TITLE:
Simultaneous Release of a Hydroxy-Methylglutaryl Coenzyme A Reductase Inhibitor and a Glycoprotein IIb/IIIa Antagonist from a Thermoresponsive NiPAAm/NtBAAm Copolymer System
AUTHORS:
J. A. Hickey, I. Lynch, K. A. Dawson, D. Cox, A. K. Keenan
KEYWORDS:
Fluvastatin, Xemilofiban, Nipaam/Ntbaam, Microgels, Local Drug Delivery
JOURNAL NAME:
Journal of Biomaterials and Nanobiotechnology,
Vol.2 No.1,
January
27,
2011
ABSTRACT: While deployment of intracoronary stents has been shown to reduce restenosis, stenting can also damage the endothelial monolayer lining the vessel wall, leading to possible in-stent thrombosis. Local drug delivery from stent surfaces represents a means of delivering therapeutic doses of drug directly to the target site. The aim of this study was to elute fluvastatin, which can inhibit vascular smooth muscle cell proliferation, and xemilofiban, which prevents platelet adhesion and aggregation, together in bioactive concentrations from the same copolymer system. Combined elution from thermoresponsive N-isopropylacrylamide (NiPAAm)/N-tert-butylacrylamide (NtBAAm)-derived copolymer systems was achieved using microgels (NiPAAm/NtBAAm 65/35 wt/wt) randomly dispersed in 85/15 matrices. Fluvastatin elution from 5 mm films over a 14-day period showed initial burst release, which leveled off. Of the total incorporated (8.33 ± 0.21 nmol, n=4), 68.5 % was eluted during this period. Xemilofiban release was measured in terms of its ability to inhibit platelet adhesion, using a microfluidic system. To investigate the influence of location and hydrophobicity on elution of bioactivity, three separate systems were employed. While elution of anti-adhesive activity from the system containing xemilofiban-loaded matrices was more dramatic in the short term, a more sustained level of inhibition was achieved when xemilofiban had been incorporated into microgels. All samples investigated for anti-adhesive activity also decreased human coronary artery smooth muscle cell proliferation. Therefore xemilofiban has potential as an agent for preventing in-stent thrombosis. Our study has demonstrated the feasibility of using this novel matrix/microgel system to regulate simultaneous release of both agents in bioactive concentrations.