title: Synthesis of DOTA-conjugated multivalent cyclic-RGD peptide dendrimers via 1,3-dipolar cycloaddition and their biological evaluation: implications for tumor targeting and tumor imaging purposes.
abstract: This report describes the design and synthesis of a series of alpha(V)beta(3) integrin-directed monomeric, dimeric and tetrameric cyclo[Arg-Gly-Asp-d-Phe-Lys] dendrimers using "click chemistry". It was found that the unprotected N-epsilon-azido derivative of cyclo[Arg-Gly-Asp-d-Phe-Lys] underwent a highly chemoselective conjugation to amino acid-based dendrimers bearing terminal alkynes using a microwave-assisted Cu(I)-catalyzed 1,3-dipolar cycloaddition. The alpha(V)beta(3) binding characteristics of the dendrimers were determined in vitro and their in vivoalpha(V)beta(3) targeting properties were assessed in nude mice with subcutaneously growing human SK-RC-52 tumors. The multivalent RGD-dendrimers were found to have enhanced affinity toward the alpha(V)beta(3) integrin receptor as compared to the monomeric derivative as determined in an in vitro binding assay. In case of the DOTA-conjugated (111)In-labeled RGD-dendrimers, it was found that the radiolabeled multimeric dendrimers showed specifically enhanced uptake in alpha(V)beta(3) integrin expressing tumors in vivo. These studies showed that the tetrameric RGD-dendrimer had better tumor targeting properties than its dimeric and monomeric congeners.
authors.affiliation: Department of Medicinal Chemistry and Chemical Biology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, P. O. Box 80082, 3508 TB Utrecht, The Netherlands.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dijkgraaf
authors.forename: Anneloes Y
authors.initials: AY
authors.lastname: Rijnders
authors.forename: Annemieke
authors.initials: A
authors.lastname: Soede
authors.forename: Annemarie C
authors.initials: AC
authors.lastname: Dechesne
authors.forename: G Wilma
authors.initials: GW
authors.lastname: van Esse
authors.forename: Arwin J
authors.initials: AJ
authors.lastname: Brouwer
authors.forename: Frans H M
authors.initials: FH
authors.lastname: Corstens
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.forename: Dirk T S
authors.initials: DT
authors.lastname: Rijkers
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
mesh_terms: D000480:Alkynes / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D001667:Binding, Competitive; D050091:Dendrimers / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D021621:Imaging, Three-Dimensional; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
chemical_list: D000480:Alkynes; D050091:Dendrimers; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; C507169:cyclic arginine-glycine-aspartic acid peptide; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid