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68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Epidermal growth factor

68Ga-DOTA-EGF
, PhD
National for Biotechnology Information, NLM, NIH, Bethesda, MD
Corresponding author.

Created: ; Last Update: April 10, 2012.

Chemical name:68Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Epidermal growth factor
Abbreviated name:68Ga-DOTA-EGF
Synonym:
Agent category:Polypeptide
Target:EGF receptor (EGFR, HER1)
Target category:Receptor
Method of detection:PET
Source of signal:68Ga
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
Click on protein, nucleotide (RefSeq), and gene for more information about EGF.

Background

[PubMed]

Epidermal growth factor (EGF) is a 53-amino acid cytokine (6.2 kDa) secreted by ectodermic cells, monocytes, kidneys, and duodenal glands (1). EGF stimulates growth of epidermal and epithelial cells. EGF and at least seven other growth factors and their transmembrane receptor kinases play important roles in cell proliferation, survival, adhesion, migration, and differentiation. The EGF receptor (EGFR) family consists of four transmembrane receptors, including EGFR (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4) (2). HER1, HER3, and HER4 comprise three major functional domains: an extracellular ligand-binding domain, a hydrophobic transmembrane domain, and a cytoplasmic tyrosine kinase domain. No ligand has been clearly identified for HER2. However, HER2 can be activated as a result of ligand binding to other HER receptors with the formation of receptor homodimers and/or heterodimers (3). HER1 as well as HER2 are overexpressed on many solid tumor cells such as breast, non–small-cell lung, head and neck, and colon cancers (4-6). The high levels of HER1 and HER2 expression on cancer cells are associated with a poor prognosis (7-10).

Trastuzumab (a humanized immunoglobulin G1 (IgG1) monoclonal antibody against the extracellular domain of recombinant HER2) (11) and C225 (an anti-EGFR, chimeric, monoclonal antibody) have been labeled as 111In-trastuzumab (12-14) and 99mTc-EC-C225 (15, 16) for imaging EGFR expression on solid tumors using single-photon emission computed tomography (SPECT). However, antibodies that are approximately 25-fold larger than EGF may not be easily transported to cells within solid tumors. Therefore, 111In-EGF and 99mTc-HYNIC-EGF have been developed for SPECT imaging studies of tumors (17, 18). However, positron emission tomography (PET) offers better sensitivity, resolution, and quantification than SPECT (19). 68Ga (t1/2 = 68 min, 89% β+ decay) is an attractive radionuclide for labeling EGF and is readily available from a commercial 68Ge/68Ga generator. Cells retain 68Ga well, providing a good signal/background ratio. For evaluation as a PET imaging agent, 68Ga has been attached to EGF via 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA) to form 68Ga-DOTA-EGF (20).

Synthesis

[PubMed]

Commercially available monofunctional N-hydroxysuccinimide ester of DOTA was used to conjugate human EGF to form DOTA-EGF, which was purified by column chromatography (20). 68Ga was conjugated to DOTA-EGF under microwave heating for 1 min to 95°C. 68Ga-DOTA-EGF was purified by column chromatography. The yield of 68Ga-DOTA-EGF was 60–77% with a radiochemical purity >95% and specific activities of 12–20 MBq/nmol (0.32–0.54 mCi/nmol).

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Velikyan et al. (20) performed cell-binding assays with 68Ga-DOTA-EGF using EGFR-expressing human cervical carcinoma A431 and glioma U343 cell lines. Binding of 68Ga-DOTA-EGF (approximately 0.01 μM) to both cell lines was completely blocked by EGF (approximately 1 μM). Saturation binding experiments determined that dissociation constant (Kd) values were 2.0 and 2.3 nM for A431 and U343 cells, respectively. The number of binding sites per cells was 1.9 × 106 per A431 cell and 7.8 × 105 per U343 cell. Both cell lines rapidly internalized 68Ga-DOTA-EGF at 37°C.

Animal Studies

Rodents

[PubMed]

Velikyan et al. (20) studied the biodistribution of 68Ga-DOTA-EGF in nude mice bearing an A431 xenograft. The organs with the highest accumulation at 30 min after 68Ga-DOTA-EGF injection were the kidneys and liver (>35%ID/g), followed by the pancreas, salivary gland, small and large intestines, stomach, and spleen. The uptake of 68Ga-DOTA-EGF in the A431 tumor xenograft was 1.51 ± 0.16 and 2.69 ± 0.29%ID/g for 0.016 and 0.16 nmol 68Ga-DOTA-EGF, respectively (P = 0.036). The radiotracer had a rapid blood clearance at 30 min with tumor/blood ratios of 4.42 ± 1.81 and 4.50 ± 2.53 for 0.016 and 0.16 nmol 68Ga-DOTA-EGF, respectively. Very high radioactivity was found in bile, urine, and feces. No blocking experiment was performed.

