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Research Articles: Therapeutics

Aerosol delivery of urocanic acid–modified chitosan/programmed cell death 4 complex regulated apoptosis, cell cycle, and angiogenesis in lungs of K-ras null mice

¹ Laboratory of Toxicology, College of Veterinary Medicine; ² Laboratory of Biomedical Polymer and Tissue Engineering, School of Agricultural Biotechnology, Seoul National University; ³ Laboratory of Molecular Oncology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea; ⁴ Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, Korea; ⁵ Laboratory of Cancer Prevention, National Cancer Institute, Frederick, Maryland; and ⁶ Graduate Center for Toxicology/Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, Kentucky

Requests for reprints: Myung-Haing Cho, Laboratory of Toxicology, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Korea. Phone: 82-2-880-1276; Fax: 82-2873-1268. E-mail: mchotox{at}snu.ac.kr or Chong Su Cho, Laboratory of Biomedical Polymer and Tissue Engineering, School of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Korea. E-mail: chocs{at}snu.ac.kr

Abstract

The low efficiency of conventional therapies in achieving long-term survival of patients with lung cancer calls for development of novel treatment options. Although several genes have been investigated for their antitumor activities through gene delivery, problems surrounding the methods used, such as efficiency, specificity, and toxicity, hinder application of such therapies in clinical settings. Aerosol gene delivery as nonviral and noninvasive method for gene therapy may provide an alternative for a safer and more effective treatment for lung cancer. In this study, imidazole ring-containing urocanic acid–modified chitosan (UAC) designed in previous study was used as a gene carrier. The efficiency of UAC carrier in lungs was confirmed, and the potential effects of the programmed cell death protein 4 (PDCD4) tumor suppressor gene on three major pathways (apoptosis, cell cycle, and angiogenesis) were evaluated. Aerosol containing UAC/PDCD4 complexes was delivered into K-ras null lung cancer model mice through the nose-only inhalation system developed by our group. Delivered UAC/PDCD4 complex facilitated apoptosis, inhibited pathways important for cell proliferation, and efficiently suppressed pathways important for tumor angiogenesis. In summary, results obtained by Western blot analysis, immunohistochemistry, and terminal deoxynucleotidyl transferase–mediated nick end labeling assay suggest that our aerosol gene delivery technique is compatible with in vivo gene delivery and can be applied as a noninvasive gene therapy. [Mol Cancer Ther 2006;5(4):1041–9]

Grant support: Nano Systems Institute-National Core Research Center of Korea Science and Engineering Foundation, Ministry of Science and Technology in Korea (M-H. Cho). BK21 fellowship (H. Jin, S-K. Hwang and H.W. Kim), Korea Research Foundation fellowship (T.H. Kim), 21C Frontier Functional Human Genome Project grant FG03-0601-003-1-0-0 (K.H. Lee), and National Nuclear R&D Program from Ministry of Science and Technology (K.H. Lee).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: H. Jin and T.H. Kim contributed equally to this work.

Received 10/19/05; revised 12/23/05; accepted 2/ 9/06.

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