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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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111Indium-diethylenetriaminepentaacetic acid-folate

111In-DTPA-folate
, PhD
National Center for Biotechnology Information, NLM, NIH
Corresponding author.

Created: ; Last Update: January 29, 2011.

Chemical name:111Indium-diethylenetriaminepentaacetic acid-folateimage 3131789 in the ncbi pubchem database
Abbreviated name:111In-DTPA-folate
Synonym:111In-P3139
Agent category:Compound
Target:Folic acid receptor
Target category:Receptor
Method of detection:Single-photon emission computed tomography (SPECT), gamma planar
Source of signal:111In
Activation:No
Studies:
  • Checkbox In vitro
  • Checkbox Rodents
  • Checkbox Humans
Click on the above structure for additional information in PubChem.

Background

[PubMed]

Folic acid is a water-soluble B vitamin (1). It is essential for methylation and DNA synthesis. The primary pathway for entry of folate into cells is through facilitated transporter, which has a low affinity for folate with Km of 1-5 μM. Some cells in choroid plexus, kidney, lung, thyroid, spleen, placenta, and thymus also possess a high affinity (Kd, 0.5 nM) receptor that allows folate retention via receptor-mediated endocytosis. Some human epithelial tumor cells were found to overexpress folate-binding protein (2). More than 90% of human ovarian and endometrial cancers express the high-affinity receptor, which is absent in the normal tissues. Breast, colorectal, renal, and lung carcinomas also over-expressed the folate receptor but to a lesser frequency (20-50%). Several folate-based conjugates have been studied in tumor imaging. 111In-DTPA-folate was synthesized and developed as a folate receptor imaging agent (3). It was recently shown to be a useful imaging agent in diagnosis of human benign ovarian cancer (4).

Synthesis

[PubMed]

111In-DTPA-folate was obtained in high radiochemical yield by ligand exchange from 111In-citrate with DTPA-folate providing a chemical purity of >92% (3). The specific activity was about 16 μCi/μg (0.6 MBq/μg). DTPA-folate was characterized by analytical HPLC, mass spectroscopy, and NMR. A molar ratio of DTPA to folate of 1:1 was identified.

In Vitro Studies: Testing in Cells and Tissues

[PubMed]

Human nasopharyngeal carcinoma KB cells have a Kd of 1.6 nM for FITC-folate (3). Cellular uptake of 100 nM 111In-DTPA-folate was saturable within 10 min of incubation at room temperature and was completely blocked by 1 mM folate. A549 cells (folate-receptor negative) did not show any specific uptake of 111In-DTPA-folate.

Kinetics of receptor-mediated endocytosis of [3H]folate, FITC-folate and 111In-DTPA-folate was studied in a panel of six folate receptor-positive (3-18 X106 folate per cell) cancer cells (5). All three folate conjugates (50 nM) associated with the cells and approached saturation within 30 min. The rate of internalization (1-3 X 105 molecules/h) for all three folate conjugates was the same for all cells indicating that the rate of internalization is not dependent on folate binding capacity. 111In-DTPA-folate was internalized as efficiently as [3H]folate. Only 10 to 25% of the total cell-bound radioactivity was internalized at 6 h of incubation. The data suggest that most of the folate conjugates either remain on the cell surface or recycle without unloading inside the cells.

Animal Studies

Rodents

[PubMed]

Following intravenous administration to normal rats, the 111In-DTPA-folate radiotracer was found to be efficiently cleared from the blood and primarily excreted into the urine at 4 h postinjection (3). The organ with the highest uptake was the kidneys, followed by the intestines, liver, and urinary bladder. A folate receptor-positive KB cell tumor transplanted in a nude mouse was readily visualized by scintigraphy 1 h following intravenous administration of 111In-DTPA-folate.

Nude mice were inoculated with KB tumor cells, followed by intravenous injection of (200 μCi/mouse, 7.4 MBq/mouse, 17 μg/mouse) 111In-DTPA-folate 15 days after tumor transplantation (6). The tumor uptake of 111In-DTPA-folate was 3.1%ID/g at 4 h postinjection. The tumor-to-blood, tumor-to-liver, tumor-to-kidney and tumor-to-muscle ratios were 346, 31, 1, and 33.3, respectively. Co-injection with 205 μmol/kg unlabeled folate blocked the tumor uptake by 90%. Delaying the injection of unlabeled folate by 3 h after the tracer injection the tumor uptake was only reduced by 22%, suggesting the tracer had mostly been internalized by the tumor cells. The tumor uptake was found to increase from 1 to 30 min and then stabilized from 30 min to 24h postinjection. Tumor uptakes of 111In-DTPA and 111In-citrate were negligible.

