LOCAL-DELIVERY OF PLATELETS WITH ENCAPSULATED ILOPROST TO BALLOON INJURED PIG CAROTID ARTERIES - EFFECT ON PLATELET DEPOSITION AND NEOINTIMA FORMATION

Local delivery of a drug to the arterial wall during angioplasty is an approach which might reduce the incidence of occlusive events such as thrombosis and restenosis, without the risk of systemic side effects. By exploiting their natural primary haemostatic properties, platelets , with encapsulated drugs, can be targeted to a vessel wall injury sit e and act as a depot for sustained release. The platelet plasma membra ne can be reversibly permeabilised by high voltage, short duration ele ctrical pulses (electroporation). Drugs will diffuse into porated plat elets and become trapped on resealing. We have studied the effects of autologous platelets, electroloaded with the stable prostacyclin analo gue, iloprost, on platelet deposition and neointima formation in a pig carotid angioplasty model. Iloprost loaded or control platelets were delivered locally and immediately to the balloon injured site using a double balloon delivery catheter. Acute platelet deposition was measur ed using (111)-Indium, and neointima formation at 21 days post angiopl asty was assessed by morphometric analysis. In pigs treated with ilopr ost loaded platelets, platelet deposition on the artery at 2 hours pos t injury was dramatically reduced (to approximately monolayer coverage ), when compared with arteries from pigs treated with control platelet s. In pigs with deeply injured arteries, i.e. with extensively rupture d internal elastic lamina (IEL), platelet deposition was reduced by 88 % compared with control arteries (118 +/- 20 x 10(6)/cm vs. 14 +/- 2 x 10(6)/cm, means +/- SE, 2P < 0.001). In minimally injured arteries (I EL intact) a 65% reduction in platelet deposition was observed (55 +/- 24 x 10(6)/cm vs. 19 +/- 3 x 10(6)/cm, 2P < 0.002). A high concentrat ion of free iloprost, delivered to the angioplasty site, with control platelets, had far less effect on platelet deposition, substantiating the advantage of platelet encapsulation. At 21 days post injury, morph ometry of the carotid arteries after treatment with iloprost loaded pl atelets showed significant reductions in intimal area and intimal/medi al ratios in minimally injured vessels (P < 0.05) as compared with ves sels from pigs treated with control platelets. With deeply injured ves sels, the mean differences (control vs. treated) for the same morphome tric parameters were not significant. This novel approach of electro-e ncapsulating drugs within autologous platelets, and using them as high ly biocompatible and biodegradable drug targeting vehicles might, with the appropriate choice of encapsulated agent, have potential for redu cing the incidence of occlusion after angioplasty and thrombolysis pro cedures.