Formulation and characterization of biodegradable nanoparticles for intravascular local drug delivery

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Various drug-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) were prepared using an emulsification/solvent evaporation technique. Different emulsion systems were employed according to the solubility of individual drugs so that an optimal drug incorporation efficiency and release profile were achieved for a variety of model compounds. Bovine serum albumin was studied as a model protein. Several specific Pharmacia and Upjohn drugs, U-86983, U-61431F, and U-74389G, as well as dexamethasone were tested because of our interest in intravascular drug delivery for the prevention of post-angioplasty restenosis. Drug loading in nanoparticles ranged from 10% to 30%. Typical particle size ranged from 60–200 nm with 85% of the particles in the range of 70–165 nm. The in vitro release rate for albumin was dependent upon the molecular weight (MW) of PLGA. Low MW (58 000) PLGA resulted in much faster BSA release than that of high MW (102 000) PLGA over 7 weeks. Cross-linking on the NP surface reduced the rate of drug release. Nanoparticle uptake by the arterial wall was evaluated by an ex vivo model utilizing freshly explanted dog carotid arteries. It was demonstrated that about 26% of the infused NP was initially retained by the intravascular matrix. A fraction (about 20%) of the initially retained NP remained in the arterial tissue 30 min or more after the end of the infusion. Nanoparticles with smaller mean size (100 nm vs. 266 nm) and lower drug loading (13.1% vs. 20.7%) resulted in higher arterial uptakes compared to nanoparticles of larger size and higher drug loadings. Sterilization of the drug-loaded nanoparticles by γ-irradiation at 2.5 Mrad dose showed no adverse effect on particle size, drug release behavior as well as ex vivo arterial uptake of the nanoparticles. In conclusion, this study demonstrated that a wide variety of water soluble and insoluble bioactive agents can be incorporated into PLGA nanoparticles with a high efficiency and adjustable drug loadings. By choosing the composition and the molecular weight of the polymeric matrix, the drug release kinetics from the nanoparticles can be controlled. Drug-loaded PLGA nanoparticles show great potential in intravascular local drug delivery.