DESENVOLVIMENTO TECNOLÓGICO DE NANOPARTÍCULAS DE PLA E PLA-PEG CONTENDO 5-FLUOROURACIL, AVALIAÇÃO DA CITOTOXICIDADE SOBRE CÉLULAS TUMORAIS E FARMACOCINÉTICA PRÉ-CLÍNICA

Abstract

The work involved the preparation, characterization and evaluation of conveying systems for sustained release 5-fluorouracil (5-FU), an antineoplastic agent. 5-FU was encapsulated in polymeric nanoparticles prepared from polymers of polylactic acid (PLA) and polyethylene glycol (PEG) by the technique of double emulsion-solvent evaporation and a factorial design was applied in order to obtain optimal formulations.These nanoparticles were characterized for encapsulation efficiency, mean diameter and size distribution, and in vitro release profile and evaluation of its cytotoxicity on tumor cell lines and preclinical pharmacokinetics. The PLA formulations (formulation 1) and PLA-PEG (formulation 3) were selected for subsequent tests because present the best efficiency results encapsulation and smaller mean diameter. The in vitro release assay performed employing the technique of Franz diffusion cell demonstrated that after 320 h of test, about 55 to 52% of 5-FU was released from the nanoparticle PLA and PLA-PEG, respectively. The release kinetics of 5-FU from nanoparticles was first order, and the release mechanism calculated by Korsmeyer-Peppas model was diffusion and erosion. In the assessment of cytotoxicity on tumor cells HEP-2 was found that PLA nanoparticles had a lower IC50 than the free drug, since there wasn`t statistically significant difference from the values of IC50. Pharmacokinetics parameters of 5-FU were improved by nanoencapsulation. The bioavailability and Cmax, Tmax, T1/2 and distribution volume were significantly increased, while the clearance were decreased. The presence of PEG in nanoparticles didn`t influence the physicochemical and biological parameters evaluated. The overall results demonstrated that PLA and PLA-PEG nanoparticles can be used as potential drug delivery systems for the treatment of solid tumors.