Secreted Matrix Metalloproteinase‑9 of Proliferating Smooth Muscle Cells as a Trigger for Drug Release from Stent Surface Polymers in Coronary Arteries

Cardiovascular
diseases are the leading causes of death in industrialized
countries. Atherosclerotic coronary arteries are commonly treated
with percutaneous transluminal coronary intervention followed by stent
deployment. This treatment has significantly improved the clinical
outcome. However, triggered vascular smooth muscle cell (SMC) proliferation
leads to in-stent restenosis in bare metal stents. In addition, stent
thrombosis is a severe side effect of drug eluting stents due to inhibition
of endothelialization. The aim of this study was to develop and test
a stent surface polymer, where cytotoxic drugs are covalently conjugated
to the surface and released by proteases selectively secreted by proliferating
smooth muscle cells. Resting and proliferating human coronary artery
smooth muscle cells (HCASMC) and endothelial cells (HCAEC) were screened
to identify an enzyme exclusively released by proliferating HCASMC.
Expression analyses and enzyme activity assays verified selective
and exclusive activity of the matrix metalloproteinase-9 (MMP-9) in
proliferating HCASMC. The principle of drug release exclusively triggered
by proliferating HCASMC was tested using the biodegradable stent surface
polymer poly-l-lactic acid (PLLA) and the MMP-9 cleavable
peptide linkers named SRL and AVR. The specific peptide cleavage by
MMP-9 was verified by attachment of the model compound fluorescein.
Fluorescein release was observed in the presence of MMP-9 secreting
HCASMC but not of proliferating HCAEC. Our findings suggest that cytotoxic
drug conjugated polymers can be designed to selectively release the
attached compound triggered by MMP-9 secreting smooth muscle cells.
This novel concept may be beneficial for stent endothelialization
thereby reducing the risk of restenosis and thrombosis.