Avaliação da atividade antitumoral de lipossomas fusogênicos contendo doxorrubicina e metformina coadministrados em camundongos portadores do tumor de mama.

Abstract

Cancer is a complex and multifaceted disease with high incidence and mortality rates worldwide. Among the most common types, breast cancer stands out, which has the problem of great heterogeneity, making treatment difficult and chemotherapy is often necessary. Doxorubicin (DOX) is widely used for the treatment of breast cancer, due to its high efficacy and success rate, but it has significant adverse effects, especially cardiotoxicity. Metformin (MET) is a hypoglycemic agent that has been studied for anticancer therapy because it exerts important activities, such as reducing circulating glucose and reducing reactive oxygen species, and can help as an adjuvant to treatment with conventional drugs. These drugs can also be encapsulated in lipid nanosystems such as liposomes, to prolong circulation time, increasing their bioavailability in the tumor environment. Liposomes are nanostructures biocompatible to the body, formed by a bilayer of phospholipids, capable of encapsulating lipophilic and hydrophilic substances. In this work, liposomes containing Metformin (Lip-MET) and Liposomes encapsulating Doxorubicin (Lip-DOX) were prepared by the lipid film hydration method and consisting of Dioleoylphosphatidylethanolamine (DOPE), Cholesteryl hemisuccinate (CHEMS) and distearoyl-phosphatidylethanolamine-N-polyethylene glycol2000 (DSPE-PEG2000). The prepared liposomes were evaluated for average diameter, zeta potential, encapsulation efficiency, and release profile. Furthermore, the antitumor activity of the co-administration of liposomes containing DOX and MET was also evaluated in an experimental model of murine breast cancer (4T1). The liposomes had a size of around 120 nm, zeta potential close to neutrality (- 5 mV), encapsulation efficiency close to 100% for DOX and 10% for MET. The evaluation of the variation in the tumor volume of the animals demonstrated that the association of DOX and MET in their encapsulated forms was able to control tumor growth more efficiently than the other treatment groups. Additionally, hematological and biochemical parameters demonstrated that treatment with Lip-DOX + Lip-MET did not present significant toxicity in addition to reducing ventricular or atrial extrasystole effects. Therefore, liposomes containing DOX and MET constitute a promising alternative for the treatment of breast cancer.