Heme oxygenase 1 inhibitor discovery and formulation into nanostructured lipid carriers as potent and selective treatment against triple negative metastatic breast cancer

Heme oxygenase-1 (HO-1) has been identified as a potential new target in anticancer therapy, being overexpressed in different tumors and crucial for cell proliferation. Advances in the development of specific HO-1 inhibitors should support the understanding of controlling HO-1 activity as antitumoral strategies, opening the path for future therapeutic applications. In the present study, small series of new HO-1 inhibitors were synthesized by joining a butylimidazolic pharmacophore together with a hydrophobic moiety spaced by a 2-oxybenzamide central linker. The most active and selective HO-1 inhibitor, VP 21-04, 2-(4-(1H-imidazol-1-yl)butoxy)-N-benzyl-5-iodobenzamide (7b) was identified. This ligand showed strong cytotoxic activity against melanoma and breast cancer cell lines. Encapsulation of VP 21-04 in nanostructured lipid carriers (NLC 21-04) was performed to exploit its therapeutic potential by passive-targeting delivery ameliorating water-solubility and toxicity. Interestingly, NLC 21-04 showed a marked antiproliferative effect in both cancer cell lines, and an improved safety profile with a wider therapeutic window when compared to the free drug. Finally, NLC 21-04 showed a marked tumor growth reduction while being safe in an in ovo tumor model, highlighting the therapeutic potential of the developed nanoparticles against triple negative metastatic breast cancer.