oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2020-19-3-137-145oncotomsk-1497Research ArticleОБЗОРЫREVIEWSИСПОЛЬЗОВАНИЕ IN VIVO МЕТОДОВ РАДИОНУКЛИДНОЙ ВИЗУАЛИЗАЦИИ В ЭКСПЕРИМЕНТАЛЬНОЙ ОНКОЛОГИИNUCLEAR MEDICINE TECHNIQUES FOR IN VIVO ANIMAL IMAGINGhttps://orcid.org/0000-0002-5144-1039ФиногеноваЮ. А.FinogenovaY. A.

лаборант-исследователь лаборатории радионуклидных и лучевых технологий в экспериментальной онкологии,

115478, г. Москва, Каширское шоссе, 24

Laboratory Research Assistant, Laboratory of Radionuclide and Radiation Technologies in Experimental Oncology,

24, Kashirskoe shosse, 115478, Moscow

lipengolts@mail.ruhttps://orcid.org/0000-0002-5631-9016ЛипенгольцА. А.LipengoltsA. A.

кандидат физико-математических наук, старший научный сотрудник лаборатории радионуклидных и лучевых технологий в экспериментальной онкологии, 115478, г. Москва, Каширское шоссе, 24;

старший научный сотрудник, лаборатория новых методов и технологий лучевой терапии, 123182, г. Москва, ул. Живописная, 46;

старший научный сотрудник лаборатории химии лёгких элементов и кластеров, 119991, г. Москва, Ленинский проспект, 31

PhD, Senior Researcher, Laboratory of Radionuclide and Radiation Technologies in Experimental Oncology, 24, Kashirskoe shosse, 115478, Moscowl;

Senior Researcher, Laboratory of New Methods and Technologies in Radiotherapy, 46, Zhivopisnaya Street, 123182;

Senior Researcher, Laboratory of Light Elements and clusters Chemistry, 31, Leninsky prospect, 119991, Moscow

lipengolts@mail.ruhttps://orcid.org/0000-0003-0386-9732СмирноваА. В.SmirnovaA. V.

кандидат биологических наук, старший научный сотрудник лаборатории радионуклидных и лучевых технологий в экспериментальной онкологии,

115478, г. Москва, Каширское шоссе, 24

PhD, Senior Researcher, Laboratory of Radionuclide and Radiation Technologies in Experimental Oncology,

24, Kashirskoe shosse, 115478, Moscow

https://orcid.org/0000-0001-7726-7991ГригорьеваЕ. Ю.GrigorievaE. Y.

доктор биологических наук, заведующая лабораторией радионуклидных и лучевых технологий в экспериментальной онкологии, 115478, г. Москва, Каширское шоссе, 24;

ведущий научный сотрудник лаборатории химии лёгких элементов и кластеров, 119991, г. Москва, Ленинский проспект, 31

DSc, Head of Laboratory of Radionuclide and Radiation Technologies in Experimental Oncology, 24, Kashirskoe shosse, 115478, Moscow;

Leading Researcher, laboratory of Light Elements and Clusters Chemistry, 31, Leninsky prospect, 119991, Moscow

ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина»РоссияN.N. Blokhin National Medical Research Center of OncologyRussian FederationФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина»; ФГБУ ГНЦ «Федеральный медицинский биофизический центр им. А.И. Бурназяна»; ФГБУН «Институт общей и неорганической химии им. Н.С. Курнакова»РоссияN.N. Blokhin National Medical Research Center of Oncology; Burnasyan Federal Medical Biophysical Center; Kurnakov Institute of General and Inorganic ChemistryRussian FederationФГБУ «Национальный медицинский исследовательский центр онкологии им. Н.Н. Блохина»; ФГБУН «Институт общей и неорганической химии им. Н.С. Курнакова»РоссияN.N. Blokhin National Medical Research Center of Oncology; Kurnakov Institute of General and Inorganic ChemistryRussian Federation202004072020193137145Copyright © Финогенова Ю.А., Липенгольц А.А., Смирнова А.В., Григорьева Е.Ю., 20202020Финогенова Ю.А., Липенгольц А.А., Смирнова А.В., Григорьева Е.Ю.Finogenova Y.A., Lipengolts A.A., Smirnova A.V., Grigorieva E.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/1497

Цель исследования – анализ возможностей радионуклидной визуализации в экспериментальной онкологии при исследованиях на лабораторных животных in vivo.

Материал и методы

Материал и методы. В анализ вошли 49 источников литературы за 2013–19 гг., найденные в системах Scopus, Web of Science, Google Scholar eLIBRARY и Pubmed.

Результаты

Результаты. Современные радионуклидные методы in vivo исследования, такие как позитронная эмиссионная томография и однофотонная эмиссионная компьютерная томография, дают широкий спектр возможностей для исследований в экспериментальной онкологии. Для визуализации опухолевых очагов разной локализации в организме мышей и крыс используются как традиционные клинические радиофармпрепараты ([18F]-FDG и [99mTc]-MDP), так и экспериментальные меченые соединения, такие как [99mTc]-3PRGD2, [99mTc]-HisoDGR, специфичные к интегринам на поверхности опухолевых клеток, [18F]-тетрафтороборат, меченые антитела и др. Помимо визуализации опухолевых очагов методы радионуклидной визуализации позволяют проводить оценку гистологических и физиологических характеристик опухолей, в том числе в динамике при проведении терапии. Моноклональные антитела, меченные 111In, 89Zr или другими изотопами, используются для in vivo оценки в опухолевых тканях уровня экспрессии различных рецепторов, таких как EGFR, HER-2 и др. Исследование гипоксии опухолевых тканей может быть успешно проведено методами радионуклидной визуализации при помощи таких трейсеров, как [64Cu]-ATSM, [18F]-FMISO, меченных антител к карбоангидразе IX и др. Позитронная эмиссионная томография и однофотонная эмиссионная компьютерная томография могут быть использованы для ранней оценки эффективности новых методов противоопухолевой терапии. Радионуклидные методы позволяют оценивать in vivo как повреждения ДНК (дву- и однонитевые разрывы), так и интенсивность апоптоза в опухолевых и нормальных тканях. Наиболее часто используемым трейсером для оценки апоптоза является [99mTc]-дурамицин. Изменение пролиферативной активности в ответ на исследуемое противоопухолевое воздействие может быть оценено при помощи ПЭТ с аналогом тимидина [18F]-FLT.

