Peptide-Platinum(IV) Conjugation Minimizes the Negative Impact of Current Anticancer Chemotherapy on Nonmalignant Cells

Abstract

The relative success of platinum (Pt)-based chemotherapycomes at the cost of severe adverse side effects and is associated with a highrisk of pro-oncogenic activation in the tumor microenvironment. Here, wereport the synthesis of C-POC, a novel Pt(IV) cell-penetrating peptideconjugate showing a reduced impact against nonmalignant cells. In vitro andin vivo evaluation using patient-derived tumor organoids and laser ablationinductively coupled plasma mass spectrometry indicates that C-POCmaintains robust anticancer efficacy while displaying diminished accumulationin healthy organs and reduced adverse toxicity compared to the standard Pt-based therapy. Likewise, C-POC uptake is significantlylowered in the noncancerous cells populating the tumor microenvironment. This results in the downregulation of versican, abiomarker of metastatic spreading and chemoresistance that we found upregulated in patients treated with standard Pt-basedtherapy. Altogether, our findings underscore the importance of considering the off-target impact of anticancer treatment on normalcells to improve drug development and patient care.