Hydroxyapatite and titanium dioxide are widely used materials in a broad spectrum of branches. Due to their appropriate properties such as a large specific surface area, radiation stability or relatively low toxicity, they could be potentially used as nanocarriers for medicinal radionuclides for diagnostics and therapy. Two radiolabelling strategies of both nanomaterials were carried out by 99mTc for diagnostic purposes and by 223Ra for therapeutic purposes. The first one was the radionuclide sorption on ready-made nanoparticles and the second one was direct radionuclide incorporation into the structure of the nanoparticles. Achieved labelling yields were higher than 94% in all cases. Afterwards, in vitro stability tests were carried out in several solutions: physiological saline, bovine blood plasma, bovine blood serum, 1% and 5% human albumin solutions. In vitro stability studies were performed as short-term (59 h for 223Ra and 31 h for 99mTc) and long-term experiments (five half-lives of 223Ra, approx. 55 days). Both radiolabelled nanoparticles with 99mTc have shown similar released activities (about 20%) in all solutions. The best results were obtained for 223Ra radiolabelled titanium dioxide nanoparticles, where overall released activities were under 6% for 59 h study in all matrices and under 3% for 55 days in a long-term perspective.

Department of Nuclear Chemistry Faculty of Nuclear Sciences and Physical Engineering Czech Technical University Prague Břehová 7 11519 Prague 1 Czech Republic

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Khan I., Saeed K., Khan I. Nanoparticles: Properties, applications and toxicities. Arab. J. Chem. 2019;12:908–931. doi: 10.1016/j.arabjc.2017.05.011. DOI

Mirshojaei S.F., Ahmadi A., Morales-Avila E., Ortiz-Reynoso M., Reyes-Perez H. Radiolabelled nanoparticles: Novel classification of radiopharmaceuticals for molecular imaging of cancer. J. Drug Target. 2015;24:91–101. doi: 10.3109/1061186X.2015.1048516. PubMed DOI

Murthy S.K. Nanoparticles in modern medicine: State of the art and future challenges. Int. J. Nanomed. 2007;2:129–141. PubMed PMC

Albernaz M.S., Ospina C.A., Rossi A.M., Santos-Oliveira R. Radiolabelled nanohydroxyapatite with 99mTc: Perspectives to nanoradiopharmaceuticals construction. Artif. Cells Nanomed. Biotechnol. 2014;42:88–91. doi: 10.3109/21691401.2013.785954. PubMed DOI

Reissig F., Hübner R., Steinbach J., Pietzsch H.-J., Mamat C. Facile preparation of radium-doped, functionalized nanoparticles as carriers for targeted alpha therapy. Inorg. Chem. Front. 2019;6:1341–1349. doi: 10.1039/C9QI00208A. DOI

Kučka J., Hrubý M., Konák C., Kozempel J., Lebeda O. Astatination of nanoparticles containing silver as possible carriers of 211At. Appl. Radiat. Isot. 2006;64:201–206. doi: 10.1016/j.apradiso.2005.07.021. PubMed DOI

Rojas J.V., Woodward J.D., Chen N., Rondinone A.J., Castano C.H., Mirzadeh S. Synthesis and characterization of lanthanum phosphate nanoparticles as carriers for 223Ra and 225Ra for targeted alpha therapy. Nucl. Med. Biol. 2015;42:614–620. doi: 10.1016/j.nucmedbio.2015.03.007. PubMed DOI

Cedrowska E., Pruszynski M., Majkowska-Pilip A., Męczyńska-Wielgosz S., Bruchertseifer F., Morgenstern A., Bilewicz A. Functionalized TiO2 nanoparticles labelled with 225Ac for targeted alpha radionuclide therapy. J. Nanopart. Res. 2018;20:83. doi: 10.1007/s11051-018-4181-y. PubMed DOI PMC