Заключение

Заключение. Современная радионуклидная визуализация позволяет решать широкий спектр задач экспериментальной онкологии при исследовании и разработке новых противоопухолевых методов. Возможность оценивать многие свойства опухолей до и после терапии в динамике прижизненно повышает эффективность разработки новых методов терапии и диагностики злокачественных опухолей. 

The object of the study was to analyze radionuclide detection techniques for in vivo animal imaging. Material and Methods. A total of 49 publications available from Scopus, Web of Science, Google Scholar eLIBRARY and Pubmed and published between 2013 and 2019 were reviewed. Results. The nuclear medicine techniques, such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) are the most suitable imaging modalities for in vivo animal imaging. Besides traditional radiopharmaceuticals, such as [18F]-FDG and [99mTc]-MDP, the new radiolabeled tracers, such as [99mTc]-3PRGD2, [ 99mTc]-HisoDGR targeted to integrin, [18F]- tetrafluoroborate, labeled antibodies and others have been used for the noninvasive detection of tumors and for monitoring their response to treatment in mice and rats. 111In and 89Zr –labeled monoclonal antibodies are used to evaluate the expression level of many receptors such as EGFR, HER-2 and others in different tumors. PET imaging has demonstrated a good efficacy in tumor hypoxia imaging with [64Cu]-ATSM, [18F]-FMISO. PET and SPECT can also be used for early evaluation of anticancer therapy response. Nuclear imaging techniques may assist in the vivo assessment of DNA damage (doubleand single-strand brakes) as well as apoptosis intensity in tumor and normal tissues. [99mTc]- duramycin is the most commonly used tracer for imaging of apoptosis. Changes in tumor cell proliferation in response to anticancer therapy can be assessed by PET imaging with [18F]-FLT. Conclusion. Nuclear medicine offers a unique means to study cancer biology in vivo and to optimize cancer therapy. 

