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

## TL;DR

This study shows that using fusogenic liposomes to deliver metformin and doxorubicin improves breast cancer treatment by reducing tumor growth and metastases while minimizing heart damage.

## Contribution

The novel use of fusogenic liposomes to co-deliver metformin and doxorubicin enhances therapeutic efficacy and safety in breast cancer treatment.

## Key findings

- Liposome-delivered metformin and doxorubicin reduced tumor volume by 87.2% in mice.
- The treatment significantly decreased lung and liver metastases compared to controls.
- Liposomal delivery reduced cardiac arrhythmias from 100% to 40% in treated animals.

## Abstract

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.