Mokhodoeva O., Vlk M., Málková E., Kukleva E., Mičolová P., Štamberg K., Šlouf M., Dzhenloda R., Kozempel J. Study of 223Ra uptake mechanism by Fe3O4 nanoparticles: Towards new prospective theranostic SPIONs. J. Nanopart. Res. 2016;18:301. doi: 10.1007/s11051-016-3615-7. DOI

Kozempel J., Vlk M. Nanoconstructs in Targeted Alpha-Therapy. Recent Pat. Nanomed. 2014;4:71–76. doi: 10.2174/1877912305666150102000549. DOI

LeGeros R.Z., Ito A., Ishikawa K., Sakae T., LeGeros J.P. Advanced Biomaterials. John Wiley & Sons; Hoboken, NJ, USA: 2009.

Rivera-Muñoz E.M. Biomedical Engineering-Frontiers and Challenges. InTechOpen; London, UK: 2009. pp. 75–98. DOI

Teixeira C.M.A., Piccirillo C., Tobaldi D.M., Pullar R.C., Labrincha J.A., Ferreira M.O., Castro P.M.L., Pintado M.M.E. Effect of preparation and processing conditions on UV absorbing properties of hydroxyapatite-Fe2O3 sunscreen. Mater. Sci. Eng. C Mater. Biol. Appl. 2017;71:141–149. doi: 10.1016/j.msec.2016.09.065. PubMed DOI

Stojanović Z.S., Ignjatović N., Wu V., Žunič V., Veselinović L., Škapin S., Miljković M., Uskoković V., Uskoković D. Hydrothermally processed 1D hydroxyapatite: Mechanism of formation and biocompatibility studies. Mater. Sci. Eng. C Mater. Biol. Appl. 2016;68:746–757. doi: 10.1016/j.msec.2016.06.047. PubMed DOI PMC

Kukleva E., Suchánková P., Štamberg K., Vlk M., Šlouf M., Kozempel J. Surface protolytic property characterization of hydroxyapatite and titanium dioxide nanoparticles. RSC Adv. 2019;9:21989–21995. doi: 10.1039/C9RA03698A. PubMed DOI PMC

Salvador A., Pascual-Martí M.C., Adell J.R., Requeni A., March J.G. Analytical methodologies for atomic spectrometric determination of metallic oxides in UV sunscreen creams. J. Pharm. Biomed. Anal. 2000;22:301–306. doi: 10.1016/S0731-7085(99)00286-1. PubMed DOI

Kreyling W.G., Holzwarth U., Haberl N., Kozempel J., Hirn S., Wenk A., Schleh C., Schäffler M., Lipka J., Semmler-Behnke M., et al. Quantitative biokinetics of titanium dioxide nanoparticles after intravenous injection in rats: Part 1. Nanotoxicology. 2017;11:434–442. doi: 10.1080/17435390.2017.1306892. PubMed DOI

Kreyling W.G., Holzwarth U., Schleh C., Kozempel J., Wenk A., Haberl N., Hirn S., Schäffler M., Lipka J., Semmler-Behnke M., et al. Quantitative biokinetics of titanium dioxide nanoparticles after oral application in rats: Part 2. Nanotoxicology. 2017;11:443–453. doi: 10.1080/17435390.2017.1306893. PubMed DOI

Kreyling W.G., Holzwarth U., Haberl N., Kozempel J., Wenk A., Hirn S., Schleh C., Schäffler M., Lipka J., Semmler-Behnke M., et al. Quantitative biokinetics of titanium dioxide nanoparticles after intratracheal instillation in rats: Part 3. Nanotoxicology. 2017;11:454–464. doi: 10.1080/17435390.2017.1306894. PubMed DOI

Toxicology Data Network, U.S. National Library of Medicine. [(accessed on 13 November 2019)]; Available online: https://toxnet.nlm.nih.gov/newtoxnet/index.html.

