Optimized effective charge density and size of polyglycerol amines leads to strong knockdown efficacy in vivo. Issue 46 (22nd October 2015)

• Record Type: Journal Article
• Authors: Staedtler, Anna Maria; Hellmund, Markus; Sheikhi Mehrabadi, Fatemeh; Thota, Bala N. S.; Zollner, Thomas M.; Koch, Markus; Haag, Rainer; Schmidt, Nicole
• Is Part Of: Journal of materials chemistry. Volume 3:Issue 46(2015)
• Page Start: 8993
• Page End: 9000
• Publication Date: 2015-10-22
• Subjects: Materials -- Periodicals; Chemistry, Analytic -- Periodicals; Biomedical materials -- Research -- Periodicals; 543.0284
• DOI: 10.1039/c5tb01466b
• Languages: English
• ISSNs: 2050-750X

Abstract

Abstract : The balance between core size, multiplicity and effective charge density plays an important role for the development of potent siRNA delivery systems. Abstract : RNA interference (RNAi)-based therapy extends the range of "druggable" targets beyond existing pharmacological drugs and enables the development of new treatment strategies for various diseases. A prerequisite are non-viral polyvalent gene delivery vectors capable for safe and effective siRNA delivery to cells in vivo allowing a broad clinical application. We synthesized hyperbranched polyglycerol amines (hPG amines) which varied in their charge density, multiplicity (absolute frequency of amine groups) and core size to successfully develop potent and safe siRNA transfer vectors. The characterization of hyperbranched polyglycerol amines with an invariable core size (8 kDa) but different amine loading revealed a correlation between the effective charge density and the transfection efficacy without impacting the cell viability in vitro . However, this correlation was not seen in tumor bearing mice in vivo treated with 8 kDa hPG amine–siRNA complexes. Improving the effective charge density and the multiplicity of amine functionalities by increasing the molecular weight (43 kDa) revealed comparable transfection efficacy in vitro but less toxic side effects after systemic administration in vivo compared to the respective hPG amine (8 kDa). In addition, in vivo delivery of 43 kDa hPG amine–siRNA–polyplexes in tumors resulted in a highly specific and significant knockdown effect. These findings demonstrate that hyperbranched polyglycerol amines with a balanced effective charge density, multiplicity and core size are promising gene delivery vectors for siRNA therapy which enable to address so far "undruggable" targets due to high tolerability and effective siRNA delivery.