Abstract
Combination therapy offers a promising strategy for treating cancer. Research shows that using drug combinations can improve effectiveness against tumors. However, the potential enhancement of adverse effects remains a major concern. The association of statins with anticancer agents has been shown to improve anticancer therapy outcomes and reduce toxicity. This study investigated a pH-sensitive liposomal formulation coencapsulating doxorubicin (DOX) and simvastatin (SIM), referred to as SpHL-D-S, at various molar ratios (DOX:SIM, 1:1, 1:2, and 2:1) for its potential in treating breast tumors. The drug combination at a 1:1 ratio had more significant cytotoxicity than DOX alone on 4T1 breast cancer cell inhibition, with lower IC50 values, and demonstrated a synergistic effect across all concentrations tested. In vivo cardiotoxicity study revealed that 1:1 SpHL-D-S attenuated the short-term cardiotoxic effects of DOX. The antitumor efficacy of the 1:1 ratio, using either the free or encapsulated form, was evaluated in BALB/c mice with 4T1 breast tumors. No significant difference in tumor volume was observed between the SpHL-D-S and DOX:SIM groups after 8 days of treatment. However, the use of SpHL-D-S demonstrated a significant advantage, notably reducing toxicity. Additionally, SpHL-D-S treatment provided important protection for SIM against cardiac and hepatic disorders. In all mice, free DOX promoted cell vacuolization in the heart, which was reduced in animals receiving SpHL-D-S. These findings suggest that the coencapsulation of DOX and SIM in pH-sensitive liposomes may enhance the safety of breast cancer treatment.