Development of Non-Viral Gene Delivery Carriers for Ischemic Heart Disease (IHD)

Abstract

Ischemic heart disease (IHD) or coronary artery disease (CAD) is a leading cause of death in the United States resulting in a major financial burden to the health care system and is projected to be one of the main contributors to disability by 2020. The poor prognosis of IHD is directly related to a build-up of atherosclerotic plaque that produces narrowing of the coronary artery lumen. The rupture of the artery and/or narrowing of the artery lumen results in myocardial ischemia, which can lead to myocardial infarction or death of the heart muscle tissue. Current treatments include bypass surgery, angioplasty, stent implantation, and pharmacotherapy but unfortunately many patients with IHD remain refractory to pharmacological treatments and are unsuitable candidates for surgical interventions. Also, restenosis of the vessel lumen due to neointimal hyperplasia is a recurrent problem. Gene therapy is a promising alternative to traditional treatment strategies since the delivery of angiogenic cytokines can stimulate neovascularisation in a process known as therapeutic angiogenesis. To this end, we have designed, synthesized, and characterized novel biodegradable polymeric carrier systems for the delivery of therapeutic angiogenic plasmids. The polymers were found to have a MW of ∼3.2 kDa. A gel retardation assay showed condensation of DNA at N/P ratios higher than 20/1. The particle sizes of the polymer/DNA complexes were 100-231 nm with surface charges of 0.8-20 mV. Preliminary data with the reporter gene luciferase showed that the complexes produced significantly higher transfection efficiencies and lower cytotoxicities in several cell lines as compared to the control. Thus, these novel nonviral carriers are very efficient, versatile, and biocompatible polymers for nonviral gene delivery.