Emprego de lipossomas pH-sensíveis de circulação prolongada contendo cisplatina e paclitaxel como alternativa para o tratamento de tumores de mama.

Abstract

Breast cancer is a neoplasia that presents the highest incidence and mortality rate in women worldwide, among them the triple negative breast cancer is the most aggressive showing a worse prognosis. Paclitaxel (PTX) and cisplatin (CDDP) have shown high antitumor activity against triple negative breast tumor cells. Studies have shown that co-administration of PTX and CDDP in nanosystems can generate synergistic effects against neoplastic cells in addition to reducing the occurrence of side effects. The purpose of this study was to evaluate, by in vitro and in vivo assays, the PTX and CDDP encapsulated into pH-sensitive and long-circulating liposomes (SpHL), at a molar ratio PTX:CDDP of 1:3, aiming to improve antitumor activity and reduce adverse effects. Liposomal formulations content PTX and CDDP, previously developed, were optimized with respect to the preparation method and encapsulation content. The formulations had their cytotoxic activity evaluated against human (MDA-MB-231 cells) and murine (4T1 cells) triple-negative breast cancer. The synergism study was conducted with the 4T1 cell line demonstrating antagonistic effect when the cells were treated with free PTX and CDDP drugs (1:3 molar ratio, respectively), while treatment with the liposomal formulations resulted in a synergistic effect. For the study of antitumor activity and toxicity, 4T1 tumor-bearing female BALB/c mice received, intravenously, the SpHL-PTX and SpHL-CDDP or PTX and CDDP free at respective doses 7.5 mg/kg and 8.0 mg/kg (molar ratio 1:3). Treatment with a single dose significantly reduced tumor growth in both treated groups compared to the control group. No significant variation in the body weight was observed during the experimental period. A mortality rate of 28% was observed in the group that received the free drugs, while 100% survival was detected in the group treated with the liposomal formulations. Metastatic sites in the lung were observed only in the control group. Hematological toxicity characterized by leukopenia and thrombocytopenia was evident only in animals receiving the free drugs. In addition, an increase in urea/creatinine ratio, suggestive of early-stage renal toxicity, was detected in this group. On the other hand, all hematological and biochemical parameters of the animals treated with the liposomal formulations were similar to the control group. These results indicated a potentiation of antitumor effect and reduction of toxicity when CDDP and PTX were administered in liposomes, demonstrating the potential of coadministration of these systems for the treatment of breast tumors.