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Molecular Imaging and Contrast Agent Database (MICAD) [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2004-2013.

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Molecular Imaging and Contrast Agent Database (MICAD) [Internet].

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Indocyanine green derivative 02-2-deoxy-d-glucose

ICG-Der-02-2DG
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: December 20, 2012.

Chemical name:Indocyanine green derivative 02-2-deoxy-d-glucoseimage 160643803 in the ncbi pubchem database
Abbreviated name:ICG-Der-02-2DG
Synonym:
Agent category:Compound
Target:Glucose transporters, hexokinases
Target category:Transporter, enzyme
Method of detection:Optical, near-infrared fluorescence (NIR) imaging
Source of signal:ICG-Der-02
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
No structure is available in PubChem.

Background

[PubMed]

Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets in small animals (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–650 nm) are used. Near-infrared (NIR) fluorescence (650–900 nm) detection avoids the natural background fluorescence interference of biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have wider dynamic range and minimal background fluorescence as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low background fluorescence, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is a noninvasive complement to radionuclide imaging in small animals or with probes in close proximity to the target in humans (4). Among the various optical imaging agents, only indocyanine green (ICG), with NIR fluorescence absorption at 780 nm and emission at 820 nm, is approved by the United States Food and Drug Administration for clinical applications in angiography, blood flow evaluation, and liver function assessment (5-8). It is also under evaluation in several clinical trials for other applications, such as optical imaging and mapping of both the lymphatic vessels and lymph nodes in cancer patients for surgical dissection of tumor cells and endoscopic imaging of the pancreas and colon.

The phosphorylation of glucose, an initial and important step in cellular metabolism, is catalyzed by hexokinases (HKs) (9). There are four HKs in mammalian tissues (HKI–HKIV). HKI, HKII, and HKIII have molecular weights of ~100,000 each; HKI is found mainly in the brain, and HKII is insulin-sensitive and is found in adipose and muscle cells. HKIII is found mainly in the liver and lung. HKIV, also known as glucokinase, has a molecular weight of ~50,000 and is specific to the liver and pancreas. Most brain HK is bound to mitochondria, enabling coordination between glucose consumption and oxidation. Tumor cells are known to be highly glycolytic because of increased expression of glycolytic enzymes and HK activity (10), which was detected in tumors from patients with lung, gastrointestinal, and breast cancers. The HKs, by converting glucose to glucose-6-phosphate, help maintain the downhill gradient that results in the transport of glucose into cells through the facilitative glucose transporters (GLUT1–GLUT13) (11). GLUT1 is considered to be the main transporter of glucose uptake. GLUT4 and HKII are the major transporter and HK isoform in skeletal muscle, heart, and adipose tissue, wherein insulin promotes glucose utilization. HKIV is associated with GLUT2 in liver and pancreatic β cells.

2-Deoxy-d-glucose (2DG) was first developed to inhibit glucose utilization by cancer cells (12). HKs phosphorylate 2DG to 2DG-6-phosphate, which inhibits phosphorylation of glucose. 2-[18F]Fluoro-2-deoxy-d-glucose ([18F]FDG) was later developed for use in molecular imaging studies (13). FDG is moved into cells by glucose transporters and is then phosphorylated by HK to FDG-6-phosphate. FDG-6-phosphate cannot be metabolized further in the glycolytic pathway and remains in the cells. Tumor cells do not contain a sufficient amount of glucose-6-phosphatase to reverse the phosphorylation. The elevated rates of glycolysis and glucose transport in many types of tumor cells and activated cells enhance the uptake of FDG in these cells relative to normal cells. Positron emission tomography (PET) with [18F]FDG has been used to assess alterations in glucose metabolism in brain, cancers, cardiovascular diseases, Alzheimer’s disease and other central nervous system disorders, and infectious, autoimmune, and inflammatory diseases (14-19). Various NIR dyes (such as Cypate, Cy5.5, and IRDye800CW) were conjugated to 2DG (20-22) as optical imaging agents for in vivo imaging of glucose utilization in tumors in mice. ICG derivative 02 (ICG-Der-02) contains one carboxyl functional group for covalent conjugation to the amino group of biomolecules. ICG-Der-02 is a hydrophilic dye. Guo et al. (23) evaluated ICG-Der-02-2DG for in vivo NIR optical imaging in tumor-bearing mice.

Synthesis

[PubMed]

ICG-Der-02-N-hydroxysuccinimide ester (0.0128 mmol) was reacted with 2-amino-2-DG (0.064 mmol) for 18 h at room temperature in sodium phosphate buffer (pH 9) (23). ICG-Der-02-2DG was purified with high-performance liquid chromatography and verified with mass spectroscopy. There is one dye molecule per ICG-Der-02-2DG molecule. The yield of ICG-Der-02-2DG was ~32%, with 92% purity. ICG-Der-02-2DG displayed spectral properties similar to those of ICG-Der-02, with maximum absorption at 783 nm and maximum emission at 811 nm.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

In vitro uptake studies of rhodamine-2DG (RhB-2DG) were performed with MCF-7/estradiol, U87MG, and MCF-7 tumor cells in culture, showing that high, medium, and low fluorescence intensity correlated respectively with the GLUT1 expression levels (23). Fluorescence confocal microscopy showed that RhB-2DG accumulated in the cytoplasm of the tumor cells. Excess 2DG was able to block the fluorescence signal in the cytoplasm. Rhodamine was used because the investigators do not have confocal fluorescence microcopy with NIR capability.

Animal Studies

Rodents

[PubMed]

Guo et al. (23) performed in vivo NIR fluorescence imaging studies in nude mice (n = 5) bearing GLUT1-expressing MCF-7/estradiol xenografts at 0.5–48 h after intravenous injection of ICG-Der-02-2DG (10 nmol per mouse). ICG-Der-02-2DG accumulated mainly in the tumors, with a peak tumor/muscle ratio of 8.87 ± 0.31 at 4 h. The tumor/muscle ratio gradually decreased to ~7 at 48 h. Among the normal tissues, only kidneys exhibited strong fluorescence signal, indicative of renal excretion of ICG-Der-02-2DG. Ex vivo NIR fluorescence imaging showed that the tumors exhibited the highest fluorescence intensity (tissue/background ratio, ~17), followed by the kidney (~12), liver (~5), lung (~4), spleen (~3), intestine (~2), and heart (~2). No blocking experiment was performed.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

No publication is currently available.

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