ARTERIAL UPTAKE OF BIODEGRADABLE NANOPARTICLES FOR INTRAVASCULAR LOCAL-DRUG DELIVERY - RESULTS WITH AN ACUTE DOG-MODEL

Biodegradable nanoparticles (NP) with a spherical diameter ranging fro m 70 to 160 nm were investigated for potential usefulness for the loca l intraluminal therapy of restenosis, the disease :process responsible for arterial reobstruction following angioplasty. NPs containing a wa ter-insoluble anti-proliferative agent U-86983 (U-86, Pharmacia and Up john, Kalamazoo, MI) were formulated from oil-water emulsions using bi odegradable polymers such as poly(lactic acid-co-glycolic acid) (PLGA) , and specific additives after particle formation, to enhance arterial I:retention using either heparin, didodecylmethylammonium bromide (DM AB), or fibrinogen, or combinations. Femoral and carotid arteries of m ale mongrel dogs were isolated in situ, and were then subjected to a b alloon angioplasty. A NP suspension of a predetermined concentration w as then infused into the artery for various durations. This was follow ed by a 30 min restoration of blood flow through the vessel. The arter ial segments were excised and analyzed for drug levels. From the drug loading of the NP and the drug levels in the artery, the quantity of n anoparticles retained was calculated and expressed as mu g per 10 mg d ry arteries. In general, repeated short infusions of nanoparticle susp ension (15sX4) were two-fold more effective in terms of higher arteria l U-86 levels than a single prolonged infusion (60 s). A single 15 s i nfusion was not significantly different than a 60 s infusion on NP art erial uptake. NPs modified with either DMAB or fibrinogen had about 2. 5-fold higher uptake levels compared to non-modified NPs (39.2+/-2.5 a nd 49.1+/-2.4 vs. 21.5+/-0.6, mu g/10 mg mean+/-s.e., respectively). A comparably enhanced NP uptake was noted with a combined heparin/DMAB modification. Increasing the concentration of NP in infusate from 5 to 30 mg ml(-1) significantly increased arterial NP uptake level (from 2 2.5+/-13.5 to 83.7+/-1.4 mu g/10 mg). Thus, the results support the vi ew that modified nanoparticles along with optimized infusion condition s could enhance arterial wall drug concentrations of agents to treat r estenosis. (C) 1998 Elsevier Science B.V.