A novel peptide–drug conjugate GV-K for anti-colorectal cancer therapy via mitochondrial apoptosis

Colorectal cancer (CRC) has the second-highest mortality rate, seriously threatening human health. Despite many advances in the field of CRC therapy, an effective cure is yet to be found. As a more potent alternative to the conventional small-molecule anti-cancer drugs, peptide-drug conjugates (PDCs) have emerged as a new class of anticancer agents. Based on the principle of drug target co-screening, our study identified a novel CRC affinity peptide, GV12, which specifically bound to the protein ANXA2 on CRC cells using phage display technology. Moreover, the peptide GV12 was capable of penetrating CRC cells but without exerting cytotoxic effects. We constructed a peptide-drug conjugate, designated GV-K, composed of GV12 and the pro-apoptotic peptide D-(KLA) 2 , which demonstrated significant anti-CRC effects both in vitro and in vivo . GV-K targeted the membrane protein ANXA2 and primarily internalized into CRC cells via receptor-mediated endocytosis. Subsequently, GV-K was successfully localized to the mitochondria and thereby induced apoptosis of CRC cells by triggering the cytochrome C-Apaf-1-Caspase signaling pathway. These findings reveal a novel PDC, GV-K, which targets the membrane protein ANXA2 to internalize and induce apoptosis in CRC cells, suggesting a promising strategy for targeted therapy of CRC.