SPC GalliaPharm Eckert & Ziegler Radiopharma GmbH Summary of Product Characteristic: GalliaPharm–Radionuclide Generator. [(accessed on 17 January 2019)];2014 Available online: http://mri.medagencies.org/download/DK_H_2294_001_FinalPI.pdf.

Sandhöfer B., Meckel M., Delgado-López J.M., Patricio T., Tampieri A., Rösch F., Iafisco M. Synthesis and preliminary in vivo evaluation of well-dispersed biomimetic nanocrystalline apatites labeled with positron emission tomographic imaging agents. ACS Appl. Mater. Interfaces. 2015;7:10623–10633. doi: 10.1021/acsami.5b02624. PubMed DOI

Das T., Banerjee S. Theranostic Applications of Lutetium-177 in Radionuclide Therapy. Curr. Radiopharm. 2016;9:94–101. doi: 10.2174/1874471008666150313114644. PubMed DOI

Chakraborty S., Vimalnath K.V., Rajeswari A., Shinto A., Sarma H.D., Kamaleshwaran K., Thirumalaisamy P., Dash A. Preparation, evaluation, and first clinical use of 177Lu-labeled hydroxyapatite (HA) particles in the treatment of rheumatoid arthritis: Utility of cold kits for convenient dose formulation at hospital radiopharmacy. J. Label. Compd. Rad. 2014;57:453–462. doi: 10.1002/jlcr.3202. PubMed DOI

Kozempel. J., Vlk M., Málková E., Bajzíková A., Bárta J., Santos-Oliveira R., Malta Rossi A. Prospective carriers of 223Ra for targeted alpha particle therapy. J. Radioanal. Nucl. Chem. 2015;304:443–447. doi: 10.1007/s10967-014-3615-y. DOI

Severin A.V., Vasiliev A.N., Gopin A.V., Vlasova I.E., Chernykh E.V. Dynamics of Sorption–Desorption of 223Ra Therapeutic α-Emitter on Granulated Hydroxyapatite. Radiochemistry. 2019;61:339–346. doi: 10.1134/S1066362219030093. DOI

Orlova M.A., Nikolaev A.L., Trofimova T.P., Orlov A.P., Severin A.V., Kalmykov S.N. Hydroxyapatite and porphyrin-fullerene nanoparticles for diagnostic and therapeutic delivery of paramagnetic ions and radionuclides. Bull. RSMU. 2008;6:86–93. doi: 10.24075/brsmu.2018.075. DOI

Torres Berdeguez M.B., Thomas S., Medeiros S., de Sá L.V., Mas Milian F., da Silva A.X. Dosimetry in Radiosynoviorthesis: 90Y vs. 153Sm. Health Phys. Soc. 2018;1:1–6. doi: 10.1097/HP.0000000000000730. PubMed DOI

Chakraborty S., Das T., Chirayil V., Lohar S.P., Sarma H.D. Erbium-169 labeled hydroxyapatite particulates for use in radiation synovectomy of digital joints–a preliminary investigation. Radiochim. Acta. 2014;102:443–450. doi: 10.1515/ract-2013-2166. DOI

Rigali M.J., Brady P.V., Moore R.C. Radionuclide removal by apatite. Am. Miner. 2016;101:2611–2619. doi: 10.2138/am-2016-5769. DOI

Abbas K., Cydzik I., Del Torchio R., Farina M., Forti E., Gibson N., Holzwarth U., Simonelli F., Kreyling W. Radiolabelling of TiO2 nanoparticles for radiotracer studies. J. Nanopart. Res. 2010;12:2435–2443. doi: 10.1007/s11051-009-9806-8. DOI

Pérez-Campaña C., Sansaloni F., Gómez-Vallejo V., Baz Z., Martin A., Moya S.E., Lagares J.I., Ziolo R.F., Llop J. Production of 18F-Labeled Titanium Dioxide Nanoparticles by Proton Irradiation for Biodistribution and Biological Fate Studies in Rats. Part. Part. Syst. Charact. 2014;31:134–142. doi: 10.1002/ppsc.201300302. DOI