ПЭТОФЭКТРФПрадионуклидные трейсерылабораторные животныеопухолевые моделиin vivoPETSPECTradiopharmaceuticalsradionuclide tracerslaboratory animalstumor modelsin vivoОбзор выполнен при финансовой поддержке гранта РНФ 18-13-00459.The study was supported by the Russian Science Foundation (Project ID 18-13-00459).ReferencesStukalov Y.V., Grigorieva E.Y., Smirnova A.V., Lipengolts A.A., Kubasova I.Y., Pozdniakova N.V., Lukashina M.I. Experimental study of dendrimer-based nanoparticles with RGD-peptide for anticancer radionuclide therapy. Bulletin of RSMU. 2018; 7(6): 113–9. doi: 10.24075/brsmu.2018.089Stukalov Y.V., Grigorieva E.Y., Smirnova A.V., Lipengolts A.A., Kubasova I.Y., Pozdniakova N.V., Lukashina M.I. Experimental study of dendrimer-based nanoparticles with RGD-peptide for anticancer radionuclide therapy. Bulletin of RSMU. 2018; 7(6): 113–9. doi: 10.24075/brsmu.2018.089Шейно И.Н., Ижевский П.В., Липенгольц А.А., Кулаков В.Н., Вагнер А.Р., Сухих Е.С., Варлачев В.А. Разработка бинарных технологий лучевой терапии злокачественных новообразований: состояние и проблемы. Бюллетень сибирской медицины. 2017; 16(3): 192–209. doi: 10.20538/1682-0363-2017-3-192.Sheino I.N., Izhevskij P.V., Lipengolts A.A., Kulakov V.N., Wagner A.A., Sukhikh E.S., Varlachev V.A. Development of binary technologies of radiotherapy of malignant neoplasms: condition and problems. Bulletin of Siberian Medicine. 2017; 16(3): 192–209. (in Russian). doi: 10.20538/1682-0363-2017-3-192.Kulakov V.N., Lipengol’ts A.A., Grigor’eva E.Y., Shimanovskii N.L. Pharmaceuticals for binary radiotherapy and their use for treatment of malignancies. Pharm Chem J. 2016; 50(6): 388–93. doi: 10.1007/s11094-016-1457-3.Kulakov V.N., Lipengol’ts A.A., Grigor’eva E.Y., Shimanovskii N.L. Pharmaceuticals for binary radiotherapy and their use for treatment of malignancies. Pharm Chem J. 2016; 50(6): 388–93. doi: 10.1007/s11094-016-1457-3.Lipengolts A.A., Cherepanov A.A., Kulakov V.N., Grigorieva E.Y., Sheino I.N., Klimanov V.A. Antitumor efficacy of extracellular complexes with gadolinium in Binary radiotherapy. Appl Radiat Isot. 2015; 106: 233–6. doi: 10.1016/j.apradiso.2015.07.051.Lipengolts A.A., Cherepanov A.A., Kulakov V.N., Grigorieva E.Y., Sheino I.N., Klimanov V.A. Antitumor efficacy of extracellular complexes with gadolinium in Binary radiotherapy. Appl Radiat Isot. 2015; 106: 233–6. doi: 10.1016/j.apradiso.2015.07.051.Липенгольц А.А., Воробьева Е.С., Черепанов А.А., Абакумов М.А., Абакумова Т.О., Смирнова А.В., Финогенова Ю.А., Григорьева Е.Ю., Шейно И.Н., Кулаков В.Н. Исследование распределения поглощенной дозы при фотон-захватной терапии с интратуморальным введением дозоповышающего агента в меланоме B16F10. Вестник РГМУ. 2018; (5): 70–5. doi: 10.24075/vrgmu.2018.062.Lipengolts A.A., Vorobyeva E.S., Cherepanov A.A., Abakumov M.A., Abakumova T.O., Smirnova A.V., Finogenova Yu.A., Grigorieva E.Yu., Sheino I.N., Kulakov V.N. Evaluation of absorbed dose distribution in melanoma B16F10 during contrast enhanced radiotherapy with intratumoral administration of dose-enhancing agent. Bulletin of Russian State Medical University. 2018; (5): 70–5. (in Russian). doi: 10.24075/vrgmu.2018.062.Lipengol’ts A.A., Cherepanov A.A., Kulakov V.N., Grigor’eva E.Y., Merkulova I.B., Sheino I.N. Comparison of the antitumor efficacy of bismuth and gadolinium as dose-enhancing agents in formulations for photon capture therapy. Pharm Chem J. 2017; 51(9): 1–4. doi: 10.1007/s11094-017-1693-1Lipengol’ts A.A., Cherepanov A.A., Kulakov V.N., Grigor’eva E.Y., Merkulova I.B., Sheino I.N. Comparison of the antitumor efficacy of bismuth and gadolinium as dose-enhancing agents in formulations for photon capture therapy. Pharm Chem J. 2017; 51(9): 1–4. doi: 10.1007/s11094-017-1693-1Rosenfeldt M.T., O’Prey J., Morton J.P., Nixon C., MacKay G., Mrowinska A., Au A., Rai T.S., Zheng L., Ridgway R., Adams P.D., Anderson K.I., Gottlieb E., Sansom O.J., Ryan K.M. p53 status determines the role of autophagy in pancreatic tumour development. Nature. 2013; 504(7479): 296–300. doi: 10.1038/nature12865.Rosenfeldt M.T., O’Prey J., Morton J.P., Nixon C., MacKay G., Mrowinska A., Au A., Rai T.S., Zheng L., Ridgway R., Adams P.D., Anderson K.I., Gottlieb E., Sansom O.J., Ryan K.M. p53 status determines the role of autophagy in pancreatic tumour development. Nature. 2013; 504(7479): 296–300. doi: 10.1038/nature12865.Graham T.J., Box G., Tunariu N., Crespo M., Spinks T.J., Miranda S., Attard G., de Bono J.., Eccles SA., Davies F.E., Robinson S.P. Preclinical evaluation of imaging biomarkers for prostate cancer bone metastasis and response to cabozantinib. J Natl Cancer Inst. 2014; 106(4): 1–10. doi: 10.1093/jnci/dju033.Graham T.J., Box G., Tunariu N., Crespo M., Spinks T.J., Miranda S., Attard G., de Bono J.., Eccles SA., Davies F.E., Robinson S.P. Preclinical evaluation of imaging biomarkers for prostate cancer bone metastasis and response to cabozantinib. J Natl Cancer Inst. 2014; 106(4): 1–10. doi: 10.1093/jnci/dju033.Collantes M., Martinez-Velez N., Zalacain M., Marrodan L., Ecay M., Garcia-Velloso M.J.., Alonso M.M., Patino-Garcia A., Penuelas I. Assessment of metabolic patterns and new antitumoral treatment in osteosarcoma xenograft models by [18F]FDG and sodium [18F]fluoride PET. BMC Cancer. 