title: Preparation and evaluation of glycosylated arginine-glycine-aspartate (RGD) derivatives for integrin targeting.
abstract: Arginine-glycine-aspartate (RGD) derivatives were prepared by a combination of solid-phase and solution-phase synthesis for selective targeting of alpha vbeta 3 integrin expressed in tumors. In order to evaluate the value of a triazole moiety as a proposed amide isostere, the side chain glycosylated cyclic RGD ( cRGD) peptides were synthesized with either a natural amide linkage or a triazole. Affinity of the cRGD constructs for the alpha vbeta 3 integrin was determined in a solid-phase competitive binding assay, showing strong similarity in binding affinity for each of the compounds under evaluation. Furthermore, the in vivo tumor targeting potential of glycosylated cRGD peptides, linked via amide or triazole, was investigated by determining the biodistribution of (125)I-labeled derivatives in mice with tumors expressing alpha vbeta 3. All of the cyclic RGD derivatives showed preferential uptake in the subcutaneous tumors, with the highest tumor-to-blood ratio measured for the triazole-linked glycosylated derivative. The results of the present study are a clear indication of the value of the triazole moiety as a suitable amide isostere in the development of glycosylated peptides as pharmaceuticals.
authors.affiliation: Synthetic Organic Chemistry, Institute for Molecules and Materials, Radboud University Nijmegen, Toernooiveld 1, 6525 ED, Nijmegen, The Netherlands.
authors.forename: Brian H M
authors.initials: BH
authors.lastname: Kuijpers
authors.forename: Stan
authors.initials: S
authors.lastname: Groothuys
authors.forename: Annemieke C
authors.initials: AC
authors.lastname: Soede
authors.forename: Peter
authors.initials: P
authors.lastname: Laverman
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.forename: Floris L
authors.initials: FL
authors.lastname: van Delft
authors.forename: Floris P J T
authors.initials: FP
authors.lastname: Rutjes
mesh_terms: D000596:Amino Acids / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006031:Glycosylation; D016023:Integrins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry* / Q000493:pharmacokinetics; D009928:Organ Specificity
chemical_list: D000596:Amino Acids; D016023:Integrins; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid