Journal
MOLECULAR PHARMACEUTICS
Volume 11, Issue 11, Pages 4118-4129Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp5003009
Keywords
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Funding
- National Basic Research Program of China (973 Program) [2012CB932500]
- National Natural Science Foundation of China [21204024, 81373360]
- Doctoral Fund of Ministry of Education of China [20120142120093]
- Fundamental Research Funds for the Central Universities [2014TS091, 2014QN134]
- Chutian Scholar Award
- 2013 Youth Scholar Award of HUST
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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-a-tocopheryl polyethylene glycol succinate (TNO3). TNO3 was able to self-assemble into stable micelles in physiological conditions, accumulate in tumors, and release similar to 90% 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 (similar to 6.25-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 t1/2, 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.
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