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Radiolabeled GX1 Peptide for Tumor Angiogenesis Imaging

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Abstract

Early and accurate detection of primary or metastatic tumors is of great value in staging, treatment management, and prognosis. Tumor angiogenesis plays an essential role in the growth, invasion, and metastatic spread of solid cancers, and so, is a promising approach for tumor imaging. The GX1 (CGNSNPKSC) peptide was identified by phage display library and has been investigated as a marker for human cancers. This study aims to evaluate the 99mTc-HYNIC-PEG4-c (GX1) as a biomarker for tumor imaging. Our results showed that GX1 specifically binds to tumor cells in vitro. SKMEL28 and MDA-MB231 cells achieved total binding peak at 60 min of incubation. For B16F10 and MKN45 cells, the total and specific binding were similar during all time points, while A549 cell line showed rapid cellular total uptake of the tracer at 30 min of incubation. Biodistribution showed low non-specific uptakes and rapid renal excretion. Melanoma tumors showed enhanced GX1 uptake in animal model at 60 min, and it was significantly blocked by cold peptide. The radiotracer showed tumor specificity, especially in melanomas that are highly vascularized tumors. In this sense, it should be considered in future studies, aiming to evaluate degree of angiogenesis, progression, and invasion of tumors.

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References

  1. Gorin, M. A., Rowe, S. P., & Denmeade, S. R. (2017). Clinical applications of molecular imaging in the management of prostate cancer. PET Clin., 12(2), 185–192. https://doi.org/10.1016/j.cpet.2016.11.001

    Article  PubMed  Google Scholar 

  2. Pennant, M., Takwoingi, Y., Pennant, L., Davenport, C., Fry-Smith, A., Eisinga, A., Andronis, L., Arvanitis, T., Deeks, J., & Hyde, C. (2010). A systematic review of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence. Health Technology Assessment, 14(50), 1–103. https://doi.org/10.3310/hta14500

    Article  CAS  PubMed  Google Scholar 

  3. Niikura, N., Costelloe, C. M., Madewell, J. E., Hayashi, N., Yu, T. K., Liu, J., Palla, S. L., Tokuda, Y., Theriault, R. L., Hortobagyi, G. N., & Ueno, N. T. (2011). FDG-PET/CT compared with conventional imaging in the detection of distant metastases of primary breast cancer. The Oncologist., 16(8), 1111–1119. https://doi.org/10.1634/theoncologist.2011-0089

    Article  PubMed  PubMed Central  Google Scholar 

  4. Ferro-Flores, G., Ocampo-García, B. E., Santos-Cuevas, C. L., Morales-Avila, E., & Azorín-Vega, E. (2014). Multifunctional radiolabeled nanoparticles for targeted therapy. Current Medicinal Chemistry, 21(1), 124–138.

    Article  CAS  PubMed  Google Scholar 

  5. Müller, C., & Schibli, R. (2013). Single photon emission computed tomography tracer. Recent Results in Cancer Research, 187, 65–105. https://doi.org/10.1007/978-3-642-10853-2_2

    Article  CAS  PubMed  Google Scholar 

  6. Dash, A., Knapp, F. F., & Pillai, M. R. A. (2013). 99Mo/99mTc separation: an assessment of technology options. Nuclear Medicine and Biology, 40(2), 167–176. https://doi.org/10.1016/j.nucmedbio.2012.10.005

    Article  CAS  PubMed  Google Scholar 

  7. Torre, L. A., Siegel, R. L., Ward, E. M., & Jemal, A. (2016). Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiology, Biomarkers & Prevention, 25(1), 16–27. https://doi.org/10.1158/1055-9965.EPI-15-0578

    Article  Google Scholar 

  8. Folkman, J. (2003). Angiogenesis and apoptosis. Seminars in Cancer Biology, 13(2), 159–167. https://doi.org/10.1016/S1044-579X(02)00133-5

    Article  CAS  PubMed  Google Scholar 

  9. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D. M., Forman, D., & Bray, F. (2015). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer, 136, E359–E386.

