Metformin-Loaded Fusogenic Liposome Improves the Therapeutic Efficacy and Safety of Doxorubicin in a Breast Cancer Treatment

Breast cancer is a tumor with high incidence and mortality rates worldwide. Chemotherapeutic treatment consists of the systemic use of anticancer agents such as Doxorubicin (DOX). Recently, Metformin (MET), an antidiabetic drug, has been studied as an adjuvant in cancer treatment due to its action on proteins that regulate cell proliferation. DOX and MET have distinct drug distribution and pharmacokinetic parameters. Thus, strategies to equalize the delivery of these drugs to tumor tissue have been developed. In this context, liposomes are a promising alternative for increasing the effectiveness of cancer treatment with DOX and MET. This study aimed to prepare, characterize, and evaluate the antitumor activity of fusogenic liposomes containing DOX or MET. The liposomes were prepared by the Bangham method and characterized physicochemically. The prepared nanosystems (Lip-MET and Lip-DOX) showed diameters of approximately 120 nm, polydispersity index lower than 0.3, zeta potential close to neutrality, and drug encapsulation content of 98.8% ± 18.7 for Lip-DOX and 10.1% ± 0.5 for Lip-MET. To evaluate the antitumor activity, 4T1 breast tumor-bearing mice were used as a model. Once the tumor reached ∼100 mm³, mice received four administrations (on days 1, 3, 5, and 7), each containing 5 mg/kg of DOX and 15 mg/kg of MET. A significant decrease in tumor volume was observed in animals treated with Lip-DOX + Lip-MET, compared to the other groups, evidenced by a tumor growth inhibition rate of 87.2%. It is also noteworthy that the Lip-DOX + Lip-MET treatment resulted in a significant decrease in lung and liver metastases. In these animals, 1-3 foci of lung metastases were observed, compared to control animals that reached 7-10 foci. In addition, 100% of the animals treated with free DOX presented arrhythmias, while only 40% of the animals treated with Lip-DOX + Lip-MET presented these cardiac alterations. Therefore, the coadministration of liposomes loading DOX and MET showed promise for increasing antitumor activity and safety in breast cancer treatment.