NGRKC16-lipopeptide assisted liposomal-withaferin delivery for efficient killing of CD13 receptor-expressing pancreatic cancer and angiogenic endothelial cells

Abstract Cancer treatment necessitates targeted and efficient drug delivery to reduce drug-mediated adverse collateral effects. We develop herein a new liposomal delivery system which targets both CD13 receptor-positive cancer epithelial and angiogenic endothelial cells using the homing peptide (NGR), as liposome surface bound targeting ligand. The ligand NGR, upon covalent conjugation to a C16-aliphatic twin-chain lipid via a lysine (K) spacer, afforded C16-lipopeptide. Importantly, the circulation stable liposomes of NGRKC16-lipopeptide containing encapsulated withaferin-A (WFA), a multipotent drug, exhibited receptor-mediated uptake and apoptosis-mediated cell death in both CD13 receptor-positive pancreatic cancer cells and angiogenic endothelial cells, while the other non-targeting control formulation failed to do so. In a Chick embryo angiogenesis assay, the targeted formulation selectively inhibited angiogenesis, i.e., sprouting of new blood vessels from the pre-existing blood vessels. These finding revealed therapeutic potential of WFA-encapsulated liposomal formulation of NGRKC16-lipopeptide for simultaneous killing of CD13-positive pancreatic cancer as well as angiogenic endothelial cells. As angiogenesis, endorsed by endothelial cells and aggressiveness in tumor epithelial cells are symbiotically related, the presently described CD13 receptor selective WFA-encapsulated liposomal formulation of NGRKC16-lipopeptide may find future use for the treatment of aggressive pancreatic cancer.