Journal of Radiopharmaceuticals and Molecular Probes (대한방사성의약품학회지)

Korean Society of Radiopharmaceuticals and Molecular Probes (대한방사성의약품학회)
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Synthesis and in vitro evaluation of 99mTc-labeled tetraiodothyroacetic acid for tumor angiogenesis imaging

  • Kim, Hyunjung (Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Koo, Hyun-Jung (Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine) ;
  • Choe, Yearn Seong (Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • Received : 2020.06.15
  • Accepted : 2020.06.26
  • Published : 2020.06.30
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Abstract

Tetraiodothyroacetic acid (tetrac) is a derivative of thyroid hormone T4 and causes anti-angiogenesis by blocking T4 binding to integrin αvβ3. In this study, we synthesized [99mTc]Tc-Cys-Asp-Gly(CDG)-tetrac and evaluated it in vitro as a tumor angiogenesis imaging ligand. The CDG was conjugated to tetrac as a chelator for technetium-99m labeling. The cold vial containing CDG-tetrac, sodium glucoheptonate, and reducing agent was completed under nitrogen-filled atmospheric glove bag. [99mTc]Tc-CDG-tetrac was synthesized in quantitative yield by heating the cold vial with [99mTc]TcO4- at 100℃ for 30 min. In vitro serum stability of [99mTc]Tc-CDG-tetrac was measured by incubating the radioligand in 50% fetal bovine serum at 37℃ and analyzing the incubation mixture by radio-TLC, which showed high stability over 6 h (≥ 98%). Cell binding study was carried out by incubating [99mTc]Tc-CDG-tetrac with human umbilical vein endothelial (HUVE) cells at 37℃ for 6 h. The cell binding of the radioligand increased from 100% at 0.5 h to 293.7% at 6 h in a time-dependent manner. For blocking study, the cells were incubated with the radioligand in the presence of either tetrac (20 μM) or cRGDyK (20 μM) at 37℃ for 4 h. The results demonstrated that the cell binding of the radioligand was inhibited by tetrac (19.1%) or cRGDyK (35.6%), indicating specific binding of the radioligand to integrin αvβ3. Thus, this study suggests that [99mTc]Tc-CDG-tetrac may be a potential radioligand for tumor angiogenesis imaging.