    Article  CAS  PubMed  Google Scholar 

  10. American Cancer Society. Key Statistics on Lung Cancer. Available online: www.cancer.org/cancer/non-small-cell-lung-cancer/about/key-statistics.html

  11. Hou, Q., Tan, H. T., Lim, K. H., Lim, T. K., Khoo, A., Tan, I. B., Yeoh, K. G., & Chung, M. C. (2013). Identification and functional validation of caldesmon as a potential gastric cancer metastasis-associated protein. Journal of Proteome Research, 12(2), 980–990. https://doi.org/10.1021/pr3010259

    Article  CAS  PubMed  Google Scholar 

  12. Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., & Forman, D. (2011). Global cancer statistics. CA: a Cancer Journal for Clinicians, 61(2), 69–90. https://doi.org/10.3322/caac.20107

    Article  Google Scholar 

  13. Durkan, K., Lambrecht, F. Y., & Unak, P. (2007). Radiolabeling of bombesin-like peptide with 99mTc: 99mTc-litorin and biodistribution in rats. Bioconjugate Chemistry, 18(5), 1516–1520. https://doi.org/10.1021/bc060400x

    Article  CAS  PubMed  Google Scholar 

  14. Okarvi, S. M. (2004). Peptide-based radiopharmaceuticals: future tools for diagnostic imaging of cancers and other diseases. Medicinal Research Reviews, 24(3), 357–397. https://doi.org/10.1002/med.20002

    Article  CAS  PubMed  Google Scholar 

  15. Oyen, W. J. G., Bodei, L., Giammarile, F., Maecke, H. R., Tennvall, J., Luster, M., & Brans, B. (2007). Targeted therapy in nuclear medicine—current status and future prospects. Annals of Oncology, 18(11), 1782–1792. https://doi.org/10.1093/annonc/mdm111

    Article  CAS  PubMed  Google Scholar 

  16. Hu, H., Yin, J., Wang, M., Liang, C., Song, H., Wang, J., Nie, Y., Liang, J., & Wu, K. (2014). GX1 targeting delivery of rmhTNFα evaluated using multimodality imaging. International Journal of Pharmaceutics, 461(1–2), 181–191. https://doi.org/10.1016/j.ijpharm.2013.11.016

    Article  CAS  PubMed  Google Scholar 

  17. Hui, X., Han, Y., Liang, S., Liu, Z., Liu, J., Hong, L., Zhao, L., He, L., Cao, S., Chen, B., Yan, K., Jin, B., Chai, N., Wang, J., Wu, K., & Fan, D. (2008). Specific targeting of the vasculature of gastric cancer by a new tumor-homing peptide CGNSNPKSC. Journal of Controlled Release, 131(2), 86–93. https://doi.org/10.1016/j.jconrel.2008.07.024

    Article  CAS  PubMed  Google Scholar 

  18. Zhi, M., Wu, K. C., Dong, L., Hao, Z. M., Deng, T. Z., Hong, L., Liang, S. H., Zhao, P. T., Qiao, T. D., Wang, Y., Xu, X., & Fan, D. M. (2004). Characterization of a specific phage-displayed peptide binding to vasculature of human gastric cancer. Cancer Biology & Therapy, 3(12), 1232–1235. https://doi.org/10.4161/cbt.3.12.1223

    Article  CAS  Google Scholar 

  19. Oliveira, E. A., Faintuch, B. L., Targino, R. C., Moro, A. M., Martinez, R. C., Pagano, R. L., Fonoff, E. T., Carneiro, C. G., Garcez, A. T., Faria, D. P., & Buchpiguel, C. A. (2016). Evaluation of GX1 and RGD-GX1 peptides as new radiotracers for angiogenesis evaluation in experimental glioma models. Amino Acids, 48(3), 821–831. https://doi.org/10.1007/s00726-015-2130-y

    Article  CAS  PubMed  Google Scholar 

  20. Oliveira, E.A., Lazovic, J., Guo, L., Soto, H., Faintuch, B.L., Akhtari, M., Pope, W. (2017) Evaluation of magnetonanoparticles conjugated with new angiogenesis peptides in intracranial glioma tumors by MRI. Appl Biochem Biotechnol. Mar 9. https://doi.org/10.1007/s12010-017-2443-2.

