Multistage Vectored siRNA Targeting Ataxia-Telangiectasia Mutated for Breast Cancer Therapy

作者：Xu, Rong; Huang, Yi; Mai, Junhua; Zhang, Guodong; Guo, Xiaojing; Xia, Xiaojun; Koay, Eugene J.; Qin, Guoting; Erm, Donald R.; Li, Qingpo; Liu, Xuewu; Ferrari, Mauro^*; Shen, Haifa

来源：Small, 2013, 9(9-10): 1799-1808.

DOI：10.1002/smll.201201510

• ataxia-telangiectasia
• siRNA delivery
• breast cancer
• cancer therapy
• toxicity

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.

• 出版日期2013-5-27
• 单位天津医科大学