Summary
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
site and act as a depot for sustained release. The platelet plasma membrane can be
reversibly permeabilised by high voltage, short duration electrical pulses (electroporation).
Drugs will diffuse into porated platelets and become trapped on resealing. We have
studied the effects of autologous platelets, electroloaded with the stable prostacyclin
analogue, 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 measured using 111-Indium, and neointima formation at 21 days post angioplasty was assessed by morphometric
analysis. In pigs treated with iloprost loaded platelets, platelet deposition on the
artery at 2 hours post injury was dramatically reduced (to approximately monolayer
coverage), when compared with arteries from pigs treated with control platelets. In
pigs with deeply injured arteries, i.e. with extensively ruptured internal elastic
lamina (IEL), platelet deposition was reduced by 88% compared with control arteries
(118 ± 20 X 106/cm vs. 14 ± 2 X 106/cm, means ± SE, 2P <0.001). In minimally injured arteries (IEL intact) a 65% reduction
in platelet deposition was observed (55 ± 24 X 106/cm vs. 19 ± 3X 106/cm, 2P <0.002). A high concentration 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, morphometry of the
carotid arteries after treatment with iloprost loaded platelets showed significant
reductions in intimal area and intimal/medial ratios in minimally injured vessels
(P <0.05) as compared with vessels from pigs treated with control platelets. With
deeply injured vessels, the mean differences (control vs. treated) for the same morphometric
parameters were not significant.
This novel approach of electro-encapsulating drugs within autologous platelets, and
using them as highly biocompatible and biodegradable drug targeting vehicles might,
with the appropriate choice of encapsulated agent, have potential for reducing the
incidence of occlusion after angioplasty and thrombolysis procedures.