2018; 18(1): 1–10. doi: 10.1186/s12885-018-5122-yCollantes M., Martinez-Velez N., Zalacain M., Marrodan L., Ecay M., Garcia-Velloso M.J.., Alonso M.M., Patino-Garcia A., Penuelas I. Assessment of metabolic patterns and new antitumoral treatment in osteosarcoma xenograft models by [18F]FDG and sodium [18F]fluoride PET. BMC Cancer. 2018; 18(1): 1–10. doi: 10.1186/s12885-018-5122-yZheng J., Miao W., Huang C., Lin H. Evaluation of 99mTc-3PRGD2 integrin receptor imaging in hepatocellular carcinoma tumour-bearing mice: comparison with 18F-FDG metabolic imaging. Ann Nucl Med. 2017; 31(6): 486–94. doi: 10.1007/s12149-017-1173-4.Zheng J., Miao W., Huang C., Lin H. Evaluation of 99mTc-3PRGD2 integrin receptor imaging in hepatocellular carcinoma tumour-bearing mice: comparison with 18F-FDG metabolic imaging. Ann Nucl Med. 2017; 31(6): 486–94. doi: 10.1007/s12149-017-1173-4.Zhao H., Gao H., Zhai L., Liu X., Jia B., Shi J., Wang F. 99mTcHisoDGR as a potential SPECT probe for orthotopic glioma detection via targeting of integrin α5 β1 . Bioconjug Chem. 2016; 27(5): 1259–66. doi: 10.1021/acs.bioconjchem.6b00098.Zhao H., Gao H., Zhai L., Liu X., Jia B., Shi J., Wang F. 99mTcHisoDGR as a potential SPECT probe for orthotopic glioma detection via targeting of integrin α5 β1 . Bioconjug Chem. 2016; 27(5): 1259–66. doi: 10.1021/acs.bioconjchem.6b00098.Huang C.W., Hsieh W.C., Hsu S.T., Lin Y.W., Chung Y.H., Chang W.C., Chiu H., Lin Y.H., Wu C.P., Yen T.C., Huang F.T. The use of PET imaging for prognostic integrin α2 β1 phenotyping to detect non-small cell lung cancer and monitor drug resistance responses. Theranostics. 2017; 7(16): 4013–28. doi: 10.7150/thno.19304.Huang C.W., Hsieh W.C., Hsu S.T., Lin Y.W., Chung Y.H., Chang W.C., Chiu H., Lin Y.H., Wu C.P., Yen T.C., Huang F.T. The use of PET imaging for prognostic integrin α2 β1 phenotyping to detect non-small cell lung cancer and monitor drug resistance responses. Theranostics. 2017; 7(16): 4013–28. doi: 10.7150/thno.19304.Ghai A., Maji D., Cho N., Chanswangphuwana C., Rettig M., Shen D., DiPersio J., Akers W., Dehdashti F., Achilefu S., Vij R., Shokeen M. Preclinical development of CD38-targeted [89Zr]Zr-DFO-daratumumab for imaging multiple myeloma. J Nucl Med. 2018; 59(2): 216–22. doi: 10.2967/jnumed.117.196063Ghai A., Maji D., Cho N., Chanswangphuwana C., Rettig M., Shen D., DiPersio J., Akers W., Dehdashti F., Achilefu S., Vij R., Shokeen M. Preclinical development of CD38-targeted [89Zr]Zr-DFO-daratumumab for imaging multiple myeloma. J Nucl Med. 2018; 59(2): 216–22. doi: 10.2967/jnumed.117.196063Vandergaast R., Khongwichit S., Jiang H., DeGrado T.R., Peng K.W., Smith D.R., Russell S.J., Suksanpaisan L. Enhanced noninvasive imaging of oncology models using the NIS reporter gene and bioluminescence imaging. Cancer Gene Ther. 2020 Apr; 27(3–4): 179–188. doi: 10.1038/s41417-019-0081-2.Vandergaast R., Khongwichit S., Jiang H., DeGrado T.R., Peng K.W., Smith D.R., Russell S.J., Suksanpaisan L. Enhanced noninvasive imaging of oncology models using the NIS reporter gene and bioluminescence imaging. Cancer Gene Ther. 2020 Apr; 27(3–4): 179–188. doi: 10.1038/s41417-019-0081-2.Carpenet H., Cuvillier A., Perraud A.., Martin O, Champier G., Jauberteau M.O., Monteil J., Quelven I. Radiolabelled polymeric IgA: from biodistribution to a new molecular imaging tool in colorectal cancer lung metastases. Oncotarget. 2017; 8(49): 85185–202. doi: 10.18632/oncotarget.19616.Carpenet H., Cuvillier A., Perraud A.., Martin O, Champier G., Jauberteau M.O., Monteil J., Quelven I. Radiolabelled polymeric IgA: from biodistribution to a new molecular imaging tool in colorectal cancer lung metastases. Oncotarget. 2017; 8(49): 85185–202. doi: 10.18632/oncotarget.19616.Hartimath S.V., Alizadeh E., Solomon V.R., Chekol R., Bernhard W., Hill W., Parada A.C., Barreto K., Geyer C.R., Fonge H. Preclinical Evaluation of 111In-Labeled PEGylated Maytansine Nimotuzumab Drug Conjugates in EGFR-Positive Cancer Models. J Nucl Med. 2019 Aug; 60(8): 1103–1110. doi: 10.2967/jnumed.118.220095.Hartimath S.V., Alizadeh E., Solomon V.R., Chekol R., Bernhard W., Hill W., Parada A.C., Barreto K., Geyer C.R., Fonge H. Preclinical Evaluation of 111In-Labeled PEGylated Maytansine Nimotuzumab Drug Conjugates in EGFR-Positive Cancer Models. J Nucl Med. 2019 Aug; 60(8): 1103–1110. doi: 10.2967/jnumed.118.220095.Izquierdo-Sanchez V., Muniz-Hernandez S., Vazquez-Becerra H., Pacheco-Yepez J., Romero-Pina M.E., Arrieta O., Medina L.A. Biodistribution and tumor uptake of 67Ga-nimotuzumab in a malignant pleural mesothelioma xenograft. Molecules. 2018; 23(12): 1–12. doi: 10.3390/molecules23123138.Izquierdo-Sanchez V., Muniz-Hernandez S., Vazquez-Becerra H., Pacheco-Yepez J., Romero-Pina M.E., Arrieta O., Medina L.A. Biodistribution and tumor uptake of 67Ga-nimotuzumab in a malignant pleural mesothelioma xenograft. Molecules. 