The whole-body distribution of 68Ga-DOTA-EGF (2.0 MBq/mouse or 0.05 mCi/mouse) was also assessed by PET imaging from 20–30 min after injection. The highest activity concentrations were visualized in the kidneys and liver with clearance of radioactivity through the urinary bladder. The accumulation of 68Ga-DOTA-EGF was clearly visible in the tumors. 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

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Carpenter G., Cohen S. Epidermal growth factor. J Biol Chem. 1990;265(14):7709–12. [PubMed: 2186024]
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Yarden Y. The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities. Eur J Cancer. 2001;37 Suppl 4:S3–8. [PubMed: 11597398]
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Rubin I., Yarden Y. The basic biology of HER2. Ann Oncol. 2001;12 Suppl 1:S3–8. [PubMed: 11521719]
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Grunwald V., Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Natl Cancer Inst. 2003;95(12):851–67. [PubMed: 12813169]
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Mendelsohn J. Anti-epidermal growth factor receptor monoclonal antibodies as potential anti-cancer agents. J Steroid Biochem Mol Biol. 1990;37(6):889–92. [PubMed: 2285602]
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Yasui W., Sumiyoshi H., Hata J., Kameda T., Ochiai A., Ito H., Tahara E. Expression of epidermal growth factor receptor in human gastric and colonic carcinomas. Cancer Res. 1988;48(1):137–41. [PubMed: 2446740]
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Ang K.K., Berkey B.A., Tu X., Zhang H.Z., Katz R., Hammond E.H., Fu K.K., Milas L. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350–6. [PubMed: 12499279]
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Costa S., Stamm H., Almendral A., Ludwig H., Wyss R., Fabbro D., Ernst A., Takahashi A., Eppenberger U. Predictive value of EGF receptor in breast cancer. Lancet. 1988;2(8622):1258. [PubMed: 2903994]
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Ethier S.P. Growth factor synthesis and human breast cancer progression. J Natl Cancer Inst. 1995;87(13):964–73. [PubMed: 7629883]
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Yarden Y. Biology of HER2 and its importance in breast cancer. Oncology. 2001;61 Suppl 2:1–13. [PubMed: 11694782]
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Carter P., Presta L., Gorman C.M., Ridgway J.B., Henner D., Wong W.L., Rowland A.M., Kotts C., Carver M.E., Shepard H.M. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci U S A. 1992;89(10):4285–9. [PMC free article: PMC49066] [PubMed: 1350088]
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Perik P.J., Lub-De Hooge M.N., Gietema J.A., van der Graaf W.T., de Korte M.A., Jonkman S., Kosterink J.G., van Veldhuisen D.J., Sleijfer D.T., Jager P.L., de Vries E.G. Indium-111-labeled trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2006;24(15):2276–82. [PubMed: 16710024]
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Lub-de Hooge M.N., Kosterink J.G., Perik P.J., Nijnuis H., Tran L., Bart J., Suurmeijer A.J., de Jong S., Jager P.L., de Vries E.G. Preclinical characterisation of 111In-DTPA-trastuzumab. Br J Pharmacol. 2004;143(1):99–106. [PMC free article: PMC1575276] [PubMed: 15289297]
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Garmestani K., Milenic D.E., Plascjak P.S., Brechbiel M.W. A new and convenient method for purification of 86Y using a Sr(II) selective resin and comparison of biodistribution of 86Y and 111In labeled Herceptin. Nucl Med Biol. 2002;29(5):599–606. [PubMed: 12088731]
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Schechter N.R., Yang D.J., Azhdarinia A., Kohanim S., Wendt R. 3rd, Oh C.S., Hu M., Yu D.F., Bryant J., Ang K.K., Forster K.M., Kim E.E., Podoloff D.A. Assessment of epidermal growth factor receptor with 99mTc-ethylenedicysteine-C225 monoclonal antibody. Anticancer Drugs. 2003;14(1):49–56. [PubMed: 12544258]
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Schechter N.R., Wendt R.E. 3rd, Yang D.J., Azhdarinia A., Erwin W.D., Stachowiak A.M., Broemeling L.D., Kim E.E., Cox J.D., Podoloff D.A., Ang K.K. Radiation dosimetry of 99mTc-labeled C225 in patients with squamous cell carcinoma of the head and neck. J Nucl Med. 2004;45(10):1683–7. [PubMed: 15471833]
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Cornelissen B., Kersemans V., Burvenich I., Oltenfreiter R., Vanderheyden J.L., Boerman O., Vandewiele C., Slegers G. Synthesis, biodistribution and effects of farnesyltransferase inhibitor therapy on tumour uptake in mice of 99mTc labelled epidermal growth factor. Nucl Med Commun. 2005;26(2):147–53. [PubMed: 15657509]
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Reilly R.M., Kiarash R., Sandhu J., Lee Y.W., Cameron R.G., Hendler A., Vallis K., Gariepy J. A comparison of EGF and MAb 528 labeled with 111In for imaging human breast cancer. J Nucl Med. 2000;41(5):903–11. [PubMed: 10809207]
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Lundqvist H., Tolmachev V. Targeting peptides and positron emission tomography. Biopolymers. 2002;66(6):381–92. [PubMed: 12658725]
20.
Velikyan I., Sundberg A.L., Lindhe O., Hoglund A.U., Eriksson O., Werner E., Carlsson J., Bergstrom M., Langstrom B., Tolmachev V. Preparation and evaluation of (68)Ga-DOTA-hEGF for visualization of EGFR expression in malignant tumors. J Nucl Med. 2005;46(11):1881–8. [PubMed: 16269603]

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