Department of Nanomedicine, The Methodist Hospital Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, USA.
Small. 2013 May 27;9(9-10):1799-808. doi: 10.1002/smll.201201510. Epub 2013 Jan 6.
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.
共济失调毛细血管扩张突变（ATM）蛋白在 DNA 损伤反应和细胞周期检查点中发挥核心作用，如果能够避免正常组织毒性，它可能成为癌症治疗的有前途的靶点。这里提出的针对 ATM 的乳腺癌治疗策略涉及使用脂质体包裹的、基因特异性 ATM siRNA，并用经过充分表征的多孔硅多阶段载体（MSV）传递系统（MSV/ATM）传递。每周两次的 MSV/ATM 治疗抑制了肿瘤组织中的 ATM 表达，从而抑制了裸鼠中 MDA-MB-231 原位肿瘤的生长。在治疗剂量下，游离脂质体 ATM siRNA 或 MSV/ATM 均未在 BALB/c 小鼠中引发急性免疫反应，包括血清细胞因子、趋化因子或集落刺激因子的变化。每周用游离脂质体 ATM siRNA 或 MSV/ATM 治疗 4 周的小鼠体重、血液学、血液生化学或主要器官组织学均未发生显著变化。这些结果表明 MSV/ATM 具有生物相容性和抑制肿瘤生长的功效，因此有必要进一步进行临床前评估，以将 MSV/ATM 开发为一种潜在的治疗剂。
