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Synthesis and Biological Characterization of Monomeric and Tetrameric RGD‐Cryptophycin Conjugates
Author(s) -
Borbély Adina,
Thoreau Fabien,
Figueras Eduard,
Kadri Malika,
Coll JeanLuc,
Boturyn Didier,
Sewald Norbert
Publication year - 2020
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201905437
Subject(s) - linker , internalization , conjugate , cytotoxicity , chemistry , ligand (biochemistry) , integrin , in vitro , stereochemistry , biochemistry , rgd motif , cell culture , combinatorial chemistry , biology , cell , receptor , mathematical analysis , genetics , mathematics , computer science , operating system
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 β 3 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 β 3 overexpressing tumor cell lines, while significantly reduced activity was observed in the integrin‐negative cell line.