Duan D., Liu H., Xu Y., Han Y., Xu M., Zhang Z., Liu Z. Activating TiO2 Nanoparticle: Gallium-68 Serves As a High-Yielded Photon Emitter for Cerenkov Induced Photodynamic Therapy. ACS Appl. Mater. Interfaces. 2018;10:5278–5286. doi: 10.1021/acsami.7b17902. PubMed DOI

Hildebrand H., Schymura S., Holzwarth U., Gibson N., Dalmiglio M., Franke K. Strategies for radiolabelling of commercial TiO2 nanopowder as a tool for sensitive nanoparticle detection in complex matrices. J. Nanopart. Res. 2015;17:278. doi: 10.1007/s11051-015-3080-8. DOI

Cedrowska E., Łyczko M., Piotrowska A., Bilewicz A., Stolarz A., Trzcińska A., Szkliniarz K., Wąs B. Silver impregnated nanoparticles of titanium dioxide as carriers for 211At. Radiochim. Acta. 2016;104:267–275. doi: 10.1515/ract-2014-2373. DOI

Comarmond M.J., Payne T.E., Harrison J.J., Thiruvoth S., Wong H.K., Aughterson R.D., Lumpkin G.R., Müller K., Foerstendorf H. Uranium Sorption on Various Forms of Titanium Dioxide Influence of Surface Area, Surface Charge, and Impurities. Environ. Sci. Technol. 2011;45:5536–5542. doi: 10.1021/es201046x. PubMed DOI

Tits J., Walther C., Stumpf T., Macé N., Wielanda E. A luminescence line-narrowing spectroscopic study of the uranium(VI) interaction with cementitious materials and titanium dioxide. Dalton Trans. 2015;44:966–976. doi: 10.1039/C4DT02172J. PubMed DOI

Suchánková P., Kukleva E., Štamberg K., Nykl P., Vlk M., Kozempel J. Study of 223Ra uptake mechanism on hydroxyapatite and titanium dioxide nanoparticles as a function of pH. RSC Adv. 2020;10:3659–3666. doi: 10.1039/C9RA08953E. PubMed DOI PMC

Suchánková P., Kukleva E., Štamberg K., Nykl P., Sakmár M., Vlk M., Kozempel J. Determination, Modeling and Evaluation of Kinetics of 223Ra Sorption on Hydroxyapatite and Titanium Dioxide Nanoparticles. Materials. 2020;13:1915. doi: 10.3390/ma13081915. PubMed DOI PMC

European Medicines Agency; [(accessed on 20 November 2019)]. SPC Xofigo (2013) Summary of Product Characteristic: Xofigo. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/xofigo.

Food and Drug Administration; [(accessed on 25 July 2019)]. PI Xofigo (2013) Prescribing Information: Xofigo. U.S. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203971lbl.pdf.

Vucina J. Technetium-99m production for use in nuclear medicine. Med. Pregl. 2000;53:631–634. PubMed

Guseva L.I., Tikhomirova G.S., Dogadkin N.N. Anion-Exchange Separation of Radium from Alkaline-Earth Metals and Actinides in Aqueous-Methanol Solutions of HNO3. 227Ac-223Ra Generator. Radiochemistry. 2004;46:58–62. doi: 10.1023/B:RACH.0000024637.39523.e4. DOI

Benjamin R.J., McLaughlin L.S. Plasma components: Properties, differences, and uses. Transfusion. 2012;52:9S–19S. doi: 10.1111/j.1537-2995.2012.03622.x. PubMed DOI

Recent Advances in Metal Oxide and Phosphate Nanomaterials Radiolabeling with Medicinal Nuclides

Study of 213Bi and 211Pb Recoils Release from 223Ra Labelled TiO2 Nanoparticles

Radiolabeled nanomaterials for biomedical applications: radiopharmacy in the era of nanotechnology