title: Delivery of lipid micelles into infarcted myocardium using a lipid-linked matrix metalloproteinase targeting peptide.
abstract: There is a great need for delivery strategies capable of efficiently localizing drugs to the damaged myocardium that do not require direct intramyocardial injection of therapeutic molecules. In the work discussed here, we exploited the myocardium-specific upregulation of matrix metalloproteinases (MMPs) that occurs during myocardium remodeling by designing a micellar vehicle containing an MMP-targeting peptide (MMP-TP). The binding of MMP-TP to MMP was evaluated with purified MMP-2 protein and U-937 cells induced to overexpress MMP. Inhibition of MMP-2 activity was not observed in the presence of unmodified micelles but was pronounced at a 5 mol % MMP-TP ligand density. In a FACS analysis, MMP-TP micelles containing 5 mol % of the MMP-targeting peptide showed ∼10-fold higher binding to activated U937 cells than plain micelles and micelles containing a control peptide with two amino acid replacements. MMP-TP-micelles and plain micelles were injected intravenously into C57BL/6 mice 1, 3, and 7 days after the induction of a myocardial infarction (MI). Immunohistochemistry performed on heart tissue sections revealed that MMP-TP-micelles colocalize with both MMP and infiltrating macrophages. MMP-TP micelles showed significantly enhanced accumulation to the necrotic area of the heart after MI on days 3 and 7 when compared to plain micelles and negative control peptide micelles. This is coincident with the measured temporal profile of MMP gene expression in the heart after MI. These results suggest that MMP-TP micelles are candidates for the development of targeted regenerative heart therapeutics because of their ability to target the infarcted myocardium in a MMP dependent manner.
authors: †Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, New York 14214, United States.
authors: Juliane
authors: J
authors: Nguyen
authors: ‡Department of Medicine, Cardiovascular Research Institute, and Institute of Regeneration Medicine, University of California-San Francisco, San Francisco, California 94143, United States.
authors: Richard
authors: R
authors: Sievers
authors: §Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, San Francisco, California 94143, United States.
authors: J P Michael
authors: JP
authors: Motion
authors: §Department of Bioengineering and Therapeutic Sciences, University of California-San Francisco, San Francisco, California 94143, United States.
authors: Saul
authors: S
authors: Kivimäe
authors: ‡Department of Medicine, Cardiovascular Research Institute, and Institute of Regeneration Medicine, University of California-San Francisco, San Francisco, California 94143, United States.
authors: Qizhi
authors: Q
authors: Fang
authors: ‡Department of Medicine, Cardiovascular Research Institute, and Institute of Regeneration Medicine, University of California-San Francisco, San Francisco, California 94143, United States.
authors: Randall J
authors: RJ
authors: Lee
mesh_terms: D000818:Animals; D002469:Cell Separation; D004337:Drug Carriers; D016503:Drug Delivery Systems; D005434:Flow Cytometry; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D008055:Lipids / Q000737:chemistry*; D008264:Macrophages / Q000187:drug effects; D008297:Male; D020782:Matrix Metalloproteinases / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008823:Micelles; D009203:Myocardial Infarction / Q000188:drug therapy*; D009336:Necrosis; D010455:Peptides / Q000737:chemistry; D012038:Regeneration; D020298:U937 Cells
chemical_list: D004337:Drug Carriers; D008055:Lipids; D008823:Micelles; D010455:Peptides; D020782:Matrix Metalloproteinases
keywords: drug targeting; matrix metalloproteinase; myocardial infarction; targeted micellar vehicles