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N-acetylglucosamine Conjugated to Nanoparticles Enhances Myocyte Uptake and Improves Delivery of a Small Molecule p38 Inhibitor for Post-infarct Healing

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Abstract

An estimated 985,000 new myocardial infarctions will occur in the USA in 2011. While many will survive the initial insult, the early damage will eventually lead to heart failure for which the only definitive cure is transplantation. Cardiomyocyte (CM) apoptosis is a large contributor to cardiac dysfunction, and although potential therapeutic molecules exist to inhibit apoptotic pathways, drug delivery methods are lacking. This damage is largely regional and thus localized delivery of therapeutics holds great potential; however, CMs are relatively non-phagocytic, which limits existing options that rely on phagocytosis. Recently, the sugar N-acetylglucosamine (GlcNAc) was shown to be bound and internalized by CMs, providing a potential mechanism for drug delivery. Here we demonstrate efficacy of a drug delivery system comprising a drug-loaded biodegradable polyketal nanoparticle that is surface-decorated with GlcNAc. Inclusion of the sugar enhanced uptake by CMs as measured by intracellular activated fluorescence. When delivered in vivo following ischemia–reperfusion injury, GlcNAc-decorated particles loaded with the p38 inhibitor SB239063 reduced apoptotic events and infarct size and improved acute cardiac function. This was in contrast to our published data demonstrating no acute effect of non-sugar-decorated, p38 inhibitor-loaded particles. These data suggest a novel therapeutic option to enhance uptake of drug-loaded nanoparticles to CMs and perhaps reduce the large amount of CM cell death following myocardial injury.

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References

  1. Lloyd-Jones, D., Adams, R. J., Brown, T. M., Carnethon, M., Dai, S., De Simone, G., et al. (2010). Heart disease and stroke statistics—2010 update: A report from the American Heart Association. Circulation, 121(7), e46.

    Article  PubMed  Google Scholar 

  2. Maulik, N., Yoshida, T., & Das, D. K. (1998). Oxidative stress developed during the reperfusion of ischemic myocardium induces apoptosis. Free Radical Biology & Medicine, 24(5), 869–875.

    Article  CAS  Google Scholar 

  3. Bialik, S., Geenen, D. L., Sasson, I. E., Cheng, R., Horner, J. W., Evans, S. M., et al. (1997). Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53. The Journal of Clinical Investigation, 100(6), 1363.

    Article  PubMed  CAS  Google Scholar 

  4. McGill, C. J., & Brooks, G. (1995). Cell cycle control mechanisms and their role in cardiac growth. Cardiovascular Research, 30(4), 557–569.

    PubMed  CAS  Google Scholar 

  5. Rumyantsev, P. P. (1977). Interrelations of the proliferation and differentiation processes during cardiac myogenesis and regeneration. International Review of Cytology, 51, 187–273.

    Article  CAS  Google Scholar 

  6. Kajstura, J., Leri, A., Finato, N., Di Loreto, C., Beltrami, C. A., & Anversa, P. (1998). Myocyte proliferation in end-stage cardiac failure in humans. Proceedings of the National Academy of Sciences of the United States of America, 95(15), 8801.

    Article  PubMed  CAS  Google Scholar 

  7. Garg, S., Narula, J., & Chandrashekhar, Y. (2005). Apoptosis and heart failure: Clinical relevance and therapeutic target. Journal of Molecular and Cell Cardiology, 38(1), 73–79.

    Article  CAS  Google Scholar 

  8. Park, M., Shen, Y. T., Gaussin, V., Heyndrickx, G. R., Bartunek, J., Resuello, R. R. G., et al. (2009). Apoptosis predominates in nonmyocytes in heart failure. American Journal of Physiology. Heart and Circulatory Physiology, 297(2), H785.

    Article  PubMed  CAS  Google Scholar 

  9. Buja, L. M., & Vela, D. (2008). Cardiomyocyte death and renewal in the normal and diseased heart. Cardiovascular Pathology, 16(6), 349–374. doi:10.1016/j.carpath.2008.02.004.

    Google Scholar 

  10. Hockenbery, D. M., Oltvai, Z. N., Yin, X. M., Milliman, C. L., & Korsmeyer, S. J. (1993). Bcl-2 functions in an antioxidant pathway to prevent apoptosis. Cell, 75(2), 241–251.

