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.