Nitric Oxide-releasing Nanofibers Prevent Restenosis After Arterial Injury in a Renal Failure Model

Restenosis from neointimal hyperplasia is a common cause of failure for vascular interventions. Targeted nitric oxide (NO)-releasing peptide amphiphile (PA) nanofibers have been successfully developed to prevent neointimal hyperplasia after vascular injury; however, it remains unknown if comorbid renal failure will affect the efficacy of this nanotherapeutic. We hypothesize that NO-releasing targeted nanofibers will effectively inhibit neointimal hyperplasia following arterial injury in a rat model of renal failure.

PA molecules were synthesized, purified, and co-assembled into nanofibers, which were visualized by transmission electron microscopy (TEM). Twelve-week-old male Sprague Dawley rats (n= 6-7/group) underwent a 5/6^th nephrectomy, followed by carotid artery balloon injury. Rats received saline, targeted nanofiber, or NO-releasing targeted nanofiber. Hemodynamics and blood chemistries were assessed at baseline, 2 wk, and 4 wk, followed by morphometric analysis of carotid arteries.

TEM confirmed nanofiber formation for all co-assemblies. Renal failure was confirmed with elevated creatinine (0.70 versus 0.35 mg/dL, P< 0.05), blood urea nitrogen (27.3 versus 18.1 mg/dL, P< 0.05), and mean arterial pressure (116.3 versus 94.8 mmHg, P< 0.05) 2 wk post-nephrectomy compared to baseline. Rats with renal failure which underwent balloon arterial injury and were treated with the NO-releasing targeted nanofiber developed 57.6% less neointimal hyperplasia compared to saline controls (59,136 versus 139,356 μm², P< 0.001).

This study demonstrates a single injection of an NO-releasing targeted nanofiber inhibits neointimal hyperplasia in the setting of renal failure with efficacy comparable to historic data in healthy rats. These data have positive implications for translation of this NO-releasing nanotherapeutic to clinical care.