    Article  PubMed  CAS  Google Scholar 

  11. Maulik, N., Engelman, R. M., Rousou, J. A., Flack, J. E., III, Deaton, D., & Das, D. K. (1999). Ischemic preconditioning reduces apoptosis by upregulating anti-death gene Bcl-2. Circulation, 100(90002), II–369.

    Google Scholar 

  12. Huang, J., Ito, Y., Morikawa, M., Uchida, H., Kobune, M., Sasaki, K., et al. (2003). Bcl-xL gene transfer protects the heart against ischemia/reperfusion injury. Biochemical and Biophysical Research Communications, 311(1), 64–70.

    Article  PubMed  CAS  Google Scholar 

  13. Potts, M. B. (2005). Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP. The Journal of Cell Biology, 171(6), 925–930. doi:10.1083/jcb.200504082.

    Article  PubMed  CAS  Google Scholar 

  14. Jolly, S., Kane, W., Bailie, M., Abrams, G., & Lucchesi, B. (1984). Canine myocardial reperfusion injury. Its reduction by the combined administration of superoxide dismutase and catalase. Circulation Research, 54(3), 277.

    PubMed  CAS  Google Scholar 

  15. Khaper, N., Kaur, K., Li, T., Farahmand, F., & Singal, P. (2003). Antioxidant enzyme gene expression in congestive heart failure following mycardial infarction. Molecular and Cellular Biochemistry, 251(1), 9–15.

    Article  PubMed  CAS  Google Scholar 

  16. Andreka, P., Zang, J., Dougherty, C., Slepak, T. I., Webster, K. A., & Bishopric, N. H. (2001). Cytoprotection by Jun kinase during nitric oxide-induced cardiac myocyte apoptosis. Circulation Research, 88(3), 305.

    PubMed  CAS  Google Scholar 

  17. Minamino, T., Yujiri, T., Papst, P. J., Chan, E. D., Johnson, G. L., & Terada, N. (1999). MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes. Proceedings of the National Academy of Sciences of the United States of America, 96(26), 15127.

    Article  PubMed  CAS  Google Scholar 

  18. Franke, T. F., Kaplan, D. R., & Cantley, L. C. (1997). PI3K: Downstream AKTion blocks apoptosis. Cell, 88(4), 435.

    Article  PubMed  CAS  Google Scholar 

  19. Wang, Y., Huang, S., Sah, V. P., Ross, J., Brown, J. H., Han, J., et al. (1998). Cardiac muscle cell hypertrophy and apoptosis induced by distinct members of the p38 mitogen-activated protein kinase family. Journal of Biological Chemistry, 273(4), 2161.

    Article  PubMed  CAS  Google Scholar 

  20. Chen, Z., Chua, C. C., Ho, Y. S., Hamdy, R. C., & Chua, B. H. L. (2001). Overexpression of Bcl-2 attenuates apoptosis and protects against myocardial I/R injury in transgenic mice. American Journal of Physiology. Heart and Circulatory Physiology, 280(5), H2313.

    PubMed  CAS  Google Scholar 

  21. Chen, Z., Siu, B., Ho, Y. S., Vincent, R., Chua, C. C., Hamdy, R. C., et al. (1998). Overexpression of MnSOD protects against myocardial ischemia/reperfusion injury in transgenic mice. Journal of Molecular and Cell Cardiology, 30(11), 2281–2289.

    Article  CAS  Google Scholar 

  22. Chua, C. C., Gao, J., Ho, Y. S., Xiong, Y., Xu, X., Chen, Z., et al. (2007). Overexpression of IAP-2 attenuates apoptosis and protects against myocardial ischemia/reperfusion injury in transgenic mice. Biochimica et Biophysica Acta, 1773(4), 577–583.

    Article  PubMed  CAS  Google Scholar 

  23. Matherne, G. P., Linden, J., Byford, A. M., Gauthier, N. S., & Headrick, J. P. (1997). Transgenic A1 adenosine receptor overexpression increases myocardial resistance to ischemia. Proceedings of the National Academy of Sciences of the United States of America, 94(12), 6541.

    Article  PubMed  CAS  Google Scholar 

  24. Matsui, T., Tao, J., del Monte, F., Lee, K. H., Li, L., Picard, M., et al. (2001). Akt activation preserves cardiac function and prevents injury after transient cardiac ischemia in vivo. Circulation, 104(3), 330.

