Synthesis and evaluation of a near-infrared fluorescent non-peptidic bivalent integrin alpha(v)beta(3) antagonist for cancer imaging.

Bioconjugate Chemistry
Feng LiZheng Li

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.

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Citations

Feb 21, 2013·Journal of Ocular Pharmacology and Therapeutics : the Official Journal of the Association for Ocular Pharmacology and Therapeutics·Megan E CapozziAshwath Jayagopal
Mar 5, 2016·Frontiers in Medicine·Shubhra Chaturvedi, Anil K Mishra
Dec 10, 2014·Molecular Pharmaceutics·Chin Siang KueKevin Burgess
Aug 22, 2013·Molecular Pharmaceutics·Yoo-Shin KimZheng Li
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Oct 5, 2010·Bioorganic & Medicinal Chemistry Letters·Feng LiZheng Li
Feb 16, 2017·ACS Medicinal Chemistry Letters·Anyanee KamkaewKevin Burgess

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