Estudo da associação de sinvastatina em lipossomas pH–sensíveis de doxorrubicina na terapêutica do câncer de mama experimental.

Abstract

Doxorubicin (DOX) is a potent chemotherapeutic drug used as the first line in breast cancer treatment; however, cardiotoxicity is the main drawback of the therapy. Preclinical studies evidenced that the association of simvastatin (SIM) with DOX decreases this side effect and deaths from breast cancer. In this work, an unprecedented pH-sensitive liposomal formulation capable of co-encapsulating DOX and SIM at different molar ratios was investigated for its potential breast tumor treatment. Studies of physicochemical characterization of the liposomal formulations were carried out. The cytotoxic effects of DOX and SIM and their combinations at different molar ratios (1:1; 1:2 and 2:1), free or co-encapsulated in pH sensitive liposomes, were evaluated against three human breast cancer cell lines (MDA-MB231; MCF-7 and SK-BR-3) and murine (4T1). Experimental protocols included cell viability, combination index, nuclear morphological changes, and migration capacity. The anti-tumor activity of the SpHL-D-S 1:1 formulation was also investigated in Balb/c mice with 4T1 breast tumor, and compared to the treatments DOX and SIM free and encapsulated in liposomes, as well as the mixture of DOX:SIM in the molar ratio of 1:1. The formulations showed diameter of less than 200 nm with a polydispersity index lower than 0.3. The encapsulation content close to 100% and about 70% for DOX and SIM, respectively. A more pronounced inhibitory effect on breast cancer cell lines was observed for the 2:1 treatments with isolated drugs or in liposomes and 1:1 for the murine. The highest rate of tumor inhibition was observed for treatments with SpHLD-S, SpHL-D and DOX:SIM in relation to the control. The great advantage of treatment with SpHL-D-S was the improvement in the cardiac toxicity profile. While greater vacuolization was observed in the hearts of all DOX-treated animals, less cardiac toxicity was observed for the SpHL-D-S treated animals. Thus, SpHL-D-S allows the co-administration of DOX and SIM and can be considered valuable for the treatment of breast cancer.