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Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction

Abstract

Cardiac dysfunction following acute myocardial infarction is a major cause of death in the world and there is a compelling need for new therapeutic strategies. In this report we demonstrate that a direct cardiac injection of drug-loaded microparticles, formulated from the polymer poly(cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK), improves cardiac function following myocardial infarction. Drug-delivery vehicles have great potential to improve the treatment of cardiac dysfunction by sustaining high concentrations of therapeutics within the damaged myocardium. PCADK is unique among currently used polymers in drug delivery in that its hydrolysis generates neutral degradation products. We show here that PCADK causes minimal tissue inflammatory response, thus enabling PCADK for the treatment of inflammatory diseases, such as cardiac dysfunction. PCADK holds great promise for treating myocardial infarction and other inflammatory diseases given its neutral, biocompatible degradation products and its ability to deliver a wide range of therapeutics.

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Figure 1: Polyketal microparticles—non-inflammatory polymer chemistry for drug delivery.
Figure 2: Macrophages are activated by PLGA microspheres in vitro, whereas PK-p38i treatment inhibits p38 activation.
Figure 3: PCADK microparticles demonstrate little inflammatory response following intramuscular injections.
Figure 4: PK-p38i particles inhibit p38 phosphorylation, superoxide production and TNF-α production in vivo following infarction.
Figure 5: PK-p38i therapy results in improved cardiac function and reduced fibrosis.

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Acknowledgements

The authors wish to thank M. Kemp for her assistance with Bioplex assays for cytokine analysis. This work was supported by a seed grant from Emtech Biotechnology Development (M.E.D.), the Georgia Tech/Emory Center for the Engineering of Living Tissues (funded by NSF-EEC-9731643) (N.M.), NIH UO1 HL80711-01 (N.M.), NIH R21 EB006418 (N.M.), J&J/GT Health Care Innovation Seed Grant Proposal (N.M.) and the Department of Homeland Security (DHS) Scholarship and Fellowship Program, administered by the Oak Ridge Institute for Science and Education (ORISE) through an interagency agreement between the US Department of Energy (DOE) and DHS (J.C.S.). ORISE is managed by Oak Ridge Associated Universities (ORAU) under DOE contract number DE-AC05-06OR23100. All opinions expressed in this paper are the authors’ and do not necessarily reflect the policies and views of DHS, DOE or ORAU/ORISE.

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The experiments were designed by J.C.S., N.M. and M.E.D., carried out by J.C.S., G.S. and T.O. and interpreted by J.C.S., N.M. and M.E.D. M.B. was responsible for all animal surgeries and echocardiography; S.D. was responsible for design and interpretation of oxidative stress studies as part of the Free Radicals in Medicine Core (FRIMCORE). The manuscript was written by J.C.S., N.M. and M.E.D.

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Correspondence to Michael E. Davis.

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Sy, J., Seshadri, G., Yang, S. et al. Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction. Nature Mater 7, 863–868 (2008). https://doi.org/10.1038/nmat2299

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