Specific Targeting of Cells by Heteromultivalent Ligands and its Implications in Cancer

摘要

Current cancer therapies involve targeting either differential metabolism, especially nucleic acid biosynthesis pathways, or overexpressed specific gene products. We propose an alternative approach - to specifically target combinations of cell-surface receptors using heteromultivalent ligands (htMVLs). We envision that a combination of cell-surface proteins, which is expressed on a cancer cell but not on a normal cell, could be targeted with htMVLs displaying cognate binding motifs of moderate to weak affinities. These constructs should bind with high avidity and specificity to cancer populations in vivo [1,2]. As a proof-of-concept, we have synthesized series of heterobivalent ligands (htBVLs) composed of human melanocortin-4 receptor (hMC4R) and cholecystokinin-2 receptor (CCK-2R) ligand motifs (Figure 1). These motifs were connected via semi-rigid poly(Pro-Gly) linkers flanked by flexible polyethylene glycol based PEGO chains.