Atividade antitumoral e toxicidade de nanocÃpsulas contendo o Ãcido fumarprotocetrÃrico isolado dec(lÃquen)

AUTOR(ES)
DATA DE PUBLICAÇÃO

2004

RESUMO

The potential of controlled release in optyimizing drug targeting has offered a tremendous advancement in the manipulation of novel dosage forms such as nanoparticles, wich are solid colloidal polymeric carriers in size range of 1-1,000 nm. Oil-in-water microemulsions as a drug delivery system include improvement of drug solubilization. The fumarprotocetraric acid, a β-orcinol depsidone, is obtained from Cladonia verticillaris and its antibacterial, antimycobacterial and antitumor activities had been evaluated. The main purpose of this work is to investigate the cytotoxicity, toxicity and antitumor activity of free and fumarprotocetraric acid (FPA) encapsulated into PLGA-nanocapsules prepared by interfacial deposition of a pre-formed copolymer method. The physicochemical and stability parameters of the nanocapsules were also investigated. The cytotoxic effect of FPA on different forms, free (FPA) and encapsulated with and without oil-in-water microemulsion (FPA-NC and FPA-NC/ME), respectively, was evaluated on human lung cancer (NCI-H 292) and larynx epidermoid carcinoma (HEp-2) cells line cultured in MEM (Minimum Essential Medium). The toxicity was analized on Swiss mice with a daily treatment for 8 weeks. After treatment, animals were sacrificed and their organs (liver, kidneys, and spleen) were submitted to histopathological analysis. The analysis of the antitumor activity was assessed against solid tumor Sarcoma 180 in Swiss mice, and was estimated by the tumor inhibition. Results showed that the encapsulation efficiency of the fumarprotocetraric acid into PLGA-nanocapsules in different carriers was 49.5% (FPA-NC) and 86.2% (FPA-NC/ME), respectively. The kinetic profile of FPA from nanocapsule-microemulsion formulation presented a gradual augmentation of the drug release, achieveing 40.8% at a 4 hours. The viability of NCI-H 292 cells treated with FPA, NC and FPA-loaded nanocapsules was maintained even at 50 μg.mL-1. In contrast, the cell treatment with o/w microemulsion (ME) or FPA-ME promoted a high cytotoxicity at 6.25 μg.mL-1 (25% cell viability). Concerning HEp-2 cells, their viability was preserved after treatment with FPA, NC or FPA-NC even at 50 μg.mL-1. Results showed that FPA have no cytotoxic effects on NCI-H 292 or HEp-2 cells, and FPA-loaded nanocapules have no cytotoxic effect on NCI-H 292 cells. In contrast, the o/w microemulsion exhibited a high cytotoxicity on both cells. No behavioral alterations were observed in animals during the toxicity assay of FPA formulations. No statiscally significant difference in body weight was detected for animals treated with free and encapsulated FPA in relation to the control group. However the treatment with FPA encapsulated in NC/ME promoted pronounced injuries in liver and kidneys of animals. Cellular and renal tubules necroses were detected in kidneys. The antitumor activity promoted by free FPA, unloaded-nanocapsules and FPA-loaded nanocapsules evaluated on Sarcoma 180-bearing mice promoted 61.4% of tumor inhibition when compared with free FPA (58.9%) in relation to the control group. Results showed that encapsulation of fumarprotocetraric acid into PLGA-nanocapsules can be a potential alternative to allow in a diversity of therapeutical applications. The nanoencapsulation with microemulsion can therefore be considered as a potential alternative to improve solubilization of lichens metabolites, such as fumarprotocetraric acid. However microemulsions prepared with Cremophor exhibited a substancial in vitro and in vivo toxicity

ASSUNTO(S)

tÃxico fumarprotocetrÃrico antitumoral antitumoral bioquimica

Documentos Relacionados