Published ahead of print on February 28, 2008, doi:10.1164/rccm.200707-1022OC Am. J. Respir. Crit. Care Med., Volume 178, Number 1, July 2008, 60-73 A more recent version of this article appeared on July 1, 2008
Submitted on July 12, 2007 Poly(ester amine)-mediated, Aerosol-Delivered Akt1 siRNA Suppresses Lung TumorigenesisCheng-Xiong Xu1,1 Laboratory of Toxicology, Seoul National University, Seoul, Korea, Republic of, 2 Laboratory of Biomedical Polymer and Tissue Engineering, School of Agricultural Biotechnology, Seoul National University, Seoul, Korea, Republic of, 3 Center for Developmental Pharmacology and Toxicology, Seattle Children's Hospital Research Institute, Seattle, WA, USA, 4 Laboratory of Toxicology, Seoul National University, Seoul, Korea, Republic of; Nano Systems Institute-National Core Research Center, Seoul National University, Seoul, Korea, Republic of, 5 Depatment of Pathology, College of Veterinary Medicine, Seoul National University, Seoul, Korea, Republic of, 6 Laboratory of Molecular Oncology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea, Republic of, 7 Division of Endocrinology, Metabolism and Lipids, Emory University School of Medicine, Atlanta, GA, USA, 8 Laboratory of Toxicology, Seoul National University, Seoul, Korea, Republic of; Nano Systems Institute-National Core Research Center, Seoul National University, Seoul, Korea, Republic of; National Institute of Toxicological Research, Seoul, Korea, Republic of * To whom correspondence should be addressed. E-mail: mchotox{at}snu.ac.kr.
Rational: The low efficiency of conventional therapies in achieving long-term survival of lung cancer patients calls for the development of novel therapeutic options. Recent advances in aerosol-mediated gene delivery have provided the possibility of an alternative for the safe and effective treatment of lung cancer. Objectives: To demonstrate the feasibility and emphasize the importance of noninvasive aerosol delivery of Akt1 small interfering RNA as an effective and selective option for lung cancer treatment through. Methods: Nanosized poly(ester amine) polymer was synthesized and used as a gene carrier. An aerosol of poly(ester amine)/Akt1 small interfering RNA complex was delivered into K-rasLA1 and urethane-induced lung cancer models through a nose-only inhalation system. The effects of Akt1 siRNA on lung cancer progression and Akt-related signals were evaluated. Results: The aerosol delivered Akt1 small interfering RNA via suppressed lung tumor progression significantly through inhibiting Akt-related signals and cell cycle. Conclusions: The use of poly(ester amine) serves as an effective carrier and aerosol delivery of Akt1 small interfering RNA may be a promising approach for lung cancer treatment and prevention. Key words: poly(ester amine), Akt1 siRNA, lung cancer, K-rasLA1 mice, urethane, aerosol gene delivery
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