Angiogenesis imaging holds considerable promise for early detection of cancer, as well as post-therapy assessment of many new molecular-targeted antiangiogenic therapies. New contrast probes such as small molecular radiotracers, optical probes, and lipid- and polymer-based nanoparticles are intensively investigated to target different biomarkers of angiogenesis. However, low tissue concentrations of intended biomarkers, lack of an amplification strategy to increase signal output, and high background signals are several major limiting factors that hamper the advances of these molecular imaging techniques. The long-term goal of this application is to develop a robust set of tunable fluorescent nanoprobes based on the homo fluorescent resonance energy transfer (homoFRET) and photo-induced electron transfer (PET) mechanisms. The micelle nanoprobes will stay silent (or in the OFF state) with minimum background signals under normal physiological conditions (e.g. blood circulation). Upon specific targeting to angiogenic target (e.g. avb3), these nanoprobes can be turned ON by pH activation (pH 5.0-7.2) inside endosomes/lysosomes after receptor-mediated endocytosis. Our central hypothesis is that a synergized strategy of signal amplification in tumor endothelium and background suppression in blood and pH-activatable micelle (pHAM) nanoprobes will be able to improve the imaging sensitivity and specificity of angiogenesis biomarkers in vascularized tumors in vivo. To test this hypothesis, we will carry out the following specific aims: (1) establish a series of near infrared (NIR) pHAM nanoprobes with tunable transition pH (pHt);(2) evaluate the activation of non-targeted pHAM in acidic tumor microenvironment;(3) establish vascular-targeted pHAM and investigate the intracellular activation of these nanoprobes in tumor endothelial cells;(4) evaluate the specificity and efficacy of targeted pHAM in the imaging of distinctive angiogenesis biomarkers (i.e. VEGFR2, avb3) in tumor-bearing mice in vivo. Successful execution of this research will establish pHAM as a valuable imaging platform to image angiogenesis- specific biomarkers on the tumor endothelium in vivo. These nanoprobes may be particularly useful for the efficacy assessment of molecular-targeted antiangiogenic therapies, where the expression levels of the therapeutic targets (e.g. VEGFR2, avb3) can be directly measured.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB013149-03
Application #
8516037
Study Section
Special Emphasis Panel (ZRG1-SBIB-A (55))
Program Officer
Conroy, Richard
Project Start
2011-08-05
Project End
2015-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$345,915
Indirect Cost
$128,358
Name
University of Texas Sw Medical Center Dallas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Wang, Yiguang; Zhou, Kejin; Huang, Gang et al. (2014) A nanoparticle-based strategy for the imaging of a broad range of tumours by nonlinear amplification of microenvironment signals. Nat Mater 13:204-12
Ma, Xinpeng; Wang, Yiguang; Zhao, Tian et al. (2014) Ultra-pH-sensitive nanoprobe library with broad pH tunability and fluorescence emissions. J Am Chem Soc 136:11085-92
Li, Yang; Wang, Yiguang; Huang, Gang et al. (2014) Chaotropic-anion-induced supramolecular self-assembly of ionic polymeric micelles. Angew Chem Int Ed Engl 53:8074-8
Zhou, Heling; Stafford, Jason H; Hallac, Rami R et al. (2014) Phosphatidylserine-targeted molecular imaging of tumor vasculature by magnetic resonance imaging. J Biomed Nanotechnol 10:846-55
Zhang, Shanrong; Zhou, Kejin; Huang, Gang et al. (2013) A novel class of polymeric pH-responsive MRI CEST agents. Chem Commun (Camb) 49:6418-20
Huang, Xiaonan; Huang, Gang; Zhang, Shanrong et al. (2013) Multi-chromatic pH-activatable 19F-MRI nanoprobes with binary ON/OFF pH transitions and chemical-shift barcodes. Angew Chem Int Ed Engl 52:8074-8
Zhou, Kejin; Liu, Haoming; Zhang, Shanrong et al. (2012) Multicolored pH-tunable and activatable fluorescence nanoplatform responsive to physiologic pH stimuli. J Am Chem Soc 134:7803-11