Linares Aceituno, Jenniffer LissetheVarese, MonicaSallent-Aragay, AnnaMéndez, AnaPalomo-Ponce, SergioIglesias Coma, MarBatlle Gómez, EduardPisonero, JorgeMontagut Viladot, ClaraGiralt, ErnestLo Re, DanieleCalon, Alexandre2024-02-132023Linares J, Varese M, Sallent-Aragay A, Méndez A, Palomo-Ponce S, Iglesias M, Batlle E, Pisonero J, Montagut C, Giralt E, Lo Re D, Calon A. Peptide-platinum(IV) conjugation minimizes the negative impact of current anticancer chemotherapy on nonmalignant cells. J Med Chem. 2023 Mar 9;66(5):3348-55. DOI: 10.1021/acs.jmedchem.2c017170022-2623http://hdl.handle.net/10230/59102The relative success of platinum (Pt)-based chemotherapy comes at the cost of severe adverse side effects and is associated with a high risk of pro-oncogenic activation in the tumor microenvironment. Here, we report the synthesis of C-POC, a novel Pt(IV) cell-penetrating peptide conjugate showing a reduced impact against nonmalignant cells. In vitro and in vivo evaluation using patient-derived tumor organoids and laser ablation inductively coupled plasma mass spectrometry indicates that C-POC maintains robust anticancer efficacy while displaying diminished accumulation in healthy organs and reduced adverse toxicity compared to the standard Pt-based therapy. Likewise, C-POC uptake is significantly lowered in the noncancerous cells populating the tumor microenvironment. This results in the downregulation of versican, a biomarker of metastatic spreading and chemoresistance that we found upregulated in patients treated with standard Pt-based therapy. Altogether, our findings underscore the importance of considering the off-target impact of anticancer treatment on normal cells to improve drug development and patient care.application/pdfengThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of medicinal chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acs.jmedchem.2c01717.Quimioteràpiainfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1021/acs.jmedchem.2c01717info:eu-repo/semantics/openAccess