Advisor(s)

Mansoor M. Amiji

Contributor(s)

Robert Campbell, Frederick Welt, Ralph H. Loring, Robert A. Schatz

Date of Award

2008

Date Accepted

11-2008

Degree Grantor

Northeastern University

Degree Level

Ph.D.

Degree Name

Doctor of Philosophy

Department or Academic Unit

Bouvé College of Health Sciences. School of Pharmacy.

Keywords

Pharmaceutical sciences, Health sciences, Coronary restenosis

Subject Categories

Coronary arteries--Stenosis--Relapse, Pharmaceutical technology

Disciplines

Pharmacy and Pharmaceutical Sciences

Abstract

Current treatments of restenosis employ cytostatic or cytotoxic drugs. Despite having a lower incidence of restenosis after intervention, other problems such as late stent thrombosis arise since these drugs stop all cell proliferation, including endothelial cells, which have been shown to be critical in the healing of the blood vessel over time. Nitric oxide synthases are enzymes responsible for generating nitric oxide, a gas responsible for inhibition of smooth muscle cells and re-endothelialization in addition to a host of other vascular responses. The use of nitric oxide releasing polymers has been investigated with limited success. Alternative approaches using viral vectors or naked plasmid DNA coated onto stents have shown promise but are not viable in the clinic due to the problems of immunogenicity in the case of viral vectors or the unrealistic high doses used on stents coated with naked plasmid DNA. Non-viral cationic vectors have been used to transfect the vasculature both in-vitro and in a number of different restenosis models in vivo. Preliminary work was conducted in-vitro do develop a gene delivery system that transfected endothelial and smooth muscle cells with no toxicity. A combination of a cationic lipid (DOTAP), a and a cationic polymer (PBAE) was found to transfect the most efficiently with no toxicity to the cells at the doses required to transfect. These lipopolyplexes were then coated onto stainless steel substrates using different types of gelatin and were incubated with smooth muscle cells to assess transfection. Based on the preliminary formulation development work in-vitro a stent coating was developed and tested for ability to transfect and efficacy in a rabbit model for restenosis. The stents were coated with lipopolyplexes that contained a plasmid DNA encoding for eNOS and type B gelatin. The studies reveal that the lipopolyplex coated stent can transfect and proves efficacious in the treatment of restenosis in a well established pre-clinical model for restenosis. The data supports the hypothesis that potent non-viral gene vector encoding for endothelial nitric oxide synthase coated onto a stent can inhibit restenosis through inhibition of smooth muscle cell growth and promotion of a healthy endothelium. Thus, a novel therapeutic strategy is presented for the treatment of restenosis that shows promise for clinical success.

Document Type

Dissertation

Rights Holder

Luis Alfred Brito


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