX to induce higher cytotoxicity (鈭?.25-fold lower IC₅₀). Moreover, for DOX-based chemotherapy in tumor-bearing mice, coadministration with TNO₃ significantly extended the blood circulation time of DOX (14.7-fold t_1/2, 6.5-fold mean residence time (MRT), and 13.7-fold area under curve (AUC)) and enhanced its tumor accumulation and penetration, thus resulting in better antitumor efficacy. In summary, this new NO donor, TNO₃, may provide a simple but effective strategy to enhance the therapeutic efficacy of chemotherapeutic drugs.

Keywords:

nitric oxide; TPGS; doxorubicin; antitumor