A team led by Prof ANG Wee Han from the Department of Chemistry has developed a class of platinum-peptide prodrugs that deliver cisplatin or oxaliplatin selectively to cancer cells by targeting the human epidermal growth factor receptor 2 (HER2) pathway. Human epidermal growth factor receptor 2 (HER2) is a clinically-validated receptor that is overexpressed in certain breast and gastric cancers. Peptides that mimic HER2 antibodies were coupled to platinum scaffolds containing cisplatin or oxaliplatin and the new conjugates were highly efficient in delivering the platinum payload to HER-positive cells, while ignoring cells with low HER2 expression. The researchers also discovered that these platinum-peptide constructs caused cell death by necrosis as a result of the massive platinum influx. This unusual form of cell-killing, targeted necrosis, is rarely reported in the literature. Importantly, the researchers showed that the new prodrugs can be harnessed to bypass apoptosis pathways to defeat dysfunctional MDR cancer cells, paving the way for the next generation of more effective metallodrugs with broader spectrum of activity.
Figure shows the platinum prodrug of cisplatin containing a HER2-targeting peptide is capable of bypassing apoptosis and selectively inducing targeted necrosis in HER2-positive NCI-N87 gastric cancer cells. [Image credit : ANG Wee Han]
Reference
Wong DYQ, Lim JH, Ang WH. “Induction of Targeted Necrosis with HER2-targeted Platinum(IV) Anticancer Prodrugs.” Chemical Science. 6 (2015) 3051.
