Virzì, Nicola FilippoÁlvarez Lorenzo, CarmenConcheiro Nine, Ángel JoaquínConsoli, ValeriaSalerno, LoredanaVanella, LucaPittalà, ValeriaDíaz Rodríguez, Patricia2025-04-232025-04-232025-01-05Virzì, N. F., Alvarez-Lorenzo, C., Concheiro, A., Consoli, V., Salerno, L., Vanella, L., et al. (2025). Heme oxygenase 1 inhibitor discovery and formulation into nanostructured lipid carriers as potent and selective treatment against triple negative metastatic breast cancer. International Journal of Pharmaceutics, 668, 124997. doi:10.1016/j.ijpharm.2024.1249970378-5173https://hdl.handle.net/10347/40976Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijpharm.2024.124997.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.eng© 2024 The Authors. This article is available under the Creative Commons CC-BY-NC license and permits non-commercial use, distribution and reproduction in any medium, provided the original work is properly cited.Attribution-NonCommercial 4.0 Internationalhttp://creativecommons.org/licenses/by-nc/4.0/Heme Oxygenase-1 (HO-1) inhibitorNanostructured lipid carriers (NLC)Metastatic cancer treatmentMelanomaTriple negative breast cancer (TNBC)Selective targetingIn ovo antitumoral testjournal article10.1016/j.ijpharm.2024.1249971873-3476open access