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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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IR-783-Glucosamine

IR-2
, PhD
National Center for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: May 11, 2009.

Chemical name:IR-783-Glucosamineimage 53799215 in the ncbi pubchem database
Abbreviated name:IR-2
Synonym:
Backbone:Compound
Target:Lysosomes
Mechanism:Unknown
Method of detection:Optical, near-infrared (NIR) fluorescence
Source of signal:IR-783
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues in small animals. NIR fluorophores have a wider dynamic range and minimal background as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low fluorescence background, 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 becoming a non-invasive alternative to radionuclide imaging in small animals (4, 5).

Lysosomes are membranous vesicles found in most mammalian cells (6). Lysosomes contain various types of proteases, which have been implicated in migration, invasion, and metastasis of malignant cancer cells by the degradation of extracellular matrix (7). Glucosamine is used to synthesize highly glycosylated lysosomal proteins (8). The sizes of lysosomes are found to be larger in malignant cancer cells than in benign cancer cells (9). Carbocyanine IR-783 was conjugated to glucosamine for imaging lysosomal content in tumors with NIR fluorescence (10, 11).

Synthesis

[PubMed]

The hydroxyl group in the 6-position of glucosamine was first converted to a primary amine, which was reacted with 3-(4-iodobutoxy)-phenyl acetate (10, 11). IR783 was conjugated to the phenol moiety of the linker of the resulting glucosamine to produce IR-783-glucosamine (IR-2). IR-2 has an extinction of coefficient of 157,000 M-1cm-1 and a quantum yield of 0.11, with a maximal excitation wavelength of 768 nm and a maximal emission wavelength of 784 nm in saline. The fluorescence intensities at pH 3–5 were higher than those at pH 6.4–7.2.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

IR-2 at concentrations up to 0.5 mM exhibited minimal cytotoxicity in four human breast cancer cell lines: MCF-12A, MCF-7, MDA-MB-231, and MDA-MB-435 (10, 11). High fluorescence intensity was observed in small intracellular vesicles with a partially punctuated pattern at 24 h of incubation, most likely as a result of lysosomal localization. IR-2 was colocalized with a lysosomal marker, dextran, and a lysosomal glycoprotein, CD63. No such pattern was observed with IR-783. The IR-2 staining was not affected by either 5 mM glucosamine or 50 mM D-glucose.

Animal Studies

Rodents

[PubMed]

Li et al. (11) performed a preliminary study of IR-2 (100 nmol/mouse) in nude mice (n = 3) bearing MDA-MB-231, MDA-MB435, or MCF-7 tumors (200–300 mm3 in volume) using a whole-body fluorescence detection system. IR-2 showed a higher fluorescence signal in the tumors than IR-783 at 1–24 h after injection. The maximum IR-2 fluorescence intensities were 9.5, 7.5, and 3.0 × 1011 p/s/cm2/sr for MDA-MB-231, MDA-MB435, and MCF-7, respectively. On the other hand, the maximum IR-783 fluorescence intensities were 4.5, 2.0, and 1.0 × 1011 p/s/cm2/sr for MDA-MB-231, MDA-MB435, and MCF-7, respectively. The tumor/muscle ratios in all three tumors were ~3 and ~1 for IR-2 and IR-786 at most time points after injection, respectively. Biodistribution studies showed that the liver, kidneys, and intestines also displayed higher fluorescence intensities than the tumors at 24 h after injection. The muscle, brain, spleen, and blood contain little accumulation of IR-2. Tumor uptakes of IR-2 were three-fold higher than that of IR-783. IR-2 exhibited higher co-localization coefficients of CD63 in the three tumors than IR-783.

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.

NIH Support

CA112216, CA103175

References

1.
Achilefu S. Lighting up tumors with receptor-specific optical molecular probes. Technol Cancer Res Treat. 2004;3(4):393–409. [PubMed: 15270591]
2.
Ntziachristos V., Bremer C., Weissleder R. Fluorescence imaging with near-infrared light: new technological advances that enable in vivo molecular imaging. Eur Radiol. 2003;13(1):195–208. [PubMed: 12541130]
3.
Becker A., Hessenius C., Licha K., Ebert B., Sukowski U., Semmler W., Wiedenmann B., Grotzinger C. Receptor-targeted optical imaging of tumors with near-infrared fluorescent ligands. Nat Biotechnol. 2001;19(4):327–31. [PubMed: 11283589]
4.
Robeson W., Dhawan V., Belakhlef A., Ma Y., Pillai V., Chaly T., Margouleff C., Bjelke D., Eidelberg D. Dosimetry of the dopamine transporter radioligand 18F-FPCIT in human subjects. J Nucl Med. 2003;44(6):961–6. [PubMed: 12791826]
5.
Tung C.H. Fluorescent peptide probes for in vivo diagnostic imaging. Biopolymers. 2004;76(5):391–403. [PubMed: 15389488]
6.
de Duve C. The lysosome turns fifty. Nat Cell Biol. 2005;7(9):847–9. [PubMed: 16136179]
7.
Mignatti P., Rifkin D.B. Biology and biochemistry of proteinases in tumor invasion. Physiol Rev. 1993;73(1):161–95. [PubMed: 8419965]
8.
Glunde K., Guggino S.E., Ichikawa Y., Bhujwalla Z.M. A novel method of imaging lysosomes in living human mammary epithelial cells. Mol Imaging. 2003;2(1):24–36. [PubMed: 12926235]
9.
Glunde K., Guggino S.E., Solaiyappan M., Pathak A.P., Ichikawa Y., Bhujwalla Z.M. Extracellular acidification alters lysosomal trafficking in human breast cancer cells. Neoplasia. 2003;5(6):533–45. [PMC free article: PMC1502575] [PubMed: 14965446]
10.
Li C., Greenwood T.R., Bhujwalla Z.M., Glunde K. Synthesis and characterization of glucosamine-bound near-infrared probes for optical imaging. Org Lett. 2006;8(17):3623–6. [PubMed: 16898776]
11.
Li C., Greenwood T.R., Glunde K. Glucosamine-bound near-infrared fluorescent probes with lysosomal specificity for breast tumor imaging. Neoplasia. 2008;10(4):389–98. [PMC free article: PMC2288541] [PubMed: 18392136]

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