期刊
ADVANCED SCIENCE
卷 5, 期 7, 页码 -出版社
WILEY
DOI: 10.1002/advs.201800368
关键词
bystander killing effects; cancer therapies; caspases; prodrugs; target therapies
资金
- Bio-Medical Technology Development Project [2016M3A9B5941836, 2017M3A9F5029655, 2016M3A9B6903384, 2017]
- ERC project from the National Research Foundation (NRF) of the Korea government [2017R1A5A1070259]
Tumor heterogeneity is associated with the therapeutic failures of targeted therapies. To overcome such heterogeneity, a novel targeted therapy is proposed that could kill tumor populations with diverse phenotypes by delivering nonselective cytotoxins to target-positive cells as well as to the surrounding tumor cells via a recurrent bystander killing effect. A representative prodrug is prepared that targets integrin alpha v beta 3 and releases cytotoxins upon entering cells or by caspase-3. This allows the prodrug to kill integrin alpha v beta 3-positive cells and upregulate caspase-3, which in turn, activates the prodrug to release a cytotoxin that could subsequently diffuse into and kill the neighboring tumor cells. Apoptotic cells further upregulate and release caspase-3, which activate more prodrugs leading to another round of adjacent cell death and caspase-3 release. Thus, the bystander killing effect could occur repeatedly, leading to augmented and widespread anticancer activity. This strategy provides an avenue that could advance the current targeted therapy.
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