Estudos in vitro e in vivo de lipossomas contendo gadolínio-159 para o tratamento do câncer

Abstract

In Brazil, estimates of new cancer cases, valid for the years 2010 and 2011 show that the disease will be responsible for the deaths of about 500,000 people. As an alternative therapythe radiotherapy technique, widely used in treating various types of tumors, act indiscriminate tumoral and healthy cells. Seeking to minimize these effects, nanostructured carriers containing radioisotopes, such as liposomes, have been studied with the aim of improving the specificity of action of ionizing radiation, delivering and retaining adequate amounts of radioactive material in tumor cells, leading them to death. In this context, the present study, we prepared liposomes stealth pH-sensitive metal complex containing the radioactive 159Gd-DTPA-BMA (159Gd-SpHL) aiming to study in vitro and in vivo its effects in cancer treatment. The vesicles showed encapsulation rate of about 20%, average diameter of 100 nm and low release kinetics of radioactivity in biological media. The formulation was characterized through physic-chemical and morphological studies and the results revealed a low polydispersity index and negative Zeta potential. We studied in vitro and in vivo its action against the cells of Ehrlich tumor models and RT2 (rat glioma). The results of in vitro studies showed that the complex has significant radioactive cytotoxicity against the cells of two of the three models studied and that, being encapsulated in liposomes, the cytotoxicity was greatly enhanced. Additionally, we investigated the involvement of caspase-3 protein in Ehrlich and RT2 cell death. The results suggest that the main mechanism involved in the cytotoxic action of radioactive complex is related to apoptosis. The results of in vivo studies showed that liposomes containing 159Gd-DTPA-BMA accumulated significantly in Ehrlich solid tumor in mice. Aiming to improve this uptake, we prepared pH-sensitive liposomes coated with folate containing the same radioactive complex (159Gd-FTSpHL). The results revealed an increase of about three times the tumor uptake. However, we observed that the two formulations were also significantly accumulated in the liver and spleen. Therefore, studies were conducted biochemical and hematological, which revealed acute changes in hepatocytes and transient bone marrow. To study the antitumor activity, tumor-bearing Swiss mice solid Ehrlich received three doses of 159Gd-SpHL and three levels of 159Gd-FTSpHL (each dose = 236mg/kg). The treatment inhibited the increase in the volume of tumors compared with animals treated with NaCl (0.9% w/v). There was also inhibition of body mass gain and an increased survival of animals studied. Considering all results, the pH-sensitive liposomes containing the radioactive complex 159Gd-DTPA-BMA can be considered a potential therapeutic agent for cancer