Evaluation of a Targeted Drug-Eluting Intravascular Nanotherapy to Prevent Neointimal Hyperplasia in an Atherosclerotic Rat Model.

OBJECTIVE: To test the hypothesis that nitric oxide-bearing collagen-targeted nanofibers will target vascular injury and inhibit neointimal hyperplasia in an atherosclerotic rat model. APPROACH AND RESULTS: Western blot confirms apolipoprotein E (ApoE) knockout (-/-) status. Serum cholesterol increases three-fold in Sprague Dawley (SD) ApoE-/- vs. wt SD rats (291.7±22.3 vs. 105.0±3.6 mg/dL, p<0.05). Oxidative stress markers are elevated in SD ApoE-/- vs. wt SD strains (p=0.002). Oil Red O staining shows lipid-rich lesions in SD ApoE-/- aortas. Transmission electron microscopy shows co-assembled peptide amphiphiles (PA) form nanofibers. Fluorescence microscopy shows targeting of collagen-binding peptide (CBP)-S-nitrosyl(SNO)-PA nanofiber to arteries 20 minutes after injury, while uninjured carotid and non-targeted SNO-PA nanofibers show minimal localization (3444.8±282.0, 11.0±2.3, and 451.4±93.6 arbitrary units, respectively, p<0.05). Two weeks after injury and injection, CBP-SNO-PA nanofibers inhibit neointimal hyperplasia by 67% vs. injury alone (p<0.0001). Intima/media (I/M) ratios are 0.3, 1.0, and 0.9 for CBP-SNO-PA nanofiber, scrambled SNO-PA nanofiber, and injury alone, respectively (p<0.0001). Results are durable out to 3 months (I/M 0.6 vs. 1.4 for CBP-SNO-PA vs. injury alone, p<0.0001). CONCLUSIONS: Targeted drug-eluting nanofibers localize to vascular injury, decrease neointimal hyperplasia after 2 weeks, and are durable out to 3 months in an atherosclerotic rat model.