Development of DNA aptamers for visualization of glial brain tumors and detection of circulating tumor cells
Kichkailo, A. S., Narodov, A. A., Komarova, M. A., Zamay, T. N., Zamay, G. S., Kolovskaya, O. S., Erakhtin, E. E., Glazyrin, Y. E., Veprintsev, D. V., Moryachkov, R. V., Zabluda, V. V., Shchugoreva, I., Artyushenko, P., Mironov, V. A., Morozov, D. I., Khorzhevskii, V. A., Gorbushin, A. V., Koshmanova, A. A., Nikolaeva, E. D., . . . Berezovski, M. V. (2023). Development of DNA aptamers for visualization of glial brain tumors and detection of circulating tumor cells. Molecular Therapy Nucleic Acids, 32, 267-288. https://doi.org/10.1016/j.omtn.2023.03.015
Julkaistu sarjassa
Molecular Therapy Nucleic AcidsTekijät
Päivämäärä
2023Tekijänoikeudet
© 2023 The Authors.
Here, we present DNA aptamers capable of specific binding to glial tumor cells in vitro, ex vivo, and in vivo for visualization diagnostics of central nervous system tumors. We selected the aptamers binding specifically to the postoperative human glial primary tumors and not to the healthy brain cells and meningioma, using a modified process of systematic evolution of ligands by exponential enrichment to cells; sequenced and analyzed ssDNA pools using bioinformatic tools and identified the best aptamers by their binding abilities; determined three-dimensional structures of lead aptamers (Gli-55 and Gli-233) with small-angle X-ray scattering and molecular modeling; isolated and identified molecular target proteins of the aptamers by mass spectrometry; the potential binding sites of Gli-233 to the target protein and the role of post-translational modifications were verified by molecular dynamics simulations. The anti-glioma aptamers Gli-233 and Gli-55 were used to detect circulating tumor cells in liquid biopsies. These aptamers were used for in situ, ex vivo tissue staining, histopathological analyses, and fluorescence-guided tumor and PET/CT tumor visualization in mice with xenotransplanted human astrocytoma. The aptamers did not show in vivo toxicity in the preclinical animal study. This study demonstrates the potential applications of aptamers for precise diagnostics and fluorescence-guided surgery of brain tumors.
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Julkaisija
Elsevier BVISSN Hae Julkaisufoorumista
2162-2531Asiasanat
Julkaisu tutkimustietojärjestelmässä
https://converis.jyu.fi/converis/portal/detail/Publication/182787807
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Lisätietoja rahoituksesta
The authors are grateful to all the patients and hospital staff participating in this research. We acknowledge the assistance of the AptamerLab LCC (www.aptamerlab.com) and personally Mr. Vasily Mezko for the aptamer 3D structure optimization and financial and technical support. The authors thank Prof. Alexey V. Protopopov, Prof. Vasily F. Shabanov, Mr. Alexey Kichkailo, Dr. Arkady B. Kogan, and Dr. Rinat G. Galeev for their general support, and Mrs. Valentina L. Grigoreva, and Irina V. Gildebrand for the help with histological staining. Technical and instrumental support was provided by the Multiple-Access Center at Tomsk State University; the Krasnoyarsk Inter-District Ambulance Hospital, named after N.S. Karpovich; John L. Holmes Mass Spectrometry Facility at the University of Ottawa; Federal Siberian Research Clinical Center under the Federal Medical Biological Agency; Shared Core Facilities of Molecular and Cell Technologies at Krasnoyarsk State Medical University and Krasnoyarsk Regional Center for Collective Use at the Federal Research Center “KSC SB RAS.” The confocal fluorescence microscopy research was carried out with the equipment of the Tomsk Regional Core Shared Research Facilities Center of the National Research Tomsk State University. The Center was supported by the Ministry of Science and Higher Education of the Russian Federation, grant no. 075-15-2021-693 (no. 13.RFC.21.0012). Acute toxicity studies were performed in a laboratory certified for preclinical studies (Laboratory of Biological Testing, Institute of Bioorganic Chemistry named after academics M.M. Shemyakin and Y.A. Ovchinnikov Russian Academy of Sciences). The authors are grateful to the Joint Super Computer Center of the Russian Academy of Sciences for providing supercomputers for computer simulations. Aptamer selection and their clinical applications were funded by the Ministry of Healthcare of the Russian Federation; project АААА-Б19-219090690032-5 (to T.N.Z.). The Ministry of Science and Higher Education of the Russian Federation project FWES-2022-0005 (to A.S.K.) supported aptamer characterization, molecular modeling, and in vivo experiments. Development of the glioma tumor model in immunosuppressed mice was supported by the Russian Science Foundation grant no. 22-64-00041 (to M.A.D.), https://rscf.ru/en/project/22-64-00041/. Synthesis of 11C-aptamer and PET/CT visualization was funded by the Federal Medical Biological Agency; project 122041800132-2 (to A.V.O.). Mass spectrometry analyses, DNA sequencing, and synthesis were supported by an NSERC Discovery Grant (to M.V.B.). We acknowledge the European Synchrotron Radiation Facility for SAXS experiments and thank Dr. Bart Van Laer for assistance in using a beamline BM29. SAXS measurements were supported by RFBR no. 18-32-00478 for young scientists (to R.V.M.). The synchrotron SEC-SAXS data for Gli-55 aptamer were also collected at beamline P12 operated by EMBL Hamburg at the PETRA III storage ring (DESY, Hamburg, Germany). ...Lisenssi
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