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

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.

Pt(iv) anticancer prodrugs bearing an oxaliplatin scaffold: what do we know about their bioactivity?

“…34). 126 Although less potent than oxaliplatin, complex 95 displayed cytotoxicities in the low micromolar range for LoVo, HT29 and SW620 cell lines. Interestingly, complex 95 demonstrated a significantly enhanced anticancer activity against 3D patient-derived organoids retaining similar genetic profiles to the tumor of origin.…”

Hyaluronic Acid Interacting Molecules Mediated Crosstalk between Cancer Cells and Microenvironment from Primary Tumour to Distant Metastasis

“…However, the multifunction of RHAMM and its specific expression in tissues have limited the application of these peptides. VCAN has been identified as a biomarker for tumour metastasis and chemotherapy resistance [293][294][295][296], assisting in the monitoring of off-target effects of platinum (Pt)-based chemotherapy and facilitating timely adjustments to therapeutic strategies [294]. Furthermore, VCAN is related to the efficacy of adjuvant chemotherapy, chemoradiotherapy, and immunotherapy in gastric cancer [149].…”

nature inspired and medicinally relevant short peptides

“…CPP-conjugation with polymers or with supramolecular nanostructures is an alternative shielding strategy to protect CPPs from proteases attack [134]. Remarkably, D-JNKI-1, a conjugated CPP, is found in vivo application in Alzheimer's disease since it is able to cross to the BBB and penetrate the brain parenchyma till its target in brain mitochondria [135].…”