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Trastuzumab Conjugated Superparamagnetic Iron Oxide Nanoparticles Labeled with 225Ac as a Perspective Tool for Combined α-Radioimmunotherapy and Magnetic Hyperthermia of HER2-Positive Breast Cancer

Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland
Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Żwirki i Wigury 101, 02-089 Warsaw, Poland
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
Department for Nuclear Safety and Security, Joint Research Centre, European Commission, 76125 Karlsruhe, Germany
Institute of Nuclear & Radiological Sciences & Technology, Energy & Safety, N.C.S.R. ‘Demokritos’, Aghia Paraskevi, 15341 Athens, Greece
Department of Physics, National and Kapodistrian University of Athens, Zografou Panepistimioupolis, 15784 Athens, Greece
Authors to whom correspondence should be addressed.
Academic Editors: Paola Luciani and Davide Brambilla
Molecules 2020, 25(5), 1025;
Received: 28 January 2020 / Revised: 23 February 2020 / Accepted: 24 February 2020 / Published: 25 February 2020
It has been proven and confirmed in numerous repeated tests, that the use of a combination of several therapeutic methods gives much better treatment results than in the case of separate therapies. Particularly promising is the combination of ionizing radiation and magnetic hyperthermia in one drug. To achieve this objective, magnetite nanoparticles have been modified in their core with α emitter 225Ac, in an amount affecting only slightly their magnetic properties. By 3-phosphonopropionic acid (CEPA) linker nanoparticles were conjugated covalently with trastuzumab (Herceptin®), a monoclonal antibody that recognizes ovarian and breast cancer cells overexpressing the HER2 receptors. The synthesized bioconjugates were characterized by transmission electron microscopy (TEM), Dynamic Light Scattering (DLS) measurement, thermogravimetric analysis (TGA) and application of 131I-labeled trastuzumab for quantification of the bound biomolecule. The obtained results show that one 225[email protected]3O4-CEPA-trastuzumab bioconjugate contains an average of 8–11 molecules of trastuzumab. The labeled nanoparticles almost quantitatively retain 225Ac (>98%) in phosphate-buffered saline (PBS) and physiological salt, and more than 90% of 221Fr and 213Bi over 10 days. In human serum after 10 days, the fraction of 225Ac released from 225[email protected]3O4 was still less than 2%, but the retention of 221Fr and 213Bi decreased to 70%. The synthesized 225[email protected]3O4-CEPA-trastuzumab bioconjugates have shown a high cytotoxic effect toward SKOV-3 ovarian cancer cells expressing HER2 receptor in-vitro. The in-vivo studies indicate that this bioconjugate exhibits properties suitable for the treatment of cancer cells by intratumoral or post-resection injection. The intravenous injection of the 225[email protected]3O4-CEPA-trastuzumab radiobioconjugate is excluded due to its high accumulation in the liver, lungs and spleen. Additionally, the high value of a specific absorption rate (SAR) allows its use in a new very perspective combination of α radionuclide therapy with magnetic hyperthermia. View Full-Text
Keywords: radionuclide therapy; hyperthermia; SPION; trastuzumab radionuclide therapy; hyperthermia; SPION; trastuzumab
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Cędrowska, E.; Pruszyński, M.; Gawęda, W.; Żuk, M.; Krysiński, P.; Bruchertseifer, F.; Morgenstern, A.; Karageorgou, M.-A.; Bouziotis, P.; Bilewicz, A. Trastuzumab Conjugated Superparamagnetic Iron Oxide Nanoparticles Labeled with 225Ac as a Perspective Tool for Combined α-Radioimmunotherapy and Magnetic Hyperthermia of HER2-Positive Breast Cancer. Molecules 2020, 25, 1025.

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