Nanotech and NO May Aid in Neointimal Hyperplasia

BY MARK S. LESNEY

Perivascular application of a new nitric oxide-releasing self-assembling nanofiber gel was found to be a simple and effective therapy to prevent neointimal hyperplasia following arterial injury, according to Dr. Muneera R. Kapadia and her colleagues from Northwestern University, Chicago. Their work was chosen as the resident-research prize-winning study at the Vascular Annual Meeting.

Previous studies have shown nitric oxide (NO) is able to inhibit neointimal hyperplasia in several animal models, according to Dr. Melina R. Kibbe, a researcher at the Institute for BioNanotechnology in Medicine at Northwestern and Dr. Kapadia's mentor.

Nitric oxide is currently one of the most studied biologic regulatory molecules, with activity detected in a wide range of physiologic processes. It is naturally produced by endothelium and has several important roles in the vasculature, including vasodilation, and antithrombotic and anti-inflammatory effects, as well as antiproliferative effects (specifically inhibition of vascular smooth muscle cell proliferation).

Despite these reported beneficial effects, NO-releasing therapies are currently not available clinically, according to Dr. Kapadia.

The award-wining study aimed to combine nanotechnology and nitric oxide chemistry to develop a more potent NO-releasing therapy that could be used clinically.

The researchers used a gel, developed by Dr. Samuel I. Stupp and his colleagues from Northwestern University, which consisted of a heparin-binding peptide amphiphile and heparin, which together spontaneously form nanofibers.

This gel was combined with one of two diazeniumdiolate nitric oxide donors, either DPTA/NO or PROLI/NO, that were developed by Dr. Larry K. Keefer and colleagues from the National Cancer Institute, Frederick, MD.

The DPTA/NO and PROLI/NO gels, both found to release nitric oxide for 4 days, were tested in vivo using the rat carotid artery balloon injury model. Periadventitial delivery of the PROLI/NO nanofiber gel dramatically reduced the formation of neointimal hyperplasia by 77% versus control groups.

The DPTA/NO nanofiber gel reduced neointimal hyperplasia by 45%. Both treatments stimulated re-endothelialization, but only the PROLI/NO nanofiber gel inhibited inflammation. Thus, the PROLI/NO nanofiber gel appears to be quite robust for therapeutic purposes, according to the researchers.

"This [NO-releasing] therapy has great clinical potential to prevent neointimal hyperplasia following open vascular and cardiovascular interventions in patients," Dr. Kapadia said in an interview.

When asked to comment on this article, Dr. Alexander W. Clowes, who is professor of surgery, University of Washington, stated: "Nitric oxide not only is the most important of the physiological vasodilators but it also has many other functions including inhibition of vascular smooth muscle growth and intimal hyperplasia.

"This study by Dr. Kapadia and colleagues provides compelling evidence that locally delivered nitric oxide using the latest nanotechnology can suppress intimal thickening in animal models.

"This formulation of nitric oxide seems ideal for local delivery, and it appears to be ready now for clinical application," Dr. Clowes concluded.