Synthesis and Biological Characterization of Monomeric and Tetrameric RGD‐Cryptophycin Conjugates

The effective delivery of cytotoxic agents to tumor cells is a key challenge in anticancer therapy. Multivalent integrinspecific ligands are considered a promising tool to increase the binding affinity, selectivity, and internalization efficiency of small-molecule drug conjugates. Herein, we report the synthesis and biological evaluation of a multimeric conjugate containing the high-affinity integrin α_v β₃ binding ligand RAFT-c(RGDfK)₄ , a lysosomally cleavable Val-Cit linker, and cryptophycin-55 glycinate, a potent inhibitor of tubulin polymerization. In vitro cytotoxicity assays verified that the multimeric RGD-cryptophycin conjugate displays improved potency compared to the monomeric analogue in integrin α_v β₃ overexpressing tumor cell lines, while significantly reduced activity was observed in the integrin-negative cell line.