Development of a polymeric matrix metalloproteinase inhibitor as a bioactive stent coating material for prevention of restenosis

Abstract

Drug-eluting stents have been developed to prevent restenosis derived from excessive growth of smooth muscle cells (SMCs) after stenting. In almost every case, however, less- or non-biocompatible polymers were selected for the platform material for impregnating drugs on the stent strut. Consideration was given principally to the physical properties of the polymers, such as their adhesion to the strut and the drug dispersibility in the polymeric matrix. In this study, we designed a matrix metalloproteinase inhibitor (MMPI)-derivatized hydrophobic polymer (PMMPI) for use as a bioactive material for stent coating. This was a copolymer of n-butylmethacrylate and a vinyl monomer of synthetic MMPI (N-Hydroxy-5-carboxyethylcarbonyloxy-2(S)-methy-4(S)-(4-phenoxybenzoyl)amino-pentanamide: ONO-M11-335) with a molecular weight of about 32,000 and MMPI content of 45 per molecule. The precursor of the MMPI monomer produced significant activity in temporally inhibiting SMC proliferation without any cellular damage. After coating with the PMMPI, adhesion and proliferation of SMCs were manifestly prevented even when a small amount of MMPI was released from the polymer. The MMPI-immobilized surface may thus be effective for inhibiting both adhesion and proliferation of SMCs, which is the first step toward in vivo experimentation. It is very much expected that coating stent struts with PMMPI containing an appropriate combination of impregnated drugs will provide a powerful tool for prevention of restenosis with little cytotoxicity.