Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

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


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others


  1. Anversa, P. Myocyte death in the pathological heart. Circ. Res. 86, 121–124 (2000).

    Article  CAS  Google Scholar 

  2. Anversa, P., Leri, A. & Kajstura, J. Cardiac regeneration. J. Am. Coll. Cardiol. 47, 1769–1776 (2006).

    Article  Google Scholar 

  3. Bolli, R. Oxygen-derived free radicals and myocardial reperfusion injury: An overview. Cardiovasc. Drugs ther. 5, 249–268 (1991).

    Article  Google Scholar 

  4. Bolli, R. et al. Direct evidence that oxygen-derived free radicals contribute to postischemic myocardial dysfunction in the intact dog. Proc. Natl Acad. Sci. USA 86, 4695–4699 (1989).

    Article  CAS  Google Scholar 

  5. Kumar, S., Boehm, J. & Lee, J. C. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat. Rev. Drug. Discov. 2, 717–726 (2003).

    Article  CAS  Google Scholar 

  6. Lee, J. C. et al. Inhibition of p38 MAP kinase as a therapeutic strategy. Immunopharmacology 47, 185–201 (2000).

    Article  CAS  Google Scholar 

  7. Peifer, C., Wagner, G. & Laufer, S. New approaches to the treatment of inflammatory disorders small molecule inhibitors of p38 MAP kinase. Curr. Top. Med. Chem. 6, 113–149 (2006).

    Article  CAS  Google Scholar 

  8. Davis, M. E., Hsieh, P. C., Grodzinsky, A. J. & Lee, R. T. Custom design of the cardiac microenvironment with biomaterials. Circ. Res. 97, 8–15 (2005).

    Article  CAS  Google Scholar 

  9. Christman, K. L. & Lee, R. J. Biomaterials for the treatment of myocardial infarction. J. Am. Coll. Cardiol. 48, 907–913 (2006).

    Article  CAS  Google Scholar 

  10. Heffernan, M. J. & Murthy, N. Polyketal nanoparticles: A new pH-sensitive biodegradable drug delivery vehicle. Bioconjug. Chem. 16, 1340–1342 (2005).

    Article  CAS  Google Scholar 

  11. Lee, S. et al. Polyketal microparticles: A new delivery vehicle for superoxide dismutase. Bioconjug. Chem. 18, 4–7 (2007).

    Article  CAS  Google Scholar 

  12. Li, Z. et al. Selective inhibition of p38alpha MAPK improves cardiac function and reduces myocardial apoptosis in rat model of myocardial injury. Am. J. Physiol. Heart Circ. Physiol. 291, H1972–H1977 (2006).

    Article  CAS  Google Scholar 

  13. Liu, Y. H. et al. Inhibition of p38 mitogen-activated protein kinase protects the heart against cardiac remodeling in mice with heart failure resulting from myocardial infarction. J. Card. Fail. 11, 74–81 (2005).

    Article  CAS  Google Scholar 

  14. Minamino, T. et al. MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes. Proc. Natl Acad. Sci. USA 96, 15127–15132 (1999).

    Article  CAS  Google Scholar 

  15. Porras, A. et al. P38 alpha mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli. Mol. Biol. Cell. 15, 922–933 (2004).

    Article  CAS  Google Scholar 

  16. Ren, J. et al. Role of p38alpha MAPK in cardiac apoptosis and remodeling after myocardial infarction. J. Mol. Cell. Cardiol. 38, 617–623 (2005).

    Article  CAS  Google Scholar 

  17. See, F. et al. p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat. J. Am. Coll. Cardiol. 44, 1679–1689 (2004).

    Article  CAS  Google Scholar 

  18. Ding, T., Sun, J. & Zhang, P. Immune evaluation of biomaterials in TNF-alpha and IL-1beta at mRNA level. J. Mater. Sci. 18, 2233–2236 (2007).

    CAS  Google Scholar 

  19. Iwasaki, Y. et al. Reduction of surface-induced inflammatory reaction on PLGA/MPC polymer blend. Biomaterials 23, 3897–3903 (2002).

    Article  CAS  Google Scholar 

  20. Fernandes, D. C. et al. Analysis of dihydroethidium-derived oxidation products by HPLC in the assessment of superoxide production and NADPH oxidase activity in vascular systems. Am. J. Physiol. Cell. Physiol. 292, C413–C422 (2006).

    Article  Google Scholar 

  21. Gongora, M. C. et al. Role of extracellular superoxide dismutase in hypertension. Hypertension 48, 473–481 (2006).

    Article  CAS  Google Scholar 

  22. Kim, M. S. et al. An in vivo study of the host tissue response to subcutaneous implantation of PLGA- and/or porcine small intestinal submucosa-based scaffolds. Biomaterials 28, 5137–5143 (2007).

    Article  CAS  Google Scholar 

  23. Davis, M. E. et al. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction. Proc. Natl Acad. Sci. USA 103, 8155–8160 (2006).

    Article  CAS  Google Scholar 

  24. Widder, J. et al. Vascular endothelial dysfunction and superoxide anion production in heart failure are p38 MAP kinase-dependent. Cardiovasc. Res. 63, 161–167 (2004).

    Article  CAS  Google Scholar 

  25. Zhao, Z. Q. & Vinten-Johansen, J. Myocardial apoptosis and ischemic preconditioning. Cardiovasc. Res. 55, 438–455 (2002).

    Article  CAS  Google Scholar 

  26. Clerk, A. & Sugden, P. H. Inflame my heart (by p38-MAPK). Circ. Res. 99, 455–458 (2006).

    Article  CAS  Google Scholar 

  27. Sugden, P. H. & Clerk, A. Oxidative stress and growth-regulating intracellular signaling pathways in cardiac myocytes. Antioxidants Redox Signal. 8, 2111–2124 (2006).

    Article  CAS  Google Scholar 

  28. Fink, B. et al. Detection of intracellular superoxide formation in endothelial cells and intact tissues using dihydroethidium and an HPLC-based assay. Am. J. Physiol. Cell. Physiol. 287, C895–C902 (2004).

    Article  CAS  Google Scholar 

  29. Sanada, S. et al. IL-33 and ST2 comprise a critical biomechanically induced and cardioprotective signaling system. J. Clin. Invest. 117, 1538–1549 (2007).

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Corresponding author

Correspondence to Michael E. Davis.

Supplementary information

Supplementary Information

Supplementary Information (PDF 652 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing