Targeted gene silencing using RGD-labeled chitosan nanoparticles
Authors
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
Citation
CLINICAL CANCER RESEARCH, Vol.16(15) : 3910-3922, 2010
PURPOSE: 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).
EXPERIMENTAL DESIGN: 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.
RESULTS: 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.
CONCLUSIONS: 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.