Targeted drug delivery for the treatment and diagnosis of cardiovascular disease

Abstract

Cardiovascular disease has accounted for more deaths than any other major cause of death in the United States every year since 1900, with the exception of 1918. Despite improvements in the management of cardiovascular disease, there is still a need for new and improved treatments and diagnostics. In peripheral artery disease (PAD), treatment with pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF), is currently being explored. However, there is a need to overcome limitations of this therapy, such as the growth factor’s short half-life, inadequate delivery to target tissue, and inadequate retention at target tissue. In myocarditis, a large number of patients go undiagnosed due to the disease’s heterogeneous etiology, pathophysiology, and clinical presentation. Current diagnostic techniques, such as endomyocardial biopsy and cardiac magnetic resonance, are inadequate, and there is a need for new technologies for the appropriate diagnosis and timely treatment of myocarditis. This dissertation aims to explore two different targeting techniques for the treatment and diagnosis of PAD and myocarditis.

In PAD, ischemic tissue undergoes necrosis and releases cellular contents, including DNA, into extracellular space. A modified Hoechst compound has been previously used to target extracellular DNA in an animal model of myocardial infarction. We explored using a similar modified Hoechst compound to target extracellular DNA in an animal model PAD and deliver VEGF to ischemic tissue. Despite promising initial results, we did not observe any improvements in the retention or targeting of our compound to ischemic tissue when compared to non-Hoechst controls.

Myocarditis is characterized by the presence of localized or diffuse inflammation in the myocardium. In an animal model of myocarditis, we used an in vivo phage display library to identify peptides that preferentially targeted this diseased myocardium. Ex vivo screening of potential peptides was then used to identify two peptides whose binding correlated with disease severity. In vivo screening was used to demonstrate that one of these peptides identified animals with severe myocarditis. Immunohistochemistry and proteonomic analysis was then used to identify potential cell and protein targets of this peptide.

Through these approaches, two different techniques for the treatment and diagnosis of cardiovascular disease have been explored. These insights will advance the development of new techniques for the better treatment and diagnosis of cardiovascular disease.