Promiscuous tumor targeting phage proteins

Abstract

Cancer cell-specific targeting ligands against numerous cancer cell lines have been selected previously and used as ligands for cell-specific delivery of chemotherapies and various nanomedicines. However, tumor heterogeneity is one recognized problem hampering clinical translation of targeted anti-cancer medicines. Therefore, a novel class of targeting ligands is required that recognize receptors expressed between a variety of cancer phenotypes, identified here as 'promiscuous' ligands. In this work, promiscuous phage fusion proteins were first identified by a novel selection scheme to enrich for pan-cancer cell binding abilities, as indicated by conserved structural motifs identified previously in other cancer types. Additionally, peptide sequences containing a combination of motifs were identified to modulate binding. A panel of phage fusion proteins was studied for their specificity and selectivity for lung and pancreatic cancer cells. Phage displaying the fusion peptides GSLEEVSTL or GEFDELMTM, the two predominate clones with greatest binding ability, were used to modify preformed, doxorubicin-loaded, liposomes. These modified liposomes increased cytotoxicity up to 8.1-fold in several cancer cell lines when compared with unmodified liposomal doxorubicin. Taken together, these data indicate that promiscuous phage proteins, selected against different cancer cell lines, can be used as targeting ligands for treatment of heterogeneous tumor populations.

Keywords: lung cancer; multi-target selection; pancreatic cancer; phage display; targeted nanomedicines.