Abstract 16159: Targeted Delivery of a Dual Cathepsin G and Chymase Inhibitor by Immunoliposomes Augments Cardioprotection in Mice
Introduction: Neutrophil- and mast-cell-mediated inflammation accounts for a substantial fraction of the myocardial injury occurring after ischemia reperfusion (IR). However, no standard anti-inflammatory therapy has been developed for clinical myocardial IR injury. Here, we designed and tested a novel immunoliposomal drug delivery vehicle targeting neutrophil- and mast cell-derived serine proteases, cathepsin G and chymase, to enhance specific delivery of drug carriers to the infarct region.
Methods and Results: C57BL/6 mice were subjected to myocardial ischemia for 30 minutes followed by reperfusion for 1 and 7 days and the effect of a potent non-peptide inhibitor of cathepsin G and chymase (ICC) on inflammation and cardioprotection were characterized. ICC was delivered just after reperfusion either systemically (2 or 10 mg/kg, i.v.) or encapsulated in anti-P-selectin conjugated immunoliposomes (ILPs) (2 mg/kg, i.v.). Targeted delivery of ICC-loaded ILPs reduced cardiac levels of cathepsin G and chymase activity induced at day 1 and 7 post-IR and attenuated neutrophil and mast cell infiltration in the infarct region compared to mice treated with empty ILPs. ILP targeted delivery of ICC also reduced myocyte apoptosis (-40% in TUNEL+ myocytes, p<0.05), limited infarct size (-40%, p<0.05) and improved cardiac function (+10% in ejection fraction, P<0.05) post-IR compared to empty ILP-treated mice. Interestingly, ICC-loaded ILPs significantly reduced fibroblast proliferation and differentiation to myofibroblasts, which resulted in less collagen accumulation. Equivalent doses of ICC (2 mg/kg/d) administered systemically were not efficacious. However, structural and functional improvements similar to those obtained with targeted delivery of ICC were obtained with systemic delivery of higher dose of ICC (10 mg/kg/d).
Conclusions: These findings reveal the role of neutrophil- and mast-cell-derived proteases as key mediators of myocyte apoptosis and cardiac dysfunction post-IR and show that immunoliposomal targeted inhibition of inflammatory proteases could be used as future therapy to enhance cardiac remodeling and function post-IR.
Author Disclosures: B. Hooshdaran: None. M. Kolpakov: None. X. Guo: None. Y. Bashkirova: None. T. Wang: None. W. Schappel: None. Y. Tang: None. M.F. Kiani: None. A. Sabri: None.
- © 2016 by American Heart Association, Inc.