Remodeling tumor microenvironment by liposomal co-delivery of DMXAA and simvastatin inhibits malignant melanoma progression

Anti-angiogenic therapies for melanoma have not yet been translated into meaningful clinical benefit for patients, due to development of drug-induced resistance in cancer cells, mainly caused by hypoxia-inducible factor 1α (HIF-1α) overexpression and enhanced oxidative stress mediated by tumor-associated macrophages (TAMs). Our previous study demonstrated synergistic antitumor actions of simvastatin (SIM) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) on an in vitro melanoma model via suppression of the aggressive phenotype of melanoma cells and inhibition of TAMs-mediated angiogenesis. Therefore, we took the advantage of long circulating liposomes (LCL) superior tumor targeting capacity to efficiently deliver SIM and DMXAA to B16.F10 melanoma in vivo , with the final aim of improving the outcome of the anti-angiogenic therapy. Thus, we assessed the effects of this novel combined tumor-targeted treatment on s . c . B16.F10 murine melanoma growth and on the production of critical markers involved in tumor development and progression. Our results showed that the combined liposomal therapy inhibited almost totally the growth of melanoma tumors, due to the enhancement of anti-angiogenic effects of LCL-DMXAA by LCL-SIM and induction of a pro-apoptotic state in the tumor microenvironment (TME). These effects were favoured by the partial re-education of TAMs towards a M1 phenotype and maintained via suppression of major invasion and metastasis promoters (HIF-1α, pAP-1 c-Jun, and MMPs). Thus, this novel therapy holds the potential to remodel the tumor microenvironment, by suppressing its most important malignant biological capabilities. Highlights Novel combined liposomal delivery of SIM and DMXAA inhibits melanoma tumor growth LCL-SIM augments the anti-angiogenic effects of LCL-DMXAA Combined liposomal therapy inhibits HIF-1α/VEGF axis, induces apoptosis and TAM re-education in tumors This novel therapy suppresses the most important malignant capabilities of melanoma