Facial amphipathic deoxycholic acid-modified polyethyleneimine for efficient MMP-2 siRNA delivery in vascular smooth muscle cells

Abstract Clinical applications of RNA interference-based therapeutics such as small interfering RNAs (siRNAs) have been limited mainly due to low intracellular delivery efficiency in vitro and in vivo . In this study, facially amphipathic deoxycholic acid (DA)-modified polyethyleneimine (PEI 1.8 ) (DA-PEI 1.8 ) was synthesized and used as a potent carrier system for siRNA targeted against matrix metalloproteinase-2 (MMP-2) to inhibit the migration of vascular smooth muscle cells (SMCs), which is the major pathomechanism in the development of atherosclerosis and restenosis after arterial injury. A representative facial amphipathic bile acid DA having a high membrane permeability was conjugated to the terminal amine groups of the low molecular weight PEI 1.8 via amide bonds. The DA-PEI 1.8 conjugates formed self-assembled nanoparticles with siRNA molecules in an aqueous phase and the DA-PEI 1.8 /siRNA polyplexes became stabilized and condensed as particle incubation time increased from 0 to 4 h. Both cellular internalization and target gene silencing were enhanced as the DA-PEI 1.8 /siRNA polyplexes stabilized. When vascular SMCs were transfected with MMP-2 siRNA, the DA-PEI 1.8 /siRNA polyplex formulation led to a significant decrease in MMP-2 gene expression, resulting in the suppression of cell migration. These results suggest that the DA-PEI 1.8 /MMP-2 siRNA delivery system may be useful in anti-restenotic treatment for various vasculoproliferative disorders such as atherosclerosis, in-stent restenosis, and vein graft failure.