  21. Yin, J., Hui, X., Yao, L., Li, M., Hu, H., Zhang, J., Xin, B., He, M., Wang, J., Nie, Y., & Wu, K. (2015). Evaluation of Tc-99 m labeled dimeric GX1 peptides for imaging of colorectal cancer vasculature. Molecular Imaging and Biology, 17(5), 661–670. https://doi.org/10.1007/s11307-015-0838-4

    Article  CAS  PubMed  Google Scholar 

  22. Oliveira, E. A., & Faintuch, B. L. (2015). Radiolabeling and biological evaluation of the GX1 and RGD-GX1 peptide sequence for angiogenesis targeting. Nuclear Medicine and Biology, 42(2), 123–130. https://doi.org/10.1016/j.nucmedbio.2014.09.004

    Article  CAS  PubMed  Google Scholar 

  23. Ferlay, F.B.J., Soerjomataram, I., Ervik, M., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., Parkin, D.M., Forman, D. (2016) GLOBOCAN 2012. Cancer incidence and mortality worldwide: IARC CancerBase No. 11 Int. Agency Res. Cancer, Lyon.

  24. Ferreira, C. A., Fuscaldi, L. L., Townsend, D. M., Rubello, D., & Barros, A. L. (2017). Radiolabeled bombesin derivatives for preclinical oncological imaging. Biomedicine & Pharmacotherapy, 87, 58–72. https://doi.org/10.1016/j.biopha.2016.12.083

    Article  CAS  Google Scholar 

  25. Laverman, P., Sosabowski, J. K., Boerman, O. C., & Oyen, W. J. G. (2012). Radiolabelled peptides for oncological diagnosis. European Journal of Nuclear Medicine and Molecular Imaging, 39(Suppl. 1), 78–92. https://doi.org/10.1007/s00259-011-2014-7

    Article  CAS  PubMed Central  Google Scholar 

  26. Schottelius, M., & Wester, H. J. (2009). Molecular imaging targeting peptide receptors. Methods, 48(2), 161–177. https://doi.org/10.1016/j.ymeth.2009.03.012

    Article  CAS  PubMed  Google Scholar 

  27. Sun, X., Li, Y., Liu, T., Li, Z., Zhang, X., Chen, X. (2016) Peptide-based imaging agents for cancer detection. Adv Drug Deliv Ver. S0169-409X(16)30191-0.

  28. Adessi, C., & Soto, C. (2002). Converting a peptide into a drug: strategies to improve stability and bioavailability. Current Medicinal Chemistry, 9(9), 963–978. https://doi.org/10.2174/0929867024606731

    Article  CAS  PubMed  Google Scholar 

  29. Davies, J. S. (2003). The cyclization of peptides and depsipeptides. Journal of Peptide Science, 9(8), 471–501. https://doi.org/10.1002/psc.491

    Article  CAS  PubMed  Google Scholar 

  30. Hashemi, M., Ayatollahi, S., Parhiz, H., Mokhtarzadeh, A., Javidi, S., & Ramezani, M. (2015). PEGylation of polypropylenimine dendrimer with alkylcarboxylate chain linkage to improve DNA delivery and cytotoxicity. Applied Biochemistry and Biotechnology, 177(1), 1–17. https://doi.org/10.1007/s12010-015-1723-y

    Article  CAS  PubMed  Google Scholar 

  31. Beer, A. J., Eiber, M., Souvatzoglou, M., Schwaiger, M., & Krause, B. J. (2011). Radionuclide and hybrid imaging of recurrent prostate cancer. The Lancet Oncology, 12(2), 181–191. https://doi.org/10.1016/S1470-2045(10)70103-0

    Article  PubMed  Google Scholar 

  32. Higgins, L. J., & Pomper, M. G. (2011). The evolution of imaging in cancer: current state and future challenges. Seminars in Oncology, 38(1), 3–15. https://doi.org/10.1053/j.seminoncol.2010.11.010

    Article  PubMed  PubMed Central  Google Scholar 

  33. Emonds, K. M., Swinnen, J. V., Mortelmans, L., & Mottaghy, F. M. (2009). Molecular imaging of prostate cancer. Methods, 48(2), 193–199. https://doi.org/10.1016/j.ymeth.2009.03.021

    Article  CAS  PubMed  Google Scholar 

  34. Santos-Cuevas, C. L., Ferro-Flores, G., Arteaga de Murphy, C., de Ramírez, F. M., Luna-Gutiérrez, M. A., Pedraza-López, M., García-Becerra, R., & Ordaz-Rosado, D. (2009). Design, preparation, in vitro and in vivo evaluation of 99mTc-N2S2-tat(49–57)-bombesin: a target-specific hybrid radiopharmaceutical. International Journal of Pharmaceutics, 375(1-2), 75–83. https://doi.org/10.1016/j.ijpharm.2009.04.018

    Article  CAS  PubMed  Google Scholar 

  35. Barros, A. L. B., & Fuscaldi, L. L. (2014). Radiolabeled peptides as imaging probes for cancer diagnosis. J Mol Pharm Org Process Res., 2, e115.

