title: Multivalent scaffolds for affinity maturation of small molecule cell surface binders and their application to prostate tumor targeting.
abstract: Adamantane scaffolds for affinity maturation of prostate cancer specific ligands of low molecular mass are described. These scaffolds are modular and can be used for conjugation of up to three ligands and an additional effector molecule by standard peptide coupling techniques. The potential of the scaffolds is demonstrated with the multimerization of GPI 1, a prostate cancer specific small molecule. A detailed study of multimerized GPI conjugates with near-infrared fluorophores and their binding properties to different prostate cancer cell lines shows the specific binding of these conjugates to cell types positive for prostate specific membrane antigen (PSMA). We demonstrate that these conjugates allow the sensitive imaging of prostate cancer cells with NIR methodology and suggest that our adamantane scaffolds might be generally useful for affinity maturation of small molecules targeting cell surface epitopes.
authors.affiliation: Institute of Organic Chemistry, Justus-Liebig-Universitat Giessen, Heinrich-Buff-Ring 58, 35390 Giessen, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Humblet
authors.forename: Preeti
authors.initials: P
authors.lastname: Misra
authors.forename: Kumar R
authors.initials: KR
authors.lastname: Bhushan
authors.forename: Khaled
authors.initials: K
authors.lastname: Nasr
authors.forename: Yao-Sen
authors.initials: YS
authors.lastname: Ko
authors.forename: Takashi
authors.initials: T
authors.lastname: Tsukamoto
authors.forename: Nadine
authors.initials: N
authors.lastname: Pannier
authors.forename: John V
authors.initials: JV
authors.lastname: Frangioni
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Maison
mesh_terms: D000954:Antigens, Surface / Q000378:metabolism; D001704:Biopolymers; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D016503:Drug Delivery Systems; D043425:Glutamate Carboxypeptidase II / Q000378:metabolism; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016339:Spectrometry, Mass, Fast Atom Bombardment; D019265:Spectroscopy, Near-Infrared
chemical_list: D000954:Antigens, Surface; D001704:Biopolymers; D017261:Glycosylphosphatidylinositols; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II