FORMULATION AND CHARACTERIZATION OF BIODEGRADABLE NANOPARTICLES FOR INTRAVASCULAR LOCAL-DRUG DELIVERY

Various drug-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP) were prepared using an emulsification/solvent evaporation techni que. Different emulsion systems were employed according to the solubil ity of individual drugs so that an optimal drug incorporation efficien cy 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 70-16 5 nm. The in vitro release rate for albumin was dependent upon the mol ecular weight (MW) of PLGA. Low MW (58 000) PLGA resulted in much fast er 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. Nanoparti cle uptake by the arterial wall was evaluated by an ex vivo model util izing freshly explanted dog carotid arteries. It was demonstrated that about 26% of the infused NP was initially retained by the intravascul ar matrix. A fraction (about 20%) of the initially retained NP remaine d 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 dr ug loading (13.1% vs. 20.7%) resulted in higher arterial uptakes compa red to nanoparticles of larger size and higher drug loadings. Steriliz ation of the drug-loaded nanoparticles by gamma-irradiation at 2.5 Mra d dose showed no adverse effect on particle size, drug release behavio r as well as ex vivo arterial uptake of the nanoparticles. In conclusi on, this study demonstrated that a wide variety of water soluble and i nsoluble bioactive agents can be incorporated into PLGA nanoparticles with a high efficiency and adjustable drug loadings. By choosing the c omposition 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 d elivery.