    Google Scholar 

  36. Ambrosini, V., Fani, M., Fanti, S., Forrer, F., & Maecke, H. R. (2011). Radiopeptide imaging and therapy in Europe. Journal of Nuclear Medicine, 52(Suppl 2), 42S–55S. https://doi.org/10.2967/jnumed.110.085753

    Article  CAS  PubMed  Google Scholar 

  37. Chen, H., Niu, G., Wu, H., & Chen, X. (2016). Clinical application of radiolabeled RGD peptides for PET imaging of integrin αvβ3. Theranostics., 6(1), 78–92. https://doi.org/10.7150/thno.13242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Mittra, E. S., Goris, M. L., Iagaru, A. H., Kardan, A., Burton, L., Berganos, R., Chang, E., Liu, S., Shen, B., & Chin, F. T. (2011). Pilot pharmacokinetic and dosimetric studies of 18F-FPPRGD2: a PET radiopharmaceutical agent for imaging avb3 integrin levels. Radiology, 260(1), 182–191. https://doi.org/10.1148/radiol.11101139

    Article  PubMed  PubMed Central  Google Scholar 

  39. Opalinska, M., Hubalewska-Dydejczyk, A., & Sowa-Staszczak, A. (2017). Radiolabeled peptides: current and new perspectives. The Quarterly Journal of Nuclear Medicine and Molecular Imaging, 61(2), 153–167. https://doi.org/10.23736/S1824-4785.17.02971-5

    Article  PubMed  Google Scholar 

  40. Christ, E., Wild, D., Forrer, F., Brändle, M., Sahli, R., Clerici, T., Gloor, B., Martius, F., Maecke, H., & Reubi, J. C. (2009). Glucagon-like peptide-1 receptor imaging for localization of insulinomas. The Journal of Clinical Endocrinology and Metabolism, 94(11), 4398–4405. https://doi.org/10.1210/jc.2009-1082

    Article  CAS  PubMed  Google Scholar 

  41. Kazmierczak, P. M., Todica, A., Gildehaus, F. J., Hirner-Eppeneder, H., Brendel, M., Eschbach, R. S., Hellmann, M., Nikolaou, K., Reiser, M. F., Wester, H. J., Kropf, S., Rominger, A., & Cyran, C. C. (2016). 68Ga-TRAP-(RGD)3 hybrid imaging for the in vivo monitoring of αvß3-integrin expression as biomarker of anti-angiogenic therapy effects in experimental breast cancer. PLoS One, 11(12), e0168248. https://doi.org/10.1371/journal.pone.0168248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Zhao, Z. Q., Yang, Y., Fang, W., & Liu, S. (2016). Comparison of biological properties of 99mTc-labeled cyclic RGD peptide trimer and dimer useful as SPECT radiotracers for tumor imaging. Nuclear Medicine and Biology, 43(11), 661–669. https://doi.org/10.1016/j.nucmedbio.2016.02.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Zhang, J., Niu, G., Lang, L., Li, F., Fan, X., Yan, X., Yao, S., Yan, W., Huo, L., Chen, L., Li, Z., Zhu, Z., & Chen, X. (2017). Clinical translation of a dual integrin αvβ3- and gastrin-releasing peptide receptor-targeting PET radiotracer, 68Ga-BBN-RGD. Journal of Nuclear Medicine, 58(2), 228–234. https://doi.org/10.2967/jnumed.116.177048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Du, Y., Zhang, Q., Jing, L., Liang, X., Chi, C., Li, Y., Yang, X., Dai, Z., & Tian, J. (2015). GX1-conjugated poly(lactic acid) nanoparticles encapsulating Endostar for improved in vivo anticolorectal cancer treatment. International Journal of Nanomedicine, 10, 3791–3802. https://doi.org/10.2147/IJN.S82029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Oliveira, E. A., Lazovic, J., Guo, L., Soto, H., Faintuch, B. L., Akhtari, M., & Pope, W. (2017). Evaluation of magnetonanoparticles conjugated with new angiogenesis peptides in intracranial glioma tumors by MRI. Applied Biochemistry and Biotechnology, 183(1), 265–279. https://doi.org/10.1007/s12010-017-2443-2