2018; 23(12): 1–12. doi: 10.3390/molecules23123138.Chekol R., Solomon V.R., Alizadeh E., Bernhard W., Fisher D., Hill W., Barreto K., DeCoteau J.F., Parada A.C., Geyer C.R., Fonge H. 89Zr-nimotuzumab for immunoPET imaging of epidermal growth factor receptor I. Oncotarget. 2018; 9(24): 17117–32. doi: 10.18632/oncotarget.24965Chekol R., Solomon V.R., Alizadeh E., Bernhard W., Fisher D., Hill W., Barreto K., DeCoteau J.F., Parada A.C., Geyer C.R., Fonge H. 89Zr-nimotuzumab for immunoPET imaging of epidermal growth factor receptor I. Oncotarget. 2018; 9(24): 17117–32. doi: 10.18632/oncotarget.24965Knight J.C., Mosley M.J., Kersemans V., Dias G.M., Allen P.D., Smart S., Cornelissen B. Dual-isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumours. Nucl Med Biol. 2019; 70: 14–22. doi: 10.1016/j.nucmedbio.2019.01.010.Knight J.C., Mosley M.J., Kersemans V., Dias G.M., Allen P.D., Smart S., Cornelissen B. Dual-isotope imaging allows in vivo immunohistochemistry using radiolabelled antibodies in tumours. Nucl Med Biol. 2019; 70: 14–22. doi: 10.1016/j.nucmedbio.2019.01.010.Branderhorst W., Blezer E.L.A., Houtkamp M., Ramakers R.M., van den Brakel J.H., Witteveen H., van der Have F., van Andel H.A.G., Vastenhouw B., Wu C., Stigter-van Walsum M., van Dongen G.A.M.S., Viergever M.A., Bleeker W.K., Beekman F.J. Three-dimensional histologic validation of high-resolution spect of antibody distributions within xenografts. J Nucl Med. 2014; 55(5): 830–7. doi: 10.2967/jnumed.113.125401.Branderhorst W., Blezer E.L.A., Houtkamp M., Ramakers R.M., van den Brakel J.H., Witteveen H., van der Have F., van Andel H.A.G., Vastenhouw B., Wu C., Stigter-van Walsum M., van Dongen G.A.M.S., Viergever M.A., Bleeker W.K., Beekman F.J. Three-dimensional histologic validation of high-resolution spect of antibody distributions within xenografts. J Nucl Med. 2014; 55(5): 830–7. doi: 10.2967/jnumed.113.125401.Al-Saden N., Cai Z., Reilly R.M. Tumor uptake and tumor/blood ratios for [89Zr]Zr-DFO-trastuzumab-DM1 on microPET/CT images in NOD/SCID mice with human breast cancer xenografts are directly correlated with HER2 expression and response to trastuzumab-DM1. Nucl Med Biol. 2018; 67: 43–51. doi: 10.1016/j.nucmedbio.2018.10.002.Al-Saden N., Cai Z., Reilly R.M. Tumor uptake and tumor/blood ratios for [89Zr]Zr-DFO-trastuzumab-DM1 on microPET/CT images in NOD/SCID mice with human breast cancer xenografts are directly correlated with HER2 expression and response to trastuzumab-DM1. Nucl Med Biol. 2018; 67: 43–51. doi: 10.1016/j.nucmedbio.2018.10.002.Mitran B., Andersson K.G., Lindstrom E., Garousi J., Rosestedt M., Tolmachev V., Stahl S., Orlova A., Lofblom J. Affibody-mediated imaging of EGFR expression in prostate cancer using radiocobalt-labeled DOTAZEGFR:2377. Oncol Rep. 2019; 41(1): 534–42. doi: 10.3892/or.2018.6792.Mitran B., Andersson K.G., Lindstrom E., Garousi J., Rosestedt M., Tolmachev V., Stahl S., Orlova A., Lofblom J. Affibody-mediated imaging of EGFR expression in prostate cancer using radiocobalt-labeled DOTAZEGFR:2377. Oncol Rep. 2019; 41(1): 534–42. doi: 10.3892/or.2018.6792.van Dijk L.K., Yim C.Bin., Franssen G.M., Kaanders J.H.A.M., Rajander J., Solin O., Gronroos T.J., Boerman O.C., Bussink J. PET of EGFR with 64Cu-cetuximab-F(ab′)2 in mice with head and neck squamous cell carcinoma xenografts. Contrast Media Mol Imaging. 2016; 11(1): 65–70. doi: 10.1002/cmmi.1659.van Dijk L.K., Yim C.Bin., Franssen G.M., Kaanders J.H.A.M., Rajander J., Solin O., Gronroos T.J., Boerman O.C., Bussink J. PET of EGFR with 64Cu-cetuximab-F(ab′)2 in mice with head and neck squamous cell carcinoma xenografts. Contrast Media Mol Imaging. 2016; 11(1): 65–70. doi: 10.1002/cmmi.1659.Deyev S., Vorobyeva A., Schulga A., Proshkina G., Guler R., Lofblom J., Mitran B., Garousi J., Altai M., Buijs J., Chernov V., Orlova A., Tolmachev V. Comparative evaluation of two DARPin variants: effect of affinity, size, and label on tumor targeting properties. Mol Pharm. 2019; 16(3): 995–1008. doi: 10.1021/acs.molpharmaceut.8b00922.Deyev S., Vorobyeva A., Schulga A., Proshkina G., Guler R., Lofblom J., Mitran B., Garousi J., Altai M., Buijs J., Chernov V., Orlova A., Tolmachev V. Comparative evaluation of two DARPin variants: effect of affinity, size, and label on tumor targeting properties. Mol Pharm. 2019; 16(3): 995–1008. doi: 10.1021/acs.molpharmaceut.8b00922.Vorobyeva A., Bragina O., Altai M., Mitran B., Orlova A., Shulga A., Proshkina G., Chernov V., Tolmachev V., Deyev S. Comparative evaluation of radioiodine and technetium-labeled DARPin 9_29 for radionuclide molecular imaging of HER2 expression in malignant tumors. Contrast Media Mol Imaging. 2018 Jun 6; 2018: 6930425. doi: 10.1155/2018/6930425.Vorobyeva A., Bragina O., Altai M., Mitran B., Orlova A., Shulga A., Proshkina G., Chernov V., Tolmachev V., Deyev S. Comparative evaluation of radioiodine and technetium-labeled DARPin 9_29 for radionuclide molecular imaging of HER2 expression in malignant tumors. Contrast Media Mol Imaging. 