Synthesis and evaluation of a near-infrared fluorescent non-peptidic bivalent integrin alpha(v)beta(3) antagonist for cancer imaging.
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.
Li
Feng
F
Department of Radiology, The Methodist Hospital Research Institute, 6565 Fannin Street, B5-022, Houston, Texas 77030, USA.
Liu
Jiacheng
J
Jas
Gouri S
GS
Zhang
Jiawei
J
Qin
Guoting
G
Xing
Jiong
J
Cotes
Claudia
C
Zhao
Hong
H
Wang
Xukui
X
Diaz
Laura A
LA
Shi
Zheng-Zheng
ZZ
Lee
Daniel Y
DY
Li
King C P
KC
Li
Zheng
Z
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
D005456:Fluorescent Dyes; D039302:Integrin alphaVbeta3