    Article  CAS  PubMed  Google Scholar 

  46. Viana, C. T., Campos, P. P., Carvalho, L. A., Cenedezi, J. M., Lavall, L., Lopes, M. T., Ferreira, M. A., & Andrade, S. P. (2013). Distinct types of tumors exhibit differential grade of inflammation and angiogenesis in mice. Microvascular Research, 86, 44–51. https://doi.org/10.1016/j.mvr.2012.12.002

    Article  CAS  PubMed  Google Scholar 

  47. Oliveira, É. A., Faintuch, B. L., Núñez, E. G., Moro, A. M., Nanda, P. K., & Smith, C. J. (2012). Radiotracers for different angiogenesis receptors in a melanoma model. Melanoma Research, 22(1), 45–53. https://doi.org/10.1097/CMR.0b013e32834e6a7e

    Article  CAS  PubMed  Google Scholar 

  48. Abdollahi, A., Lipson, K. E., Sckell, A., Zieher, H., Klenke, F., Poerschke, D., Roth, A., Han, X., Krix, M., Bischof, M., Hahnfeldt, P., Grone, H. J., Debus, J., Hlatky, L., & Huber, P. E. (2003). Combined therapy with direct and indirect angiogenesis inhibition results in enhanced antiangiogenic and antitumor effects. Cancer Research, 63(24), 8890–8898.

    CAS  PubMed  Google Scholar 

  49. Katkoori, V. R., Basson, M. D., Bond, V. C., Manne, U., & Bumpers, H. L. (2015). Nef-M1, a peptide antagonist of CXCR4, inhibits tumor angiogenesis and epithelial-to-mesenchymal transition in colon and breast cancers. Oncotarget, 6(29), 27763–27777. https://doi.org/10.18632/oncotarget.4615

    Article  PubMed  PubMed Central  Google Scholar 

  50. Zhang, X., Xiong, Z., Wu, Y., Cai, W., Tseng, J. R., Gambhir, S. S., & Chen, X. (2006). Quantitative PET imaging of tumor integrin alphavbeta3 expression with 18F-FRGD2. Journal of Nuclear Medicine, 47(1), 113–121.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Aktaş, S. H., Akbulut Yazici, H. O., Zengin, N., Akgün, H. N., Üstüner, Z., & Içli, F. (2017). A new angiogenesis prognostic index with VEGFA, PlGF, and angiopoietin1 predicts survival in patients with advanced gastric cancer. Turk J Med Sci, 47(2), 399–406.

    Article  PubMed  Google Scholar 

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Acknowledgements

The authors are grateful for a postgraduate Grant by Fundação de Amparo a Pesquisa do Estado de São Paulo, Brazil (Fapesp 2011/12405-0). Also, we would like to thank Natanael Gomes da Silva for their technical assistance.

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  1. Érica Aparecida de Oliveira

    Present address: School of Pharmaceutical Sciences, University of Sao Paulo, Av. Prof. Lineu Prestes, 580 Bloco 17, São Paulo, SP, 05508-900, Brazil

Authors and Affiliations

  1. Radiopharmacy Center, Institute of Energy and Nuclear Research, Av. Prof. Lineu Prestes, 2242, São Paulo, 05508-000, Brazil

    Érica Aparecida de Oliveira, Bluma Linkowski Faintuch & Daniele Seo

  2. Radiation Technology Center, Institute of Energy and Nuclear Research, Av. Prof. Lineu Prestes, 2242, São Paulo, 05508-000, Brazil

    Angélica Bueno Barbezan & Ana Funari

  3. Laboratory of Biopharmacology in Animal Cells, Butantan Institute, Av. Vital Brasil, 1500, Sao Paulo, 05503-900, Brazil

    Roselaine Campos Targino & Ana Maria Moro

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de Oliveira, É.A., Faintuch, B.L., Seo, D. et al. Radiolabeled GX1 Peptide for Tumor Angiogenesis Imaging. Appl Biochem Biotechnol 185, 863–874 (2018). https://doi.org/10.1007/s12010-018-2700-z

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