Localized drug delivery from poly(ethylene glycol) copolymers for the prevention of restenosis
Lipke, Elizabeth Ann
West, Jennifer L.
Doctor of Philosophy
The studies presented in this thesis demonstrate the ability of nitric oxide (NO)-generating hydrogels and YC-1 releasing hydrogels to influence key components of the restenosis cascade both in vitro and in vivo. Using these poly(ethylene glycol) copolymers, which can be rapidly photopolymerized in situ, localized drug delivery can be achieved at the site of vascular injury. PEG-Cys-NO hydrogels inhibited smooth muscle cell proliferation, increased endothelial cell proliferation, and inhibited platelet adhesion in vitro. Moreover, in vivo, PEG-Cys-NO hydrogels inhibited intimal thickening in a rat carotid balloon injury model. The perivascular application of NO-generating polymers post-injury reduced neointima formation at 14 d by approximately 80% compared to controls (I/M: PEG-Cys-NO = 0.20 +/- 0.17, control = 0.84 +/- 0.19, p < 0.00002; intimal thickness: PEG-Cys-NO = 12.7 +/- 10.4 mum, control = 60.4 +/- 18.0 mum, p < 0.00002). Treatment with the PEG-Cys-NO hydrogels caused a significant decrease in the percent of proliferating cell nuclear antigen positive medial cells (28.9 +/- 4.7%) at 4 d as compared to treatment with the control hydrogels (51.3 +/- 0.6%, p < 0.02). Additionally, vessel re-endothelialization at 14 d was slightly enhanced in the presence of the NO-generating hydrogels. Changes in gene expression in response to PEG-Cys-NO hydrogels were characterized both in vitro and in vivo to further elucidate the mechanisms by which NO influenced cell proliferation and neointima formation. YC-1 releasing hydrogels inhibited smooth muscle cell proliferation and platelet adhesion in vitro, and reduced neointima formation at 14 d by approximately 40% compared to controls (UM: YC-1 = 0.41 +/- 0.18, control = 0.65 +/- 0.14, p < 0.05; intimal thickness: YC-1 = 21.0 +/- 6.0 mum, control = 36.7 +/- 9.0 mum, p < 0.05). In addition, delivery of YC-1 in combination with NO from PEG-CYS-NO hydrogels decreased SMC proliferation in vitro to a greater extent than seen for delivery of YC-1 or NO alone. These data indicate that localized delivery of NO and/or YC-1 from poly(ethylene glycol) hydrogels can significantly inhibit neointima formation in a rat carotid balloon injury model and suggest that these materials may be useful in preventing restenosis.
Biomedical engineering; Chemical engineering