Synergistic in vivo anticancer effects of 1,7-heptanediol and doxorubicin co-loadedliposomes in highly aggressive breast cancer

Breast cancer holds the highest incidence rate among women. Doxorubicin (DOX) is a potent frontline drug for the treatment of breast cancer. The anticancer mechanisms of DOX include inducing immunogenic cell death in tumor cells, causing damage to tumor DNA, and generating free radicals. However, its pharmacological efficacy and wide use are restricted by its substantial dose-dependent side effects. We have recently revealed that 1,7-Heptanediol (1,7-Hept) severely impairs the bioenergetics and metabolism of aggressive human cancer cells. In the present work, we prepared liposomes co-loaded with DOX and 1,7-Hept (DOX/1,7-Hept-lipo) and assessed their potential synergistic anti-tumor effects. In vitro studies demonstrated that 4T1 cells (the mouse breast cancer cell) exhibited higher sensitivity to 1,7-Hept and DOX/1,7-Hept-lipo could induce ICD of 4T1 cells. Cell viability was markedly reduced when 4T1 cells were treated with a combination of DOX and 1,7-Hept. In a mouse breast cancer model, the DOX/1,7-Hept-lipo exhibited superior anti-tumor efficacy compared to liposomes loaded with individual drugs, resulting in almost total elimination of the tumors at lower doses of DOX with reduced systemic toxicity. Notably, the number of immune cells significantly increased in the tumor microenvironment, and macrophages were more transformed into the anti-tumor M1 phenotype. Our findings suggest strong synergistic anti-tumor effects of DOX and 1,7-Hept, enhancing the efficacy of tumor immunotherapy and mitigating the toxic side effects of DOX.