Novel Strategies for Treating Cardiac Dysfunction
Michael Davis, PhD, Assistant Professor, Wallace H. Coulter Department of Biomedical Engineering
"Novel Strategies for Treating Cardiac Dysfunction"
Cardiac dysfunction as a result of myocardial infarction is a progressive disease and sustained therapy is critical in improving function. Additionally, the eventual dysfunction is the results of several pathways, thus finding the optimal drug to deliver at the right time is difficult. As a result, ideal drug delivery vehicles must be non-inflammatory and deliver therapeutics on time in order to spur regeneration.
Our published data demonstrates that the polyketal PCADK can be used to deliver small molecule therapeutics, specifically an inhibitor of the p38 pathway. When delivered in vivo, this inhibitor sustained p38 inhibition for at least 1 week and inhibited cytokine production resulting in an eventual improvement in cardiac function over time. Interestingly, despite the early inhibition of p38 and inflammatory cytokines, there was no effect on function at 7 days, indicating the p38 inhibitor was not released in time, or that p38 itself plays no role in the early phase of myocardial infarction. We then created polymers containing the antioxidant protein superoxide dismutase (SOD). When delivered in vivo, the SOD microparticles, and not the free enzyme or empty particles, significantly inhibited superoxide levels within the border zones and significantly improved cardiac function at 3 days. While there was a trend for improvement later, the effect was not as great. However, when combined with p38-inhibitor loaded particles, there was a significant improvement in function suggesting the need for dual delivery. We have now synthesized particles that can encapsulate multiple molecules, as well as small interfering RNA and are using these for cardiac therapy. Finally, targeting can be achieved by using surface modification approaches to target cardiac and endothelial cells.
New work in our lab has focused on developing small molecule (<1 kDa) targeting ligands for ischemic tissues. A common marker for ischemic tissue is exposed DNA generated by necrotic cell death. We hypothesized that DNA binding agents - such the commonly used dye, Hoechst - can be used to target extracellular DNA in ischemic tissue for imaging and drug delivery purposes. Hoechst was conjugated to a fluorescent dye (IR786) to serve as a near-infrared (NIR) imaging agent for necrotic tissue. Mice treated with Hoechst-IR786 injected intravenously 2 hours following infarction showed significant increases in NIR fluorescence only in the infarct zone. This work suggests that targeting extracellular DNA may be an alternative to antibody targeting strategies for ischemic diseases. Work in our lab is currently focusing on Hoechst-protein conjugates for therapeutic neovascularization. Due to nanomolar affinity for DNA and low toxicity, Hoechst-targeted compounds have the potential to improve imaging and regeneration in the heart.
Continental breakfast and coffee will be served.