2018 Jun 6; 2018: 6930425. doi: 10.1155/2018/6930425.Aranda-Lara L., Ferro-Flores G., Azorin-Vega E., Ramirez F. de M., Jimenez-Mancilla N., Ocampo-Garcia B., Santos-Cuevas C., IsaacOlive K. Synthesis and evaluation of Lys1 (α,γ-Folate)Lys3 (177LuDOTA)-Bombesin(1-14) as a potential theranostic radiopharmaceutical for breast cancer. Appl Radiat Isot. 2016; 107: 214–9. doi: 10.1016/j.apradiso.2015.10.030.Aranda-Lara L., Ferro-Flores G., Azorin-Vega E., Ramirez F. de M., Jimenez-Mancilla N., Ocampo-Garcia B., Santos-Cuevas C., IsaacOlive K. Synthesis and evaluation of Lys1 (α,γ-Folate)Lys3 (177LuDOTA)-Bombesin(1-14) as a potential theranostic radiopharmaceutical for breast cancer. Appl Radiat Isot. 2016; 107: 214–9. doi: 10.1016/j.apradiso.2015.10.030.Dalm S.U., Bakker I.L., de Blois E., Doeswijk G.N., Konijnenberg M.W., Orlandi F., Barbato D., Tedesco M., Maina T., Nock B.A., de Jong M. 68Ga/177Lu-NeoBOMB1, a novel radiolabeled GRPR antagonist for theranostic use in oncology. J Nucl Med. 2017; 58(2): 293–9. doi: 10.2967/jnumed.116.176636.Dalm S.U., Bakker I.L., de Blois E., Doeswijk G.N., Konijnenberg M.W., Orlandi F., Barbato D., Tedesco M., Maina T., Nock B.A., de Jong M. 68Ga/177Lu-NeoBOMB1, a novel radiolabeled GRPR antagonist for theranostic use in oncology. J Nucl Med. 2017; 58(2): 293–9. doi: 10.2967/jnumed.116.176636.Nock B.A., Charalambidis D., Sallegger W., Waser B., Mansi R., Nicolas G.P., Ketani E., Nikolopoulou A., Fani M., Reubi J.C., Maina T. New gastrin releasing peptide receptor-directed [99mTc]Demobesin 1 mimics: synthesis and comparative evaluation. J Med Chem. 2018; 61(7): 3138–50. doi: 10.1021/acs.jmedchem.8b00177.Nock B.A., Charalambidis D., Sallegger W., Waser B., Mansi R., Nicolas G.P., Ketani E., Nikolopoulou A., Fani M., Reubi J.C., Maina T. New gastrin releasing peptide receptor-directed [99mTc]Demobesin 1 mimics: synthesis and comparative evaluation. J Med Chem. 2018; 61(7): 3138–50. doi: 10.1021/acs.jmedchem.8b00177.Lisova K., Sergeev M., Evans-Аxelsson S., Stuparu A.D., Beykan S., Collins J., Jones J., Lassmann M., Herrmann K., Perrin D., Lee J.T., Slavik R., van Dam M. Microscale radiosynthesis, preclinical imaging and dosimetry study of [18F]AMBF3 -TATE: a potential PET tracer for clinical imaging of somatostatin receptors. Nucl Med Biol. 2018; 61: 36–44. doi: 10.1016/j.nucmedbio.2018.04.001.Microscale.Lisova K., Sergeev M., Evans-Аxelsson S., Stuparu A.D., Beykan S., Collins J., Jones J., Lassmann M., Herrmann K., Perrin D., Lee J.T., Slavik R., van Dam M. Microscale radiosynthesis, preclinical imaging and dosimetry study of [18F]AMBF3 -TATE: a potential PET tracer for clinical imaging of somatostatin receptors. Nucl Med Biol. 2018; 61: 36–44. doi: 10.1016/j.nucmedbio.2018.04.001.Microscale.Nicolas G.P., Mansi R., McDougall L., Kaufmann J., Bouterfa H., Wild D., Fani M. Biodistribution, pharmacokinetics, and dosimetry of 177Lu-, 90Y-, and 111In-labeled somatostatin receptor antagonist OPS201 in comparison to the agonist 177Lu-DOTATATE: the mass effect. J Nucl Med. 2017; 58(9): 1435–41. doi: 10.2967/jnumed.117.191684.Nicolas G.P., Mansi R., McDougall L., Kaufmann J., Bouterfa H., Wild D., Fani M. Biodistribution, pharmacokinetics, and dosimetry of 177Lu-, 90Y-, and 111In-labeled somatostatin receptor antagonist OPS201 in comparison to the agonist 177Lu-DOTATATE: the mass effect. J Nucl Med. 2017; 58(9): 1435–41. doi: 10.2967/jnumed.117.191684.Willekens S.M.A., Joosten L., Boerman O.C., Brom M., Gotthardt M. Characterization of 111In-labeled glucose-dependent insulinotropic polypeptide as a radiotracer for neuroendocrine tumors. Sci Rep. 2018; 8(1): 1–11. doi: 10.1038/s41598-018-21259-3.Willekens S.M.A., Joosten L., Boerman O.C., Brom M., Gotthardt M. Characterization of 111In-labeled glucose-dependent insulinotropic polypeptide as a radiotracer for neuroendocrine tumors. Sci Rep. 2018; 8(1): 1–11. doi: 10.1038/s41598-018-21259-3.Yoshii Y., Yoshimoto M., Matsumoto H., Furukawa T., Zhang M.-R., Inubushi M., Tsuji A.B., Fujibayashi Y., Higashi T., Saga T. 64Cu-ATSM internal radiotherapy to treat tumors with bevacizumab-induced vascular decrease and hypoxia in human colon carcinoma xenografts. Oncotarget. 2017; 8(51): 88815–26. doi: 10.18632/oncotarget.21323.Yoshii Y., Yoshimoto M., Matsumoto H., Furukawa T., Zhang M.-R., Inubushi M., Tsuji A.B., Fujibayashi Y., Higashi T., Saga T. 64Cu-ATSM internal radiotherapy to treat tumors with bevacizumab-induced vascular decrease and hypoxia in human colon carcinoma xenografts. Oncotarget. 2017; 8(51): 88815–26. doi: 10.18632/oncotarget.21323.Huizing F.J., Hoeben B.A.W., Franssen G.M., Boerman O.C., Heskamp S., Bussink J. Quantitative imaging of the hypoxia-related marker CAIX in head and neck squamous cell carcinoma xenograft models. Mol Pharm. 2019; 16(2): 701–8. doi: 10.1021/acs.molpharmaceut.8b00950.Huizing F.J., Hoeben B.A.W., Franssen G.M., Boerman O.C., Heskamp S., Bussink J. Quantitative imaging of the hypoxia-related marker CAIX in head and neck squamous cell carcinoma xenograft models. Mol Pharm. 2019; 16(2): 701–8. doi: 10.1021/acs.molpharmaceut.8b00950.Iikuni S., Ono M., Watanabe H., Shimizu Y., Sano K., Saji H. Cancer radiotheranostics targeting carbonic anhydrase-IX with 111Inand 90Y-labeled ureidosulfonamide scaffold for SPECT imaging and radionuclide-based therapy. Theranostics. 