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References

  1. Bielenberg DR, Zetter BR. The Contribution of angiogenesis to the process of metastasis. Cancer J 2015;21:267-73. https://doi.org/10.1097/PPO.0000000000000138
  2. Nishida N, Yano H, Nishida T, Kamura T, Kojiro M. Angiogenesis in cancer. Vasc Health Risk Manag 2006;2:213-9. https://doi.org/10.2147/vhrm.2006.2.3.213
  3. Brooks PC. Role of integrins in angiogenesis. Eur J Cancer 1996;32:2423-9. https://doi.org/10.1016/S0959-8049(96)00381-4
  4. Jin H, Varner J. Integrins: roles in cancer development and as treatment targets. Br J Cancer 2004;90:561-5. https://doi.org/10.1038/sj.bjc.6601576
  5. Varner JA, Cheresh DA. Integrins and cancer. Curr Opin Cell Biol 1996;8:724-30. https://doi.org/10.1016/S0955-0674(96)80115-3
  6. Hood JD, Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer 2002;2:91-100. https://doi.org/10.1038/nrc727
  7. Brooks PC, Clark RA, Cheresh DA. Requirement of vascular integrin ${\alpha}_{v}{\beta}_{3}$ for angiogenesis. Science 1994;264:569-71. https://doi.org/10.1126/science.7512751
  8. Choe YS, Lee KH. Targeted in vivo imaging of angiogenesis: present status and perspectives. Curr Pharm Design 2007;13:17-31. https://doi.org/10.2174/138161207779313812
  9. Haubner R, Wester HJ, Reuning U, Senekowitsch-Schmidtke R, Diefenbach B, Kessler H, Stocklin G, Schwaiger M. Raiolabeled ${\alpha}_{v}{\beta}_{3}$ integrin antagonists: a new class of tracers for tumor targeting. J Nucl Med 1999;40:1061-71.
  10. Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, Senekowitsch-Schmidtke R, Kessler H, Schwaiger M. Noninvasive imaging of ${\alpha}_{v}{\beta}_{3}$ integrin expression using $^{18}F$-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res 2001; 61:1781-5.
  11. Jung KH, Lee KH, Paik JY, Ko BH, Bae JS, Lee BC, Sung HJ, Kim DH, Choe YS, Chi DY. Favorable biokinetic and tumor-targeting properties of $^{99m}Tc$-labeled glucosamino RGD and effect of Paclitaxel therapy. J Nucl Med 2006;47:2000-7.
  12. Bergh JJ, Lin HY, Lansing L, Mohamed SN, Davis FB, Mousa SA, Davis PJ. Integrin ${\alpha}_{v}{\beta}_{3}$ contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 2005;146:2864-71. https://doi.org/10.1210/en.2005-0102
  13. Mousa SA, Bergh JJ, Dier E, Rebbaa A, O'Connor LJ, Yalcin M, Aljada A, Dyskin E, Davis FB, Lin HY, Davis PJ. Tetraiodothyroacetic acid, a small molecule integrin ligand, blocks angiogenesis induced by vascular endothelial growth factor and basic fibroblast growth factor. Angiogenesis 2008;11:183-90. https://doi.org/10.1007/s10456-007-9088-7
  14. Kang CM, Koo HJ, Lee S, Lee KC, Oh YK, Choe YS. $^{64}Cu$-Labeled tetraiodothyroacetic acid-conjugated liposomes for PET imaging of tumor angiogenesis. Nucl Med Biol 2013;40:1018-24. https://doi.org/10.1016/j.nucmedbio.2013.08.003
  15. Kim H, Koo HJ, Ahn J, Kim JY, Choi JY, Lee KH, Kim BT, Choe YS. Synthesis and characterization of $^{64}Cu$and Cy5.5-labeled tetraiodothyroacetic acid derivatives for tumor angiogenesis imaging. Bioorg Med Chem 2020;28:115212. https://doi.org/10.1016/j.bmc.2019.115212
  16. Nunez R, Erwin WD, Wendt RE 3rd, Stachowiak A, Mar M, Stevens D, Madewell JE, Yeung HW, Macapinlac HA. Acquisition parameters for oncologic imaging with a new SPECT/multislice CT scanner. Mol Imaging Biol 2010;12:110-38. https://doi.org/10.1007/s11307-009-0266-4
  17. Saha GB. Fundamentals of nuclear pharmacy. 5th ed. New York: Springer; 2004. p. 97.
  18. Choe YS. Radiolabeling methods used for preparation of molecular probes. Korean J Nucl Med 2004;38:121-30.
  19. Leamon CP, Parker MA, Vlahov IR, Xu LC, Reddy JA, Vetzel M, Douglas N. Synthesis and biological evaluation of EC20: a new folate-derived, $^{99m}Tc$-based radiopharmaceutical. Bioconjugate Chem 2002;13:1200-10. https://doi.org/10.1021/bc0200430
  20. Kim MH, Kim WH, Kim CG, Kim DW. Synthesis and evaluation of $^{99m}Tc$-labeled folate-tripeptide conjugate as a folate receptor-targeted imaging agent in a tumor-bearing mouse model. Nucl Med Mol Imaging 2015;49:200-7. https://doi.org/10.1007/s13139-015-0336-2
  21. Liu S. Bifunctional coupling agents for radiolabeling of biomolecules and target-specific delivery of metallic radionuclides. Adv Drug Deliv Rev 2008;60:1347-70. https://doi.org/10.1016/j.addr.2008.04.006
  22. Saha GB. Fundamentals of nuclear pharmacy. 5th ed. New York: Springer; 2004. p. 111.
  23. Turaga RC, Yin L, Yang JJ, Lee H, Lvanov L, Yan C, Yang H, Grossniklaus HE, Wang S, Ma C, Sun L, Liu ZR. Rational design of a protein that binds integrin ${\alpha}_{v}{\beta}_{3}$ outside the ligand binding site. Nat Commun 2016;31:11675.
  24. Zhang X, Xiong Z, Wu Y, Cai W, Tseng JR, Gambhir SS, Chen X. Quantitative PET imaging of tumor integrin ${\alpha}_{v}{\beta}_{3}$ expression with $^{18}F$-FRGD2. J Nucl Med 2006;47:113-21