Avaliação da toxicidade de lipossomas contendo doxorrubicina e lipossomas contendo metformina coadministrados em modelo experimental.

Abstract

Breast cancer is the second most common type in the world and the most common among women, and its incidence has been increasing over time, making it the second leading cause of death related to cancer. Chemotherapy therapy can often cause high toxic effects, therefore, therapeutic innovations are sought to treat this disease in an attempt to minimize adverse effects. In this context, the use of liposomes has shown promise. These systems have an amphiphilic nature, high biocompatibility and biodegradability. Doxorubicin (DOX) is a drug widely used in oncology treatments, and despite being effective in the treatment and control of some types of tumors, this drug causes drastic effects on the patient's myocardial cells and can also generate toxicity in other organs such as the spinal cord. bone and liver. Currently, another drug that has been investigated in the treatment of breast cancer for combined therapy is metformin (MET), which can exert synergistic effects with DOX in terms of antitumor activity, in addition to contributing to the mitigation of the toxic effects of DOX. Given the above, the purpose of the present study was to investigate the safety of combined treatment between DOX and MET encapsulated in liposomes. In this work, metformin liposomes (Lipo-MET) and doxorubicin liposomes (Lipo-DOX) were prepared using the lipid film hydration method. The liposomes were characterized in terms of average diameter, zeta potential and encapsulation efficiency. Furthermore, hemocompatibility and stability studies in the presence of different biological media were carried out, as well as the assessment of acute systemic toxicity in an experimental model. The liposomes had a size of around 120 nm, zeta potential close to neutrality (- 5 mV), encapsulation efficiency close to 100% for DOX and close to 10% for MET. The Lipo-MET system proved to be hemocompatible and the Lipo-MET and Lipo-DOX systems were stable in the presence of different biological environments, encouraging in vivo studies. Toxicity studies demonstrated that coadministration of Lipo-DOX + Lipo-MET significantly reduced systemic toxicity effects. On the other hand, the administration of Lipo-MET at a dose of 80 mg/kg together with Lipo-DOX may have contributed to the reduction of tissue changes characteristically induced by DOX, however a more detailed analysis of the electrocardiographic findings is necessary to verify occurrences of changes in cardiac electrophysiology that may reveal signs of cardioprotection obtained by the formulations in this study. Given the above, Lipo-DOX and Lipo-MET may be a promising idea for formulations for the treatment of breast cancer, with reduced systemic toxicity of the drugs.