2018; 8(11): .2992–3006. doi: 10.7150/thno.20982.Iikuni S., Ono M., Watanabe H., Shimizu Y., Sano K., Saji H. Cancer radiotheranostics targeting carbonic anhydrase-IX with 111Inand 90Y-labeled ureidosulfonamide scaffold for SPECT imaging and radionuclide-based therapy. Theranostics. 2018; 8(11): .2992–3006. doi: 10.7150/thno.20982.Ali R., Apte S., Vilalta M., Subbarayan M., Miao Z., Chin F.T., Graves E.E. 18F-EF5 PET is predictive of response to fractionated radiotherapy in preclinical tumor models. PLoS One. 2015; 10(10): 1–14. doi: 10.1371/journal.pone.0139425.Ali R., Apte S., Vilalta M., Subbarayan M., Miao Z., Chin F.T., Graves E.E. 18F-EF5 PET is predictive of response to fractionated radiotherapy in preclinical tumor models. PLoS One. 2015; 10(10): 1–14. doi: 10.1371/journal.pone.0139425.Kilian K., Rogulski Z., Cheda L., Drzal A., Gerszewska M., Cudny M., Elas M. Imaging of hypoxia in small animals with 18F fluoromisonidasole. Nukleonika. 2016; 61(2): 219–23. doi: 10.1515/nuka2016-0037.Kilian K., Rogulski Z., Cheda L., Drzal A., Gerszewska M., Cudny M., Elas M. Imaging of hypoxia in small animals with 18F fluoromisonidasole. Nukleonika. 2016; 61(2): 219–23. doi: 10.1515/nuka2016-0037.Федянин М.Ю., Трякин А.А., Покатаев И.А. Критический взгляд на развитие онкологии в последние 20 лет (надежды и разочарования) – антиангиогенная терапия. Практическая онкология. 2018; 19(3): 200–225. doi: 10.31917/1903200.Fedyanin M.Yu., Tryakin A.A., Pokataev I.A. Critical view of efficacy antiangiogenic therapy in oncology. Practical oncology. 2018; 19(3): 200–225. (in Russian). doi: 10.31917/1903200.Hernandez-Agudo E., Mondejar T., Soto-Montenegro M.L., Megias D., Mouron S., Sanchez J., Hidalgo M., Lopez-Casas P.P., Mulero F., Desco M., Quintela-Fandino M. Monitoring vascular normalization induced by antiangiogenic treatment with 18F-fluoromisonidazole-PET. Mol Oncol. 2016; 10(5): 704–18. doi: 10.1016/j.molonc.2015.12.011.Hernandez-Agudo E., Mondejar T., Soto-Montenegro M.L., Megias D., Mouron S., Sanchez J., Hidalgo M., Lopez-Casas P.P., Mulero F., Desco M., Quintela-Fandino M. Monitoring vascular normalization induced by antiangiogenic treatment with 18F-fluoromisonidazole-PET. Mol Oncol. 2016; 10(5): 704–18. doi: 10.1016/j.molonc.2015.12.011.Cui Y., Liu H., Liang S., Zhang C., Cheng W., Hai W., Yin B., Wang D. The feasibility of 18F-AlF-NOTA-PRGD2 PET/CT for monitoring early response of Endostar antiangiogenic therapy in human nasopharyngeal carcinoma xenograft model compared with 18F-FDG. Oncotarget. 2016; 7(19): 27243–54. doi: 10.18632/oncotarget.8402.Cui Y., Liu H., Liang S., Zhang C., Cheng W., Hai W., Yin B., Wang D. The feasibility of 18F-AlF-NOTA-PRGD2 PET/CT for monitoring early response of Endostar antiangiogenic therapy in human nasopharyngeal carcinoma xenograft model compared with 18F-FDG. Oncotarget. 2016; 7(19): 27243–54. doi: 10.18632/oncotarget.8402.Bao X., Wang M.W., Luo J.M., Wang S.Y., Zhang Y.P., Zhang Y.J. Optimization of early response monitoring and prediction of cancer antiangiogenesis therapy via noninvasive PET molecular imaging strategies of multifactorial bioparameters. Theranostics. 2016; 6 (12): 2084–98. doi: 10.7150/thno.13917.Bao X., Wang M.W., Luo J.M., Wang S.Y., Zhang Y.P., Zhang Y.J. Optimization of early response monitoring and prediction of cancer antiangiogenesis therapy via noninvasive PET molecular imaging strategies of multifactorial bioparameters. Theranostics. 2016; 6 (12): 2084–98. doi: 10.7150/thno.13917.Norregaard K., Jorgensen J.T., Simon M., Melander F., Kristensen L.K., Bendix P.M., Andresen T.L., Oddershede L.B., Kjaer A. 18F-FDG PET/CT-based early treatment response evaluation of nanoparticle-assisted photothermal cancer therapy. PLoS One. 2017; 12(5): 1–14. doi: 10.1371/journal.pone.0177997.Norregaard K., Jorgensen J.T., Simon M., Melander F., Kristensen L.K., Bendix P.M., Andresen T.L., Oddershede L.B., Kjaer A. 18F-FDG PET/CT-based early treatment response evaluation of nanoparticle-assisted photothermal cancer therapy. PLoS One. 2017; 12(5): 1–14. doi: 10.1371/journal.pone.0177997.Zhu Y., Dong M., Yang J., Zhang J. Evaluation of iodine-125 interstitial brachytherapy using micro-positron emission tomography/ computed tomography with 18F-fluorodeoxyglucose in hepatocellular carcinoma HepG2 xenografts. Med Sci Monit. 2019; 25: 371–80. doi: 10.12659/MSM.912590.Zhu Y., Dong M., Yang J., Zhang J. Evaluation of iodine-125 interstitial brachytherapy using micro-positron emission tomography/ computed tomography with 18F-fluorodeoxyglucose in hepatocellular carcinoma HepG2 xenografts. Med Sci Monit. 2019; 25: 371–80. doi: 10.12659/MSM.912590.Knight J.C., Mosley M.J., Bravo L.C., Kersemans V., Allen P.D., Mukherjee S., O'Neill E., Cornelissen B. 89Zr-anti-γH2AX-TAT but not 18F-FDG allows early monitoring of response to chemotherapy in a mouse model of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2017; 23(21): 6498–504. doi: 10.1158/1078-0432.CCR-17-0664.Knight J.C., Mosley M.J., Bravo L.C., Kersemans V., Allen P.D., Mukherjee S., O'Neill E., Cornelissen B. 89Zr-anti-γH2AX-TAT but not 18F-FDG allows early monitoring of response to chemotherapy in a mouse model of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2017; 23(21): 6498–504. doi: 10.1158/1078-0432.CCR-17-0664.Wilson T.C., Xavier M.