Vascular bypass grafting is a routine treatment for cardiovascular diseases; however, nearly 50% of bypass grafts fail within a few years following surgery due to cellular inflammatory responses at the suture sites. To overcome this problem, we synthesized novel diblock polymers 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. The polymers self-assemble with anionic nucleic acids in solution to form nanoparticle 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, from the nanocomplexes. More significantly, our soft nanoparticles maintained stability in serum, exhibited robust cellular uptake, facilitated nanocarrier imaging, 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 inflammatory 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 was achieved by modulating the polyplex dosing regimen by taking input from a recently developed kinetic model, whose created was enabled by our polymer design.

Photo-responsive polymeric nanoplexes for gene therapeutics delivery and wound healing applications

256th National Meeting (2018)

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