Arterial uptake of biodegradable nanoparticles for intravascular local drug delivery: results with an acute dog model.
Biodegradable nanoparticles (NP) with a spherical diameter ranging from 70 to 160 nm were investigated for potential usefulness for the local intraluminal therapy of restenosis, the disease process responsible for arterial reobstruction following angioplasty. NPs containing a water-insoluble anti-proliferative agent U-86983 (U-86, Pharmacia and Upjohn, Kalamazoo, MI) were formulated from oil-water emulsions using biodegradable polymers such as poly(lactic acid-co-glycolic acid) (PLGA), and specific additives after particle formation, to enhance arterial retention using either heparin, didodecylmethylammonium bromide (DMAB), or fibrinogen, or combinations. Femoral and carotid arteries of male mongrel dogs were isolated in situ, and were then subjected to a balloon angioplasty. A NP suspension of a predetermined concentration was then infused into the artery for various durations. This was followed by a 30 min restoration of blood flow through the vessel. The arterial segments were excised and analyzed for drug levels. From the drug loading the NP and the drug levels in the artery, the quantity of nanoparticles retained was calculated and expressed as microgram per 10 mg dry arteries. In general, repeated short infusions of nanoparticle suspension (15 s x 4) were two-fold more effective in terms of higher arterial U-86 levels than a single prolonged infusion (60 s). A single 15 s infusion was not significantly different than a 60 s compared to non-modified NPs (39.2 +/- 2.5 and 49.1 +/- 2.4 vs. 21.5 +/- 0.6 micrograms/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 22.5 +/- 3.5 to 83.7 +/- 1.4 micrograms/10 mg). Thus, the results support the view that modified nanoparticles along with optimized infusion conditions could enhance arterial wall drug concentrations of agents to treat restenosis.
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Department of Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, USA. levyr@email.chop.edu
Labhasetwar
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Underwood
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Levy
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D000800:Angioplasty, Balloon; D000818:Animals; D001158:Arteries / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D001672:Biocompatible Materials / Q000737:chemistry; D001673:Biodegradation, Environmental; D002867:Chromones / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D003327:Coronary Disease / Q000517:prevention & control; D004195:Disease Models, Animal; D004285:Dogs; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000187:drug effects; D005340:Fibrinogen / Q000032:analysis / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000032:analysis / Q000494:pharmacology; D006493:Heparin / Q000032:analysis / Q000494:pharmacology; D007261:Infusions, Intra-Arterial; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D009025:Morpholines / Q000008:administration & dosage / Q000032:analysis / Q000627:therapeutic use*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011108:Polymers / Q000737:chemistry; D011183:Postoperative Complications / Q000517:prevention & control
D001672:Biocompatible Materials; D002867:Chromones; D005343:Fibrinolytic Agents; D009025:Morpholines; D011108:Polymers; C090113:U 86983; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D005340:Fibrinogen; D006493:Heparin