Sustained Intramural Retention and Regional Redistribution Following Local Vascular Delivery of Polylactic-Coglycolic Acid and Liposomal Nanoparticulate Formulations Containing Probucol.

Abstract

BACKGROUND: Probucol reduces restenosis after angioplasty, provided oral administration is begun 1 month before the procedure. Local vascular delivery of a nonoparticulate formulation of probucol may obviate the need for drug loading by acutely raising arterial intramural concentration while providing sustained intramural retention. To test this hypothesis, we compared the retention and redistribution of (35)S-probucol encapsulated in either liposomal or polylactic-coglycolic acid (PLGA) nanoparticles after local vascular delivery. METHODS: Nanoparticles were delivered using a Crescendo microporous infusion catheter (Cordis, Warren, NJ) after balloon angioplasty of rabbit iliac arteries (n = 12-18 arteries per formulation per time point). Animals were euthanized on day 0, 3, or 7 after delivery. Iliac arteries, perivascular fat, and downstream tissues were harvested and the radioactivity disintegrations per minute was measured. Autoradiographic and confocal microscopic analyses of tissue sections were performed to evaluate intramural distribution of probucol. RESULTS: Immediately after delivery, radioactivity in the iliac arteries (log[dpm/mg], mean +/- SEM) was greater with PLGA (2.72 +/- 0.08) than with liposomal encapsulation (2.10 +/- 0.08, P = 0.001). Intramural retention of probucol was 23% at 7 days using liposomes and 10% using PLGA, corresponding to a probucol concentration of 0.1 ng/mg tissue for both formulations. By the third day after delivery, radioactivity in peri-iliac fat, femoral arteries, and hindlimb muscle increased by 88%, 29%, and 154%, respectively. Thereafter, radioactivity decreased to 56%, 43%, and 134% of initial dpm respectively, by day 7. CONCLUSIONS: although delivery efficiency was superior with PLGA encapsulation, intramural probucol concentrations were similar on day 7 using both formulations. Radial and axial redistribution of probucol was observed, indicating that this technique can be exploited to increase adjacent tissue delivery.