title: Multistage vectored siRNA targeting ataxia-telangiectasia mutated for breast cancer therapy.
abstract: 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.
authors.affiliation: Department of Nanomedicine, The Methodist Hospital Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, USA.
authors.forename: Rong
authors.initials: R
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.forename: Junhua
authors.initials: J
authors.lastname: Mai
authors.forename: Guodong
authors.initials: G
authors.lastname: Zhang
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Guo
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xia
authors.forename: Eugene J
authors.initials: EJ
authors.lastname: Koay
authors.forename: Guoting
authors.initials: G
authors.lastname: Qin
authors.forename: Donald R
authors.initials: DR
authors.lastname: Erm
authors.forename: Qingpo
authors.initials: Q
authors.lastname: Li
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.forename: Haifa
authors.initials: H
authors.lastname: Shen
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002455:Cell Division; D045744:Cell Line, Tumor; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D008819:Mice, Nude; D034741:RNA, Small Interfering / Q000235:genetics*; D059551:Toxicity Tests, Subacute; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins