Reducible poly(amido ethylenimine) directed to enhance RNA interference


Jeong, Jo Hoon and Christensen, Lane V. and Yockman, James W. and Zhong, Zhiyuan and Engbersen, Johan F.J. and Kim , Won Jong and Feijen, Jan and Kim, Sung Wan (2007) Reducible poly(amido ethylenimine) directed to enhance RNA interference. Biomaterials, 28 (10). pp. 1912-1917. ISSN 0142-9612

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Abstract:Designing synthetic macromolecular vehicles with high transfection efficiency and low cytotoxicity has been a major interest in the development of non-viral gene carriers. A reducible poly(amido ethylenimine) (SS-PAEI) synthesized by addition copolymerization of triethylenetetramine and cystamine bis-acrylamide (poly(TETA/CBA)) was used as a carrier for small interference RNA (siRNA). Poly(TETA/CBA) could efficiently condense siRNA to form stable complexes under physiological conditions and perform complete release of siRNA in a reductive environment. When formulated with VEGF-directed siRNA, poly(TETA/CBA) demonstrated significantly higher suppression of VEGF than linear-polyethylenimine (PEI) (L-PEI, 25 kDa) in human prostate cancer cells (PC-3). After 5 h of transfection, substantial dissociation and intracellular distribution of siRNA was observed in the poly(TETA/CBA) formulation, but not in the L-PEI formulation. The triggered release of siRNA by reductive degradation of poly(TETA/CBA) in the cytoplasm may affect the RNAi activity by increasing cytoplasmic availability of siRNA. These results suggest that the rational design of non-viral carriers should involve considerations for intracellular dissociation and trafficking of a nucleic acid drug to maximize its effect, in conjunction with formation of stable complexes under physiological conditions.
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