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Multistage Vectored siRNA Targeting Ataxia‐Telangiectasia Mutated for Breast Cancer Therapy
Author(s) -
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
Publication year - 2013
Publication title -
small
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.785
H-Index - 236
eISSN - 1613-6829
pISSN - 1613-6810
DOI - 10.1002/smll.201201510
Subject(s) - cancer research , ataxia telangiectasia , medicine , pharmacology , immunology , dna damage , biology , dna , genetics
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.