Vascular bypass grafting is a routine treatment for cardiovascular diseases; however, ~50% of bypass grafts fail in the few years following surgery due to cellular inflammatory responses at the suture sites. To address this problem, we synthesized novel diblock copolymers to deliver nucleic acid therapeutics capable of promoting healing in a spatiotemporal manner. A key component of our design is a monomer containing photocleavable <i>o</i>-nitrobenzyl moieties linking cationic groups to the polymer backbone so that light irradiation can induce polymer hydrolysis and charge reversal. This monomer was polymerized off a PEG macroinitiator <i>via</i> ATRP and then deprotected to form the final material. The polymers self-assemble with anionic nucleic acids in solution to form nanoscale complexes with a PEG “stealth” coating. Application of a photo-stimulus disrupts the electrostatic interactions to trigger the release of bound nucleic acids, such as siRNA. The nanocarriers maintained stability in serum, exhibited robust cellular uptake, and were capable of photo-responsive on/off control over gene expression. These formulations enabled the knockdown of two key functional genes, IL1β and CDH11, that are implicated in maladaptive responses in human aortic adventitial fibroblasts. The complete knockdown of both genes, in combination, resulted in significant attenuation of TGF-β1-triggered fibroblast proliferation and differentiation into myofibroblasts, two of the primary hallmarks of fibrosis. Further attenuation over clinically relevant time scales could be achieved by modulating the polyplex dosing regimen. In summary, this photo-responsive system provides a robust framework for addressing key challenges in cardiovascular tissue engineering.

Photo-Responsive polymeric formulations to attenuate inflammation in cardiovascular tissues

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.