    PubMed  CAS  Google Scholar 

  25. Harris, J. M., & Chess, R. B. (2003). Effect of pegylation on pharmaceuticals. Nature Reviews. Drug Discovery, 2(3), 214–221.

    Article  PubMed  CAS  Google Scholar 

  26. Hsieh, P. C. H., Davis, M. E., Gannon, J., MacGillivray, C., & Lee, R. T. (2006). Controlled delivery of PDGF-BB for myocardial protection using injectable self-assembling peptide nanofibers. The Journal of Clinical Investigation, 116(1), 237–248.

    Article  PubMed  CAS  Google Scholar 

  27. Lee, S., & Murthy, N. (2007). Targeted delivery of catalase and superoxide dismutase to macrophages using folate. Biochemical and Biophysical Research Communications, 360(1), 275–279.

    Article  PubMed  CAS  Google Scholar 

  28. Lee, S., Yang, S. C., Heffernan, M. J., Taylor, W. R., & Murthy, N. (2007). Polyketal microparticles: A new delivery vehicle for superoxide dismutase. Bioconjugate Chemistry, 18(1), 4–7.

    Article  PubMed  CAS  Google Scholar 

  29. Sy, J., Phelps, E., García, A., Murthy, N., & Davis, M. (2010). Surface functionalization of polyketal microparticles with nitrilotriacetic acid–nickel complexes for efficient protein capture and delivery. Biomaterials, 31(18), 4987–4994.

    Article  PubMed  CAS  Google Scholar 

  30. Sy, J., Seshadri, G., Yang, S., Brown, M., Oh, T., Dikalov, S., et al. (2008). Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction. Nature Materials, 7(11), 863–868.

    Article  PubMed  CAS  Google Scholar 

  31. Sutton, M. G., & Sharpe, N. (2000). Left ventricular remodeling after myocardial infarction: Pathophysiology and therapy. Circulation, 101(25), 2981.

    PubMed  CAS  Google Scholar 

  32. Aso, S., Ise, H., Takahashi, M., Kobayashi, S., Morimoto, H., Izawa, A., et al. (2007). Effective uptake of N-acetylglucosamine-conjugated liposomes by cardiomyocytes in vitro. Journal of Controlled Release, 122(2), 189–198.

    Article  PubMed  CAS  Google Scholar 

  33. Ise, H., Kobayashi, S., Goto, M., Sato, T., Kawakubo, M., Takahashi, M., et al. (2010). Vimentin and desmin possess GlcNAc-binding lectin-like properties on cell surfaces. Glycobiology, 20(7), 843.

    Article  PubMed  CAS  Google Scholar 

  34. Vemuri, S., & Rhodes, C. (1995). Preparation and characterization of liposomes as therapeutic delivery systems: A review. Pharmaceutica Acta Helvetiae, 70(2), 95–111.

    Article  PubMed  CAS  Google Scholar 

  35. Seshadri, G., Sy, J. C., Brown, M., Dikalov, S., Yang, S. C., Murthy, N., et al. (2010). The delivery of superoxide dismutase encapsulated in polyketal microparticles to rat myocardium and protection from myocardial ischemia–reperfusion injury. Biomater, 31(6), 1372–1379.

    Article  CAS  Google Scholar 

  36. Yuan, X. B., Gu, M. Q., Kang, C. S., Zhao, Y. H., Tian, N. J., Pu, P. Y., et al. (2007). Surface biofunctionalization of PLA nanoparticles through amphiphilic polysaccharide coating and ligand coupling: Evaluation of biofunctionalization and drug releasing behavior. Carbohydrate Polymers, 67(3), 417–426.

    Article  Google Scholar 

  37. Granger, B. L., & Lazarides, E. (1979). Desmin and vimentin coexist at the periphery of the myofibril Z disc. Cell, 18(4), 1053–1063.

    Article  PubMed  CAS  Google Scholar 

  38. Li, Z., Mericskay, M., Agbulut, O., Butler-Browne, G., Carlsson, L., Thornell, L. E., et al. (1997). Desmin is essential for the tensile strength and integrity of myofibrils but not for myogenic commitment, differentiation, and fusion of skeletal muscle. The Journal of Cell Biology, 139(1), 129–144.

    Article  PubMed  CAS  Google Scholar 

  39. Bogoyevitch, M. A., Gillespie-Brown, J., Ketterman, A. J., Fuller, S. J., Ben-Levy, R., Ashworth, A., et al. (1996). Stimulation of the stress-activated mitogen-activated protein kinase subfamilies in perfused heart. p38/RK mitogen-activated protein kinases and c-Jun N-terminal kinases are activated by ischemia/reperfusion. Circulation Research, 79(2), 162–173.

