Tumour-Targetting Peptidomimetics


There are a number of peptidic tumour-homing vectors capable of distinguishing a tumour from normal tissue, including the arginine-glycine-aspartic acid (RGD) and asparagine-glycine-arginine (NGR) motifs; these bind to the integrin αvβ3 (vitronectin) receptor and aminopeptidase N (CD13) respectively.  The former receptor is involved in endothelial cell adhesion and plays a key role in angiogenesis and tumour metastasis; the latter is a protease isoform specific to the tumour neovasculature. Both are overexpressed in a number of tumours, including lung, breast, colon, ovarian, prostate and secondary bone cancers.  However, these peptides do not have sufficient metabolic stability to permit fully selective delivery.  Our team has developed a small molecule mimic of the-RGD peptide, which retains low nanomolar affinity for the surface recognition pattern on the tumour cell and should be metabolically stable.

As proof of concept, we are conjugating small molecule-RGD mimetics to tubulysins, a class of inhibitors of tubulin polymerisation, which have sub-nanomolar potency against a range of multi-drug resistant tumour cell lines but do not have sufficient window between the therapeutic and toxic doses to permit clinical use.  We are testing the selectivity and cytotoxicity of these conjugates in a number of in vitro cancer models

Project Team: Prof Matteo Zanda, Dr Ian Fleming, Monica Piras, Andrea Testa