The major cause of heart failure is the regional loss of myocardium following myocardial infarction. Because the loss of tissue is highly localized, and the endogenous response is not sufficient for repair, recent efforts have focused on the prevention of initial cell death using a variety of treatment options. Inhibition of p38 activation has been associated with improved function following myocardial infarction, however the size of the inhibitor makes it difficult to sustain in larger animals. The objective of this proposal is to encapsulate SB239063, a potent inhibitor of p38 phosphorylation, within polyketal particles to enhance myocardial retention and improve function following infarction. In vivo inhibitor studies and dominant negative mouse approaches demonstrate a clear potential of p38 inhibition to treat cardiac dysfunction following myocardial infarction;however the relatively small size of the inhibitor has limited its use in larger animal studies. Polyketal particles are a new class of polymers that are stable, degrade in to FDA-approved compounds, can be modified easily and can encapsulate proteins while retaining activity. The central hypothesis of this proposal is that polyketal particles encapsulate this p38 inhibitor and block apoptosis of cardiac myocytes, as well as prevent stimulated cytokine release from macrophages both in vitro and in vivo following myocardial infarction. We also believe this effect will extend to endogenous cardiac stem cells, in addition to serving a protective role for implanted stem cells as well. The successful completion of this R01 proposal will demonstrate that polyketal particles loaded with this small molecule inhibitor can be used to treat cardiac dysfunction following myocardial infarction. We further believe completion of this proposal will also demonstrate a role for polyketal-encapsulated p38 inhibition as an adjunct therapy for cell transplantation. Given the complicated endogenous response following myocardial infarction, we believe that data from this proposal will generate widespread interest in using polyketals for myocardial drug delivery.
Congestive heart failure is a leading cause of morbidity and mortality worldwide and effective treatment options are greatly needed. We propose to encapsulate and deliver SB239063, a potent p38 inhibitor with therapeutic potential, directly to the myocardium using a new class of polymers called polyketals. This proposal will demonstrate that p38 inhibition with polyketals can be used to help regenerate cardiac tissue following myocardial infarction.
|Acharya, Abhinav P; Rafi, Mohammad; Woods, Elliot C et al. (2014) Metabolic engineering of lactate dehydrogenase rescues mice from acidosis. Sci Rep 4:5189|
|Somasuntharam, Inthirai; Boopathy, Archana V; Khan, Raffay S et al. (2013) Delivery of Nox2-NADPH oxidase siRNA with polyketal nanoparticles for improving cardiac function following myocardial infarction. Biomaterials 34:7790-8|
|Sohn, Young-Doug; Somasuntharam, Inthirai; Che, Pao-Lin et al. (2013) Induction of pluripotency in bone marrow mononuclear cells via polyketal nanoparticle-mediated delivery of mature microRNAs. Biomaterials 34:4235-41|
|Cabigas, E Bernadette; Ding, Guoliang; Chen, Tao et al. (2012) Age- and chamber-specific differences in oxidative stress after ischemic injury. Pediatr Cardiol 33:322-31|
|Gray, Warren D; Che, Paolin; Brown, Milton et al. (2011) N-acetylglucosamine conjugated to nanoparticles enhances myocyte uptake and improves delivery of a small molecule p38 inhibitor for post-infarct healing. J Cardiovasc Transl Res 4:631-43|
|Sy, Jay C; Phelps, Edward A; Garcia, Andres J et al. (2010) Surface functionalization of polyketal microparticles with nitrilotriacetic acid-nickel complexes for efficient protein capture and delivery. Biomaterials 31:4987-94|
|Seshadri, Gokulakrishnan; Sy, Jay C; Brown, Milton et al. (2010) The delivery of superoxide dismutase encapsulated in polyketal microparticles to rat myocardium and protection from myocardial ischemia-reperfusion injury. Biomaterials 31:1372-9|
|Sy, Jay C; Davis, Michael E (2010) Delivering regenerative cues to the heart: cardiac drug delivery by microspheres and peptide nanofibers. J Cardiovasc Transl Res 3:461-8|
|Sy, Jay C; Seshadri, Gokulakrishnan; Yang, Stephen C et al. (2008) Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction. Nat Mater 7:863-8|