Lipossomas fusogênicos de circulação prolongada contendo glicoevatromonosídeo com as hidroxilas da glicose peracetiladas: preparo, caracterização, avaliação do potencial citotóxico e antitumoral

Abstract

Cancer is an important public health problem, being the second cause of death in the world. Chemotherapy is the most commonly used cancer treatment modality. However, most antineoplastic agents cause innumerable toxic effects, which makes it necessary to search for new therapeutic strategies. Epidemiological evidence has led to the initiation of the investigation of the cytotoxic activity of cardenolides, and in view of their differentiated effect on healthy cells, this class has been widely studied regarding the possibility of use in the treatment of cancer. The aim of this study was to search for an alternative for the cancer treatment, by means of the synthesis of glucoevatromonoside with peracetylated glucose hydroxyl groups (GEVPG), which has high lipophilicity, allowing its entrapment in long-circulating and pH-sensitive liposomes (SpHLGEVPG). The mean diameter of the vesicles was of 182.2 ± 2.7 nm, the polydispersity index was equal to 0.36 and the zeta potential close to neutrality, allowing the application of this formulation for in vivo studies. The liposomes encapsulated GEVPG content was equal to 75,0 ± 7,0%. The evaluation of the storage stability of the liposomes at 4 ° C confirmed the maintenance of the physical chemical characteristics of the formulation for at least 30 days. pH-sensitivity studies of the liposomal formulation containing GEVPG showed a reduction of the sensitivity when submitted to acid pH, which can be explained by the alteration of the lipid bilayer structure by the GEVPG. The cytotoxic activity of liposomes containing cardenolide against three different human breast tumor cell lines (triple negative breast cancer MDA-MB-231, ER positive MCF-7 and HER 2 positive SKBR3) and human non-small cell lung cancer cells (A549) was evaluated by the Sulforhodamine B assay and demonstrated a high cytotoxic potential. In addition, the cytotoxic activity of liposomes was evaluated in nontumor human fibroblasts. SpHL-GEVPG was selective for tumor cells relative to human non-tumor cells. Long-term in vitro studies have confirmed that SpHL-GEVPG decrease the growth capacity of surviving tumor cells after treatment, as well the formation of colonies from these cells. The evaluation of antitumoral efficacy of the treatment with SpHL-GEVPG using Balb/c nude female mice bearing A549 tumor showed that the treatment with SpHL-GEVPG at doses 1.0 and 2.0 mg / kg had similar capacity at dose of paclitaxel at the 10 mg / kg dose, to inhibit lung tumor growth. Considering the above, SpHL-GEVPG is a promising formulation for the treatment of breast and lung cancer, since it allowed the systemic administration of GEVPG, demonstrated high cytotoxic potential and selectivity, antitumor activity similar to paclitaxel and absence of signs toxicity from a preliminary study.