LOCAL-DELIVERY OF BIODEGRADABLE MICROPARTICLES CONTAINING COLCHICINE OR A COLCHICINE ANALOG - EFFECTS ON RESTENOSIS AND IMPLICATIONS FOR CATHETER-BASED DRUG-DELIVERY

Objectives. This study sought to evaluate the delivery efficiency, int ramural retention and antirestenotic efficacy of soluble colchicine or a colchicine analogue delivered into the arterial wall after angiopla sty as well as the efficacy of these medications after prolonged local release from biodegradable microparticles. Background. Local delivery of pharmacologic agents is a potential treatment for restenosis. Howe ver, the delivery efficiency of the technique and the choice of agent to modulate cellular proliferation are unknown. It was hypothesized th at restenosis would be unaffected by colchicine or a hydrophobic colch icine analogue with short intramural retention, whereas it would be re duced after prolonged local release. Methods. Rabbit atherosclerotic f emoral arteries underwent angioplasty followed by local delivery. Deli very efficiency and intramural retention of H-3-colchicine were evalua ted. The effect of agents in soluble formulation or released from micr oparticles on angiographic and morphometric restenosis was evaluated a t 2 weeks and compared with that in the control groups (angioplasty on ly and local infusion of carrier solution). Results. Delivery efficien cy was 0.01% and intramural retention <24 h. Neither soluble colchicin e formulation reduced restenosis. Microparticles releasing the colchic ine analogue reduced restenosis compared with control and colchicine m icroparticles but not angioplasty alone (p = 0.002). Delivery outside the artery was observed, and the long-term release of both colchicines resulted in toxicity to the adjacent musculature. Conclusions. Colchi cine or the colchicine analogue did not reduce restenosis, although th e long-term local release of the colchicine analogue reduced neointima l proliferation resulting from local delivery. Local delivery of cytot oxic agents with insufficient vascular specificity may be limited by t oxicity to adjacent tissues resulting from a larger than expected deli very area and prolonged agent retention.