Mice were subcutaneously implanted with L1210A, M109, and Line 01 tumors, followed by injections of 50 to 4000 nmol/kg of 111In-DTPA-folate. The three tumors and kidneys all saturated at concentrations of about 2000 nmol/kg. L1210A had the highest uptake, followed by the kidneys, M109 and Line 01. The rate of folate receptor recycling was estimated to be <5.7 h for L1210A, but 13.3 to 20 h for Line 01 and M109 cells. Recycling in the kidney was about 5.7 h. The other normal tissues such as the heart, lung, liver, spleen, intestine, and muscle express fewer folate receptors than the tumor cells; they still recycled their receptors near 8 h. The retention time of a saturable dose of 111In-DTPA-folate in tumor-bearing mice was studied. The unloading rates of 111In-DTPA-folate (about 5.2-6.2 X10-3 nmol/kg/h) were similar for all tumors and the kidney. Although other normal tissues have much lower uptake of 111In-DTPA-folate, their unloading rates are similar to the tumors and kidney.

Other Non-Primate Mammals

[PubMed]

No publication is currently available.

Non-Human Primates

[PubMed]

No publication is currently available.

Human Studies

[PubMed]

111In-DTPA-folate was evaluated for diagnosis of ovarian cancer in women (4). Imaging was performed 4 h post injection of 185 MBq (5 mCi). Among 33 patients who had surgical intervention, 14 had new or recurrent malignant tumors. All of 7 newly diagnosed ovarian carcinomas were identified by both masked and unmasked readers (sensitivity, 100%). The sensitivity for detection of 7 recurrent tumors was 38% for masked readings and 85% for unmasked readings, indicating that correlation with anatomic imaging studies by computer tomography was highly important in diagnosis of these lesions. Eighteen of the studied patients were found to have benign lesions; the specificity of 111In-DTPA-folate scintigraphy was 76% and 82% for the masked and unmasked analyses, respectively. Therefore, 111In-DTPA-folate is safe and effective for scintigraphy differentiating between malignant and benign ovarian lesions.

NIH Support

P30-CA23168, R01-CA70845, R43 CA73260

References

1.
Stanger O. Physiology of folic acid in health and disease. Curr Drug Metab. 2002;3(2):211–23. [PubMed: 12003352]
2.
Ke C.Y., Mathias C.J., Green M.A. The folate receptor as a molecular target for tumor-selective radionuclide delivery. Nucl Med Biol. 2003;30(8):811–7. [PubMed: 14698784]
3.
Wang S., Luo J., Lantrip D.A., Waters D.J., Mathias C.J., Green M.A., Fuchs P.L., Low P.S. Design and synthesis of [111In]DTPA-folate for use as a tumor-targeted radiopharmaceutical. Bioconjug Chem. 1997;8(5):673–9. [PubMed: 9327130]
4.
Siegel B.A., Dehdashti F., Mutch D.G., Podoloff D.A., Wendt R., Sutton G.P., Burt R.W., Ellis P.R., Mathias C.J., Green M.A., Gershenson D.M. Evaluation of 111In-DTPA-folate as a receptor-targeted diagnostic agent for ovarian cancer: initial clinical results. J Nucl Med. 2003;44(5):700–7. [PubMed: 12732670]
5.
Paulos C.M., Reddy J.A., Leamon C.P., Turk M.J., Low P.S. Ligand binding and kinetics of folate receptor recycling in vivo: impact on receptor-mediated drug delivery. Mol Pharmacol. 2004;66(6):1406–14. [PubMed: 15371560]
6.
Mathias C.J., Wang S., Waters D.J., Turek J.J., Low P.S., Green M.A. Indium-111-DTPA-folate as a potential folate-receptor-targeted radiopharmaceutical. J Nucl Med. 1998;39(9):1579–85. [PubMed: 9744347]

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