Nitroreductase, a Near-Infrared Reporter Platform for In Vivo Time-Domain Optical Imaging of Metastatic Cancer

Abstract

The ability to visualize reporter gene expression in vivo has revolutionized all facets of biologic investigation and none more so than imaging applications in oncology. Near-infrared reporter gene imaging may facilitate more accurate evaluation of chemotherapeutic response in preclinical models of orthotopic and metastatic cancers. We report the development of a cell permeable, quenched squarine probe (CytoCy5S), which is reduced by Escherichia coli nitroreductase (NTR), resulting in a near-infrared fluorescent product. Time-domain molecular imaging of NTR/CytoCy5S reporter platform permitted noninvasive monitoring of disease progression in orthotopic xenografts of disseminated leukemia, lung, and metastatic breast cancer. This methodology facilitated therapeutic evaluation of NTR gene-directed enzymatic prodrug therapy with conventional metronidazole antibiotics. These studies show NTR/CytoCy5S as a near-infrared gene reporter system with broad preclinical and prospective clinical applications within imaging, and gene therapy, of cancer. Cancer Res; 73(4); 1276-86. Ó2012 AACR.

Generation of Prostate Tumor–Initiating Cells Is Associated with Elevation of Reactive Oxygen Species and IL-6/STAT3 Signaling

“…4A). STAT3 has been reported important in IL-6-type signaling in prostate cancer (19)(20)(21)(22). Activated STAT3 signaling in D5HS was verified by Western blotting using an antibody against phosphorylated (Y705) STAT3 (pSTAT3; Fig.…”

A “Caged” Luciferin for Imaging Cell–Cell Contacts

“…NTR is known to reduce aryl nitro groups to hydroxylamines, [22][23][24][25]33,34 although nitroso and amine products have been detected in a few cases. 26,28,35 Diagnostic proton resonances for 6 were observed during the first few hours of incubation ( Figure 2B), prior to compound degradation ( Figure S6). Formation of the fully reduced 6-amino luciferin (S1) was not observed ( Figure S5) during the course of the reaction.…”

Establishment of a bioluminescence model for microenvironmentally induced oral carcinogenesis with implications for screening bioengineered scaffolds

“…Different in vivo optical imaging modalities have been tested in various tumor models . However, there is a need for a noninvasive head and neck cancer model with the ability to detect possible tumorigenic effects of various microenvironmental cues, including implanted scaffolds.…”

“…23 Different in vivo optical imaging modalities have been tested in various tumor models. [24][25][26] However, there is a need for a noninvasive head and neck cancer model with the ability to detect possible tumorigenic effects of various microenvironmental cues, including implanted scaffolds. Bioluminescent imaging is a well-established method in preclinical investigation of the complexity of cancers [27][28][29] including head and neck cancer, 30,31 but for a screening of the potential to fully transform and generate malignant tumors from the early neoplastic cells, the application of bioluminescence would offer a novel noninvasive approach.…”