期刊
SMALL
卷 9, 期 9-10, 页码 1799-1808出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/smll.201201510
关键词
ataxia-telangiectasia; siRNA delivery; breast cancer; cancer therapy; toxicity
类别
资金
- Department of Defense [W81XWH-09-1-0212]
- state of Texas [RP121071]
- National Institute of Health [U54CA143837, U54CA151668]
- Ernest Cockrell Jr. Distinguished Endowed Chair
The ataxia-telangiectasia mutated (ATM) protein plays a central role in DNA damage response and cell cycle checkpoints, and may be a promising target for cancer therapy if normal tissue toxicity could be avoided. The strategy presented here to target ATM for breast cancer therapy involves the use of liposomal-encapsulated, gene-specific ATM siRNA delivered with a well-characterized porous silicon-based multistage vector (MSV) delivery system (MSV/ATM). Biweekly treatment of MSV/ATM suppressed ATM expression in tumor tissues, and consequently inhibited growth of MDA-MB-231 orthotopic tumor in nude mice. At the therapeutic dosage, neither free liposomal ATM siRNA nor MSV/ATM triggered an acute immune response in BALB/c mice, including changes in serum cytokines, chemokines or colony-stimulating factors. Weekly treatments of mice with free liposomal ATM siRNA or MSV/ATM for 4 weeks did not cause significant changes in body weight, hematology, blood biochemistry, or major organ histology. These results indicate that MSV/ATM is biocompatible and efficacious in inhibiting tumor growth, and that further preclinical evaluation is warranted for the development of MSV/ATM as a potential therapeutic agent.
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