-A., Knight J., Verhoog S., Baguna Torres J., Mosley M., Hopkins S.L., Wallington S., Allen P.D., Kersemans V., Hueting R., Smart S., Gouverneur V., Cornelissen B. PET Imaging of PARP Expression Using 18F-Olaparib. J Nucl Med. 2019; 60(4): 502–3. doi: 10.2967/jnumed.118.219733.Wilson T.C., Xavier M.-A., Knight J., Verhoog S., Baguna Torres J., Mosley M., Hopkins S.L., Wallington S., Allen P.D., Kersemans V., Hueting R., Smart S., Gouverneur V., Cornelissen B. PET Imaging of PARP Expression Using 18F-Olaparib. J Nucl Med. 2019; 60(4): 502–3. doi: 10.2967/jnumed.118.219733.Luo R., Niu L., Qiu F., Fang W., Fu T., Zhao M., Zhang Y.J., Hua Z.C., Li X.F., Wang F. Monitoring apoptosis of breast cancer xenograft after paclitaxel treatment with 99mTc-labeled duramycin SPECT/CT. Mol Imaging. 2016; 15: 1–10. doi: 10.1177/1536012115624918.Luo R., Niu L., Qiu F., Fang W., Fu T., Zhao M., Zhang Y.J., Hua Z.C., Li X.F., Wang F. Monitoring apoptosis of breast cancer xenograft after paclitaxel treatment with 99mTc-labeled duramycin SPECT/CT. Mol Imaging. 2016; 15: 1–10. doi: 10.1177/1536012115624918.Elvas F., Boddaert J., Vangestel C., Pak K., Gray B., KumarSingh S., Staelens S., Stroobants S., Wyffels L. 99mTc-duramycin SPECT imaging of early tumor response to targeted therapy: a comparison with 18F-FDG PET. J Nucl Med. 2017; 58(4): 665–70. doi: 10.2967/jnumed.116.182014.Elvas F., Boddaert J., Vangestel C., Pak K., Gray B., KumarSingh S., Staelens S., Stroobants S., Wyffels L. 99mTc-duramycin SPECT imaging of early tumor response to targeted therapy: a comparison with 18F-FDG PET. J Nucl Med. 2017; 58(4): 665–70. doi: 10.2967/jnumed.116.182014.Elvas F., Vangestel C., Pak K., Vermeulen P., Gray B., Stroobants S., Staelens S., Wyffels L. Early prediction of tumor response to treatment: preclinical validation of 99mTc-duramycin. J Nucl Med. 2016; 57(5): 805–11. doi: 10.2967/jnumed.115.168344.Elvas F., Vangestel C., Pak K., Vermeulen P., Gray B., Stroobants S., Staelens S., Wyffels L. Early prediction of tumor response to treatment: preclinical validation of 99mTc-duramycin. J Nucl Med. 2016; 57(5): 805–11. doi: 10.2967/jnumed.115.168344.Rapic S., Vangestel C., Elvas F., Verhaeghe J., den Wyngaert T.V., Wyffels L., Pauwels P., Staelens S., Stroobants S. Evaluation of [18F]CP18 as a substrate-based apoptosis imaging agent for the assessment of early treatment response in oncology. Mol Imaging Biol. 2017; 19(4): 560–9. doi: 10.1007/s11307-016-1037-7.Rapic S., Vangestel C., Elvas F., Verhaeghe J., den Wyngaert T.V., Wyffels L., Pauwels P., Staelens S., Stroobants S. Evaluation of [18F]CP18 as a substrate-based apoptosis imaging agent for the assessment of early treatment response in oncology. Mol Imaging Biol. 2017; 19(4): 560–9. doi: 10.1007/s11307-016-1037-7.Heinzmann K., Nguyen Q.De., Honess D., Smith D.M., Stribbling S., Brickute D., Barnes C., Griffiths J., Aboagye E. Depicting changes in tumor biology in response to cetuximab monotherapy or combination therapy by apoptosis and proliferation imaging using 18F-ICMT-11 and 18F-FLT PET. J Nucl Med. 2018; 59(10): 1558–65. doi: 10.2967/jnumed.118.209304.Heinzmann K., Nguyen Q.De., Honess D., Smith D.M., Stribbling S., Brickute D., Barnes C., Griffiths J., Aboagye E. Depicting changes in tumor biology in response to cetuximab monotherapy or combination therapy by apoptosis and proliferation imaging using 18F-ICMT-11 and 18F-FLT PET. J Nucl Med. 2018; 59(10): 1558–65. doi: 10.2967/jnumed.118.209304.Raccagni I., Belloli S., Valtorta S., Stefano A., Presotto L., Pascali C., Bogni A., Tortoreto M., Zaffaroni N., Daidone M.G., Russo G., Bombardieri E., Moresco R.M. [18F]FDG and [18F]FLT PET for the evaluation of response to neo-adjuvant chemotherapy in a model of triple negative breast cancer. PLoS One. 2018; 13(5): 1–14. doi: 10.1371/journal.pone.0197754.Raccagni I., Belloli S., Valtorta S., Stefano A., Presotto L., Pascali C., Bogni A., Tortoreto M., Zaffaroni N., Daidone M.G., Russo G., Bombardieri E., Moresco R.M. [18F]FDG and [18F]FLT PET for the evaluation of response to neo-adjuvant chemotherapy in a model of triple negative breast cancer. PLoS One. 2018; 13(5): 1–14. doi: 10.1371/journal.pone.0197754.Nielsen C.H., Jensen M.M., Kristensen L.K., Dahlman A., Frohlich C., Jacobsen H.J., Poulsen T.T., Lantto J., Horak I.D., Kragh M., Kjaer A. In vivo imaging of therapy response to a novel Pan-HER antibody mixture using FDG and FLT positron emission tomography. Oncotarget. 2015; 6(35): 37486–99. doi: 10.18632/oncotarget.6060.Nielsen C.H., Jensen M.M., Kristensen L.K., Dahlman A., Frohlich C., Jacobsen H.J., Poulsen T.T., Lantto J., Horak I.D., Kragh M., Kjaer A. In vivo imaging of therapy response to a novel Pan-HER antibody mixture using FDG and FLT positron emission tomography. Oncotarget. 2015; 6(35): 37486–99. doi: 10.18632/oncotarget.6060.

The authors declare that there are no conflicts of interest present.