A dual targeting dendrimer-mediated siRNA delivery system for effective gene silencing in cancer therapy
Annonce en anglais
Gene therapy based on small interfering RNA (siRNA) is emerging as a promising therapeutic option for treating various diseases. Particularly exciting is the first ever gene-silencing siRNA drug “patisiran”, which was approved this year. A breakthrough of RNAi technology in therapeutic application depends critically on safe and specific delivery system for siRNA, which can protect siRNA from degradation and bring siRNA specifically to the site of interest for effective silencing of disease’s associate genes. In this work, we report a ballistic approach for targeted siRNA delivery to cancer cells using an amphiphilic dendrimer equipped with a dual targeting peptide bearing a RGDK sequence (Figure). The amphiphilic dendrimer is a proven vector for effective siRNA delivery, while the targeting peptide aims to home in on tumors via interaction of its RGDK warhead with integrin and the neuropilin-1 receptor on cancer cells. Coating the positively charged siRNA/dendrimer delivery complex with the negatively charged segment of the targeting peptide via electrostatic interactions led to small and stable nanoparticles which were able to protect siRNA from degradation while maintaining the accessibility of RGDK for targeting cancer cells and preserving the ability of the siRNA to escape from endosomes. The targeted system had enhanced siRNA delivery, stronger gene silencing and more potent anticancer activity compared to non-targeted system. In addition, neither acute toxicity nor induced inflammation was observed. This is the first report to explore a targeting strategy for self-assembling dendrimer-mediated siRNA delivery, which can be further developed to provide siRNA-based personalized medicine against cancer.
This is a collaborative work between Centre Interdisciplinaire de Nanoscience de Marseille (CINaM) and Centre de Recherche en Cancérologie de Marseille (CRCM) at Aix-Marseille University along with China Pharmaceutical University, Beijing University of Technology in China and Trieste University in Italy.
A dual targeting dendrimer-mediated siRNA delivery system for effective gene silencing in cancer therapy
Yiwen Dong, Tianzhu Yu, Ling Ding, Erik Laurini, Yuanyu Huang, Mengjie Zhang, Yuhua Weng, Shuting Lin, Peng Chen, Domenico Marson, Yifan Jiang, Suzanne Giorgio, Sabrina Pricl, Xiaoxuan Liu, Palma Rocchi, Ling Peng
J. Am. Chem. Soc. 2018, 140, 16264-16274. (doi : 10.1021/jacs.8b10021) (supplementary cover).
Contact : Dr. Ling Peng Aix-Marseille Université, CNRS, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM) UMR 7325, Equipe Labellisé par La Ligue, Marseille, France Email : ling.peng@univ-amu.fr
