title: Synthesis and evaluation of a near-infrared fluorescent non-peptidic bivalent integrin alpha(v)beta(3) antagonist for cancer imaging.
abstract: Computer modeling approaches to identify new inhibitors are essentially a very sophisticated and efficient way to design drugs. In this study, a bivalent nonpeptide intergrin alpha(v)beta(3) antagonist (bivalent IA) has been synthesized on the basis of an in silico rational design approach. A near-infrared (NIR) fluorescent imaging probe has been developed from this bivalent compound. In vitro binding assays have shown that the bivalent IA (IC(50) = 0.40 +/- 0.11 nM) exhibited improved integrin alpha(v)beta(3) affinity in comparison with the monovalent IA (IC(50) = 22.33 +/- 4.51 nM), resulting in an over 50-fold improvement in receptor affinity. NIR imaging probe, bivalent-IA-Cy5.5 conjugate, also demonstrated significantly increased binding affinity (IC(50) = 0.13 +/- 0.02 nM). Fluorescence microscopy studies showed integrin-mediated endocytosis of bivalent-IA-Cy5.5 in U87 cells which was effectively blocked by nonfluorescent bivalent IA. We also demonstrated tumor accumulation of this NIR imaging probe in U87 mouse xenografts.
authors.affiliation: Department of Radiology, The Methodist Hospital Research Institute, 6565 Fannin Street, B5-022, Houston, Texas 77030, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Liu
authors.forename: Gouri S
authors.initials: GS
authors.lastname: Jas
authors.forename: Jiawei
authors.initials: J
authors.lastname: Zhang
authors.forename: Guoting
authors.initials: G
authors.lastname: Qin
authors.forename: Jiong
authors.initials: J
authors.lastname: Xing
authors.forename: Claudia
authors.initials: C
authors.lastname: Cotes
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Xukui
authors.initials: X
authors.lastname: Wang
authors.forename: Laura A
authors.initials: LA
authors.lastname: Diaz
authors.forename: Zheng-Zheng
authors.initials: ZZ
authors.lastname: Shi
authors.forename: Daniel Y
authors.initials: DY
authors.lastname: Lee
authors.forename: King C P
authors.initials: KC
authors.lastname: Li
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D003198:Computer Simulation; D055088:Early Detection of Cancer; D005260:Female; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007259:Infrared Rays; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008958:Models, Molecular; D057054:Molecular Imaging / Q000379:methods*; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D005456:Fluorescent Dyes; D039302:Integrin alphaVbeta3