Targeted gene silencing using RGD-labeled chitosan nanoparticles.

Clinical cancer research : an official journal of the American Association for Cancer Research 2010 Aug 01

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This study aimed to develop an Arg-Gly-Asp (RGD) peptide-labeled chitosan nanoparticle (RGD-CH-NP) as a novel tumor targeted delivery system for short interfering RNA (siRNA). RGD peptide conjugated with chitosan by thiolation reaction was confirmed by proton-NMR (H-NMR). Binding of RGD-CH-NP with alphanubeta3 integrin was examined by flow cytometry and fluorescence microscopy. Antitumor efficacy was examined in orthotopic mouse models of ovarian carcinoma. We show that RGD-CH-NP loaded with siRNA significantly increased selective intratumoral delivery in orthotopic animal models of ovarian cancer. In addition, we show targeted silencing of multiple growth-promoting genes (POSTN, FAK, and PLXDC1) along with therapeutic efficacy in the SKOV3ip1, HeyA8, and A2780 models using siRNA incorporated into RGD-CH-NP (siRNA/RGD-CH-NP). Furthermore, we show in vivo tumor vascular targeting using RGD-CH-NP by delivering PLXDC1-targeted siRNA into the alphanubeta3 integrin-positive tumor endothelial cells in the A2780 tumor-bearing mice. This approach resulted in significant inhibition of tumor growth compared with controls. This study shows that RGD-CH-NP is a novel and highly selective delivery system for siRNA with the potential for broad applications in human disease. (c) 2010 AACR.

Citation

Hee Dong Han, Lingegowda S Mangala, Jeong Won Lee, Mian M K Shahzad, Hye Sun Kim, Deyu Shen, Eun Ji Nam, Edna M Mora, Rebecca L Stone, Chunhua Lu, Sun Joo Lee, Ju Won Roh, Alpa M Nick, Gabriel Lopez-Berestein, Anil K Sood. Targeted gene silencing using RGD-labeled chitosan nanoparticles. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010 Aug 01;16(15):3910-22