Desenvolvimento de formulação lipossomal contendo alfa-succinato de tocoferila e doxorrubicina e investigação da eficácia antitumoral e toxicidade

Abstract

Doxorubicin plays an important role in breast cancer treatment. However, cardiotoxicity and low penetration in solid tumors are some limitations of its use. The encapsulation of doxorubicin in liposomes allowed the reduction of adverse effects, although it did not bring benefits in antitumor efficiency when compared to free drug. pH-sensitive liposomes containing associations of antitumor agents may be a strategy to improve the efficiency of drug delivery at cellular level and thus improving its antitumor efficiency. In the present work, pH-sensitive liposomes containing alpha -tocopheryl succinate and doxorubicin (pHSL-TS-DOX) were developed and their biological behavior in an experimental model of breast tumor was compared with a formulation already used in the clinic. Spherical vesicles of homogeneous content with an average diameter of less than 200 nm, monodisperse, with zeta potential close to neutrality, encapsulation content above 90% and stable for up to 30 days were obtained. The formulation showed a controlled release at pH 7.4 and a high release rate at pH 5.0, given its pH-sensitivity, also proven by Small-angle X-ray scattering. In in vitro studies, a higher rate of cell uptake of doxorubicin was observed from the developed formulation, which allowed more advanced levels of apoptosis and block of the cell cycle than the commercial formulation. pHSL-TS-DOX reached a lower plasma concentration of doxorubicin in healthy animals, however, in animals bearing tumor, there was a greater accumulation doxorubicin inside the tumor, which may justify its better performance in studies of antitumor activity. This formulation proved to be safe, since it conferred cardiac and liver protection and did not induce considerable weight loss or myelosuppression. Therefore, considering the obtained results, pHSL- TS-DOX is a potential alternative for the treatment of breast cancer.