Inhalable Porous Microspheres Loaded with Metformin and Docosahexaenoic Acid Suppress Tumor Metastasis by Modulating Premetastatic Niche

Cancer metastasis is the major cause of cancer-related death; therefore, achieving suppression of tumor metastasis is a long-sought goal in cancer therapy. As the premetastatic niche acts as a prerequisite for tumor metastasis, it serves as an effective target for metastasis suppression. This study tests the feasibility of inhalable porous microspheres loaded with two premetastatic niche modulation agents, metformin and docosahexaenoic acid, as orthotopic delivery carriers for the reversion of lung premetastatic microenvironments and targeted suppression of tumor lung metastasis. The microspheres were prepared via an improved emulsion-solvent evaporation method and exhibit an excellent lung deposition, leading to significant inhibition of circulating tumor cells (CTCs)-endothelial cells adhesion, reduction of vascular permeability, and suppression of adhesion protein expression in lung premetastatic microenvironments. As a result, inhalable microspheres can prevent tumor lung metastasis formation excellently in vivo. Overall, this study proved that the encapsulation of metformin and docosahexaenoic acid in inhalable microspheres could be a promising strategy for tumor lung metastasis inhibition via orthotopically modulating premetastatic niche in the lungs.