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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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Gly-Ala-Cys-Leu-Arg-Ser-Gly-Arg-Gly-Cys-Gly-(PEG)3-DOTA-68Ga

68Ga-DOTA-TCTP-1
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD

Created: ; Last Update: April 7, 2011.

Chemical name:Gly-Ala-Cys-Leu-Arg-Ser-Gly-Arg-Gly-Cys-Gly-(PEG)3-DOTA-68Ga
Abbreviated name:68Ga-DOTA-TCTP-1
Synonym:
Agent category:Peptide
Target:Gelatinase B (matrix metalloproteinase 9, MMP-9)
Target category:Enzyme
Method of detection:Positron emission tomography (PET)
Source of signal/contrasat:68Ga
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on MMP-9 for protein information.

Background

[PubMed]

Extracellular matrix (ECM) adhesion molecules consist of a complex network of fibronectins, collagens, chondroitins, laminins, glycoproteins, heparin sulfate, tenascins, and proteoglycans that surround connective tissue cells, and they are mainly secreted by fibroblasts, chondroblasts, and osteoblasts (1). Cell substrate adhesion molecules are considered essential regulators of cell migration, differentiation, and tissue integrity and remodeling. These molecules play a role in inflammation and atherogenesis, but they also participate in the process of invasion and metastasis of malignant cells in the host tissue (2). Invasive tumor cells adhere to the ECM, which provides a matrix environment for permeation of tumor cells through the basal lamina and underlying interstitial stroma of the connective tissue. Overexpression of matrix metalloproteinases (MMPs) and other proteases by tumor cells allows intravasation of tumor cells into the circulatory system after degrading the basement membrane and ECM (3).

Several families of proteases are involved in atherogenesis, inflammation, myocardial infraction, angiogenesis, and tumor invasion and metastases (4-8). The gelatinase family is a subgroup of MMPs consisting of gelatinase A (MMP-2) and gelatinase B (MMP-9) (9). Gelatinase expression in normal cells, such as trophoblasts, osteoclasts, neutrophils, and macrophages, is highly regulated. Elevated levels of gelatinases have been found in tumors that are associated with a poor prognosis for cancer patients (10). A number of synthetic MMP inhibitors have been developed to block the activated MMPs in pathological conditions (11). A tumor cell targeting peptide, Gly-Ala-Cys-Leu-Arg-Ser-Gly-Arg-Gly-Cys-Gly (TCTP-1), was identified via phage display screening against MMP-9. Ujula et al. (12) prepared a cyc-cys cyclicpeptide, Gly-Ala-Cys-Leu-Arg-Ser-Gly-Arg-Gly-Cys-Gly-(PEG)3-DOTA-68Ga (68Ga-DOTA-TCTP-1), for preliminary evaluation of MMP-9 overexpression in tumors.

Synthesis

[PubMed]

A solution of 185 MBq (5 mCi) 68Ga and DOTA-TCTP-1 (30 nmol) was incubated in acetate buffer (pH 3.0) for 25 min at 95°C (12). 68Ga-DOTA-TCTP-1 was identified with high-performance liquid chromatography. 68Ga-DOTA-TCTP-1 exhibited a radiochemical purity of >95% and a specific activity of 2 GBq/µmol (54 mCi/µmol). 68Ga-DOTA-lactam-TCTP-1 and linear 68Ga-DOTA-lin-TCTP-1 (control linear peptide) were also prepared similarly with similar specific activity. 68Ga-DOTA-TCTP-1 has a log D7.4 value of -3.6.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

68Ga-DOTA-TCTP-1and the other two 68Ga-labeled peptides were stable in saline at room temperature for > 4 h (12). 68Ga-DOTA-TCTP-1 and 68Ga-DOTA-lin-TCTP-1 had half-lives of 2.5 h and 1 h in human plasma, respectively. 68Ga-DOTA-lactam-TCTP-1 was stable in human plasma up to 4 h.

