期刊
NANOSCALE
卷 15, 期 1, 页码 237-247出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2nr04021b
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资金
- National Key R&D Program of China [2021YFA1201200, 2021YFF1200404]
- National Natural Science Foundation of China [U1967217, 22176137]
- Fundamental Research Funds for Central Universities [226-2022-00043, 226-2022-00192]
- National Independent Innovation Demonstration Zone Shanghai Zhangjiang Major Projects [ZJZX2020014]
- Starry Night Science Fund of Zhejiang University Shanghai Institute for Advanced Study [SN-ZJU-SIAS-003]
- BirenTech Research [BR-ZJU-SIAS-001]
- Natural Science Foundation of Zhejiang Province [2022LQ22H220001]
- W. M. Keck Foundation
This study developed a dual-response delivery system that releases the drug at tumor sites by using low-dose X-ray and reactive oxygen species, which significantly improves tumor hypoxia levels and enhances the antitumor efficacy. The system shows high accuracy and low side effects on normal cells.
The selective anti-tumor activity and less toxic nature of hypoxia-activated prodrugs including tirapazamine (TPZ) are harbored by hypoxia levels in tumors, the inadequacy of which leads to failure in clinical trials. Thus, the development of effective clinical applications of TPZ requires advanced strategies to intensify hypoxia levels in tumors effectively and safely. In this study, we designed and fabricated a paclitaxel (PTX)-loaded dual-response delivery system with a low dose (e.g., 2 Gy) of X-ray and reactive oxygen species on the basis of diselenide block copolymers. Upon the external X-ray stimulus, the system accurately released encapsulated PTX at tumor sites and remarkably improved tumor hypoxia levels by causing severe damage to tumor blood vessels. Subsequently, these enhanced tumor hypoxia levels effectively activated the reduction of TPZ into benzotriazinyl free radicals, which significantly improved the antitumor efficacy of our system against 4T1 breast cancer cells with an initial tumor volume of 500 mm(3). Moreover, the dual-stimulus coordinated and controlled release of PTX was found to largely avoid the off-target effects of PTX on normal cells while exhibiting very limited side effects in experimental mice. The current novel strategy for regulating tumor hypoxia levels offers an effective and safe way to activate TPZ for the treatment of large solid tumors.
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