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Multimerization of cRGD Peptides by Click Chemistry: Synthetic Strategies, Chemical Limitations, and Influence on Biological Properties
Author(s) -
Wängler Carmen,
Maschauer Simone,
Prante Olaf,
Schäfer Martin,
Schirrmacher Ralf,
Bartenstein Peter,
Eisenhut Michael,
Wängler Björn
Publication year - 2010
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201000386
Subject(s) - chemistry , in vitro , peptide , integrin , monomer , click chemistry , conjugated system , in vivo , biophysics , dendrimer , combinatorial chemistry , biochemistry , cell , organic chemistry , biology , polymer , microbiology and biotechnology
Integrin α ν β 3 is overexpressed on endothelial cells of growing vessels as well as on several tumor types, and so integrin‐binding radiolabeled cyclic RGD pentapeptides have attracted increasing interest for in vivo imaging of α ν β 3 integrin expression by positron emission tomography (PET). Of the cRGD derivatives available for imaging applications, systems comprising multiple cRGD moieties have recently been shown to exhibit highly favorable properties in relation to monomers. To assess the synthetic limits of the cRGD‐multimerization approach and thus the maximum multimer size achievable by using different efficient conjugation reactions, we prepared a variety of multimers that were further investigated in vitro with regard to their avidities to integrin α ν β 3. The synthesized peptide multimers containing increasing numbers of cRGD moieties on PAMAM dendrimer scaffolds were prepared by different click chemistry coupling strategies. A cRGD hexadecimer was the largest construct that could be synthesized under optimized reaction conditions, thus identifying the current synthetic limitations for cRGD multimerization. The obtained multimeric systems were conjugated to a new DOTA‐based chelator developed for the derivatization of sterically demanding structures and successfully labeled with 68 Ga for a potential in vivo application. The evaluated multimers showed very high avidities—increasing with the number of cRGD moieties—in in vitro studies on immobilized α ν β 3 integrin and U87MG cells, of up to 131‐ and 124‐fold, respectively, relative to the underivatized monomer.