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纳米粒度测量应用案例-58-Omni
阅读：162 发布时间：2015-7-23
文献名： Delivery of Lipid Micelles into Infarcted
Myocardium Using a Lipid-Linked Matrix Metalloproteinase
Targeting Peptide
作者： Juliane Nguyen *†, Richard Sievers ‡, J. P. Michael
Motion §, Saul Kivimäe §, Qizhi Fang ‡, and Randall J.
Lee *‡
† 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
‡ Department of Medicine, Cardiovascular Research
Institute, and Institute of Regeneration Medicine,
University of California—San Francisco, San Francisco,
California 94143, United States
§ Department of Bioengineering and Therapeutic Sciences,
University of California—San Francisco, San Francisco,
California 94143, United States
摘要：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.
关键词：myocardial infarction; matrix metalloproteinase;
targeted micellar vehicles; drug targeting