Animal Studies

Rodents

[PubMed]

Ujula et al. (12) performed ex vivo biodistribution studies of 19 MBq (0.51 mCi) 68Ga-DOTA-TCTP-1 in athymic rats (n = 3) bearing MMP-9 expressing C8161T/M1 human melanoma cell line at week 3 after the tumor inoculation. The tumor accumulation was 0.20 ± 0.03% injected dose/gram (ID/g) at 60 min after injection. The accumulations in the lung, liver, blood and muscle were 0.6 ± 0.2% ID/g, 0.4 ± 0.1% ID/g, 0.20 ± 0.03% ID/g, and 0.04 ± 0.01% ID/g, respectively. The tumor/muscle ratio was 4.8 ± 0.4. Approximately 71% and 35% of radioactivity in the plasma was intact 68Ga-DOTA-TCTP-1 at 15 min and 120 min after injection, respectively. As a comparison, 68Ga-DOTA-lactam-TCTP-1 and 68Ga-DOTA-lin-TCTP-1 exhibited tumor/muscle ratio of ~3.0. Immunohistochemistry of tumor sections showed the localization of MMP-9 in the endothelium and ECM of the blood vessels. However, there was only a weak correlation between MMP-9 levels and the ex vivo tumor accumulation. No blocking experiment was performed.

Positron emission tomography imaging showed that tumors were clearly visualized by 68Ga-DOTA-lactam-TCTP-1 and 68Ga-DOTA-TCTP-1 but not by 68Ga-DOTA-lin-TCTP-1 at 10-55 min after injection. The heart, liver, kidneys, and urinary bladder were also visualized. 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.

References

1.
Bosman F.T., Stamenkovic I. Functional structure and composition of the extracellular matrix. J Pathol. 2003;200(4):423–8. [PubMed: 12845610]
2.
Jiang W.G., Puntis M.C., Hallett M.B. Molecular and cellular basis of cancer invasion and metastasis: implications for treatment. Br J Surg. 1994;81(11):1576–90. [PubMed: 7827878]
3.
Albelda S.M. Role of integrins and other cell adhesion molecules in tumor progression and metastasis. Lab Invest. 1993;68(1):4–17. [PubMed: 8423675]
4.
Keppler D., Sameni M., Moin K., Mikkelsen T., Diglio C.A., Sloane B.F. Tumor progression and angiogenesis: cathepsin B & Co. Biochem Cell Biol. 1996;74(6):799–810. [PubMed: 9164649]
5.
Liu J., Sukhova G.K., Sun J.S., Xu W.H., Libby P., Shi G.P. Lysosomal cysteine proteases in atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24(8):1359–66. [PubMed: 15178558]
6.
Berchem G., Glondu M., Gleizes M., Brouillet J.P., Vignon F., Garcia M., Liaudet-Coopman E. Cathepsin-D affects multiple tumor progression steps in vivo: proliferation, angiogenesis and apoptosis. Oncogene. 2002;21(38):5951–5. [PubMed: 12185597]
7.
Brix, K., A. Dunkhorst, K. Mayer, and S. Jordans, Cysteine cathepsins: Cellular roadmap to different functions. Biochimie, 2007. [PubMed: 17825974]
8.
Beaudeux J.L., Giral P., Bruckert E., Foglietti M.J., Chapman M.J. Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives. Clin Chem Lab Med. 2004;42(2):121–31. [PubMed: 15061349]
9.
Nelson A.R., Fingleton B., Rothenberg M.L., Matrisian L.M. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol. 2000;18(5):1135–49. [PubMed: 10694567]
10.
Deryugina E.I., Quigley J.P. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2006;25(1):9–34. [PubMed: 16680569]
11.
Skiles J.W., Gonnella N.C., Jeng A.Y. The design, structure, and clinical update of small molecular weight matrix metalloproteinase inhibitors. Curr Med Chem. 2004;11(22):2911–77. [PubMed: 15544483]
12.
Ujula T., Huttunen M., Luoto P., Perakyla H., Simpura I., Wilson I., Bergman M., Roivainen A. Matrix metalloproteinase 9 targeting peptides: syntheses, 68Ga-labeling, and preliminary evaluation in a rat melanoma xenograft model. Bioconjug Chem. 2010;21(9):1612–21. [PubMed: 20795647]
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