    PubMed  CAS  Google Scholar 

  40. Pombo, C. M., Bonventre, J. V., Avruch, J., Woodgett, J. R., Kyriakis, J. M., & Force, T. (1994). The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion. Journal of Biological Chemistry, 269(42), 26546–26551.

    PubMed  CAS  Google Scholar 

  41. Yin, T., Sandhu, G., Wolfgang, C. D., Burrier, A., Webb, R. L., Rigel, D. F., et al. (1997). Tissue specific pattern of stress kinase activation in ischemia/reperfused heart and kidney. Journal of Biological Chemistry, 272, 19943–19950.

    Article  PubMed  CAS  Google Scholar 

  42. Amado, L. C., Saliaris, A. P., Schuleri, K. H., St John, M., Xie, J. S., Cattaneo, S., et al. (2005). Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America, 102(32), 11474–11479.

    Article  PubMed  CAS  Google Scholar 

  43. Krause, K., Jaquet, K., Schneider, C., Haupt, S., Lioznov, M. V., Otte, K. M., et al. (2009). Percutaneous intramyocardial stem cell injection in patients with acute myocardial infarction: First-in-man study. Heart, 95(14), 1145–1152.

    Article  PubMed  CAS  Google Scholar 

  44. Herreros, J., Prosper, F., Perez, A., Gavira, J. J., Garcia-Velloso, M. J., Barba, J., et al. (2003). Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. European Heart Journal, 24(22), 2012–2020.

    Article  PubMed  Google Scholar 

  45. Li, Q., Li, B., Wang, X., Leri, A., Jana, K. P., Liu, Y., et al. (1997). Overexpression of insulin-like growth factor-1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. The Journal of Clinical Investigation, 100(8), 1991–1999.

    Article  PubMed  CAS  Google Scholar 

  46. Sabbah, H. N., Sharov, V. G., Gupta, R. C., Todor, A., Singh, V., & Goldstein, S. (2000). Chronic therapy with metoprolol attenuates cardiomyocyte apoptosis in dogs with heart failure. Journal of the American College of Cardiology, 36(5), 1698–1705.

    Article  PubMed  CAS  Google Scholar 

  47. Jones, S. P., Zachara, N. E., Ngoh, G. A., Hill, B. G., Teshima, Y., Bhatnagar, A., et al. (2008). Cardioprotection by N-acetylglucosamine linkage to cellular proteins. Circulation, 117(9), 1172.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, as a Program of Excellence in Nanotechnology Award, N01 HV-08234, to NM and MED. Additionally, this work was supported by award HL090601 from the National Institutes of Health to MED, as well as a GAANN Fellowship from the Center for Drug Design, Development, and Delivery at Georgia Institute of Technology to WDG.

Conflict of Interest Statement

Drs. Davis and Murthy, as well as Emory University, are entitled to equity and royalties derived from Ketal Biomedical Incorporated, which is developing products related to the technology described in this paper. This study could affect his/her/their personal financial status. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict of interest policies.

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Authors and Affiliations

  1. The Wallace H. Coulter Department of Biomedical Engineering, Emory University, 101 Woodruff Circle, Suite 2001, Atlanta, GA, 30322, USA

    Warren D. Gray, Paolin Che, Milton Brown, Xinghai Ning, Niren Murthy & Michael E. Davis

  2. The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, 315 Ferst Drive, Room 3303, Atlanta, GA, 30332-0535, USA

    Warren D. Gray, Paolin Che, Milton Brown, Xinghai Ning, Niren Murthy & Michael E. Davis

  3. Division of Cardiology, Emory University School of Medicine, Atlanta, GA, USA

    Warren D. Gray, Paolin Che, Milton Brown & Michael E. Davis

  4. Parker H. Petit Institute for Bioengineering and Bioscience, Atlanta, GA, USA

    Niren Murthy

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Gray, W.D., Che, P., Brown, M. et al. N-acetylglucosamine Conjugated to Nanoparticles Enhances Myocyte Uptake and Improves Delivery of a Small Molecule p38 Inhibitor for Post-infarct Healing. J. of Cardiovasc. Trans. Res. 4, 631–643 (2011). https://doi.org/10.1007/s12265-011-9292-0

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