Peptide-platinum(IV) conjugation minimizes the negative impact of current anticancer chemotherapy on nonmalignant cells

Linares Aceituno, Jenniffer Lissethe; Varese, Monica; Sallent-Aragay, Anna; Méndez, Ana; Palomo-Ponce, Sergio; Iglesias Coma, Mar; Batlle Gómez, Eduard; Pisonero, Jorge; Montagut Viladot, Clara; Giralt, Ernest; Lo Re, Daniele; Calon, Alexandre

doi:http://dx.doi.org/10.1021/acs.jmedchem.2c01717

Peptide-platinum(IV) conjugation minimizes the negative impact of current anticancer chemotherapy on nonmalignant cells

Citation

Linares 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.2c01717

Abstract

The 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.