Nanoparticles of various materials were proposed as carriers of nuclides in targeted alpha particle therapy to at least partially eliminate the nuclear recoil effect causing the unwanted release of radioactive progeny originating in nuclear decay series of so-called in vivo generators. Here, we report on the study of 211Pb and 211Bi recoils release from the 223Ra surface-labelled TiO2 nanoparticles in the concentration range of 0.01-1 mg/mL using two phase separation methods different in their kinetics in order to test the ability of progeny resorption. We have found significant differences between the centrifugation and the dialysis used for labelled NPs separation as well as that the release of 211Pb and 211Bi from the nanoparticles also depends on the NPs dispersion concentration. These findings support our previously proposed recoils-retaining mechanism of the progeny by their resorption on the NPs surface. At the 24 h time-point, the highest overall released progeny fractions were observed using centrifugation (4.0% and 13.5% for 211Pb and 211Bi, respectively) at 0.01 mg/mL TiO2 concentration. The lowest overall released fractions at the 24 h time-point (1.5% and 2.5% for 211Pb and 211Bi respectively) were observed using dialysis at 1 mg/mL TiO2 concentration. Our findings also indicate that the in vitro stability tests of such radionuclide systems designed to retain recoil-progeny may end up with biased results and particular care needs to be given to in vitro stability test experimental setup to mimic in vivo dynamic conditions. On the other hand, controlled and well-defined progeny release may enhance the alpha-emitter radiation therapy of some tumours.

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

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Guerra Liberal F.D.C., O’Sullivan J.M., McMahon S.J., Prise K.M. Targeted alpha therapy: Current clinical applications. Cancer Biother. Radiopharm. 2020;35:404–417. doi: 10.1089/cbr.2020.3576. PubMed DOI

Kim Y.S., Brechbiel M.W. An overview of targeted alpha therapy. Tumour Biol. 2012;33:573–590. doi: 10.1007/s13277-011-0286-y. PubMed DOI PMC

Bayer Xofigo, SPC. [(accessed on 4 October 2022)]. Available online: https://www.ema.europa.eu/en/documents/product-information/xofigo-epar-product-information_en.pdf.

Hallqvist A., Bergmark K., Back T., Andersson H., Dahm-Kahler P., Johansson M., Lindegren S., Jensen H., Jacobsson L., Hultborn R., et al. Intraperitoneal alpha-Emitting Radioimmunotherapy with 211At in Relapsed Ovarian Cancer: Long-Term Follow-up with Individual Absorbed Dose Estimations. J. Nucl. Med. 2019;60:1073–1079. doi: 10.2967/jnumed.118.220384. PubMed DOI PMC

Watabe T., Kaneda-Nakashima K., Shirakami Y., Liu Y., Ooe K., Teramoto T., Toyoshima A., Shimosegawa E., Nakano T., Kanai Y., et al. Targeted Alpha Therapy Using Astatine (211At)-Labeled Phenylalanine: A Preclinical Study in Glioma Bearing Mice. Oncotarget. 2020;11:1388–1398. doi: 10.18632/oncotarget.27552. PubMed DOI PMC

Frantellizzi V., Cosma L., Brunotti G., Pani A., Spanu A., Nuvoli S., De Cristofaro F., Civitelli L., De Vincentis G. Targeted Alpha Therapy with Thorium-227. Cancer Biother. Radiopharm. 2020;35:437–445. doi: 10.1089/cbr.2019.3105. PubMed DOI

Satapathy S., Sharma A., Sood A., Maheshwari P., Gill H.J.S. Delayed Nephrotoxicity After 225Ac-PSMA-617 Radioligand Therapy. Clin. Nucl. Med. 2022;47:e466–e467. doi: 10.1097/RLU.0000000000004149. PubMed DOI

Lawal I.O., Morgenstern A., Vorster M., Knoesen O., Mahapane J., Hlongwa K.N., Maserumule L.C., Ndlovu H., Reed J.D., Popoola G.O., et al. Hematologic toxicity profile and efficacy of [225Ac]Ac-PSMA-617 α-radioligand therapy of patients with extensive skeletal metastases of castration-resistant prostate cancer. Eur. J. Nucl. Med. Mol. Imaging. 2022;49:3581–3592. doi: 10.1007/s00259-022-05778-w. PubMed DOI

Kratochwil C., Bruchertseifer F., Giesel F., Apostolidis C., Haberkorn U., Morgenstern A. Ac-225-DOTATOC—An Empiric Dose Finding for Alpha Particle Emitter Based Radionuclide Therapy of Neuroendocrine Tumors. J. Nucl. Med. 2015;56:1232.

Atallah E., Berger M., Jurcic J., Roboz G., Tse W., Mawad R., Rizzieri D., Begna K., Orozco J., Craig M., et al. A Phase 2 Study of Actinium-225 (225Ac)-Lintuzumab in Older Patients with Untreated Acute Myeloid Leukemia (AML) J. Med. Imaging Radiat. Sci. 2019;50:37. doi: 10.1016/j.jmir.2019.03.113. DOI

De Kruijff R.M., Wolterbeek H.T., Denkova A.G. A Critical Review of Alpha Radionuclide Therapy—How to Deal with Recoiling Daughters? Pharmaceuticals. 2015;8:321–336. doi: 10.3390/ph8020321. PubMed DOI PMC

Lin W. Introduction: Nanoparticles in medicine. Chem. Rev. 2015;115:10407–10409. doi: 10.1021/acs.chemrev.5b00534. PubMed DOI

Kozempel J., Mokhodoeva O., Vlk M. Progress in Targeted Alpha-Particle Therapy. What We Learned about Recoils Release from In Vivo Generators. Molecules. 2018;23:581. doi: 10.3390/molecules23030581. PubMed DOI PMC

Wolfram J., Zhu M., Yang Y., Shen J., Gentile E., Paolino D., Fresta M., Nie G., Chen C., Shen H., et al. Safety of Nanoparticles in Medicine. Curr. Drug Targets. 2015;16:1671–1681. doi: 10.2174/1389450115666140804124808. PubMed DOI PMC

Czerwińska M., Fracasso G., Pruszyński M., Bilewicz A., Kruszewski M., Majkowska-Pilip A., Lankoff A. Design and Evaluation of (223)Ra-Labeled and Anti-PSMA Targeted NaA Nanozeolites for Prostate Cancer Therapy—Part I. Materials. 2020;13:3875. doi: 10.3390/ma13173875. PubMed DOI PMC

Kleynhans J., Sathekge M., Ebenhan T. Obstacles and Recommendations for Clinical Translation of Nanoparticle System-Based Targeted Alpha-Particle Therapy. Materials. 2021;14:4784. doi: 10.3390/ma14174784. PubMed DOI PMC

Wang G., De Kruijff R.M., Rol A., Thijssen L., Mendes E., Morgenstern A., Bruchertseifer F., Stuart M.C.A., Wolterbeek H.T., Denkova A.G. Retention studies of recoiling daughter nuclides of 225Ac in polymer vesicles. Appl. Radiat. Isot. 2014;85:45–53. doi: 10.1016/j.apradiso.2013.12.008. PubMed DOI

Chang M.-Y., Seideman J., Sofou S. Enhanced loading efficiency and retention of 225Ac in rigid liposomes for potential targeted therapy of micrometastases. Bioconjug. Chem. 2008;19:1274–1282. doi: 10.1021/bc700440a. PubMed DOI

Souza B.N.R.F., Ribeiro E.R.F.R., da Silva de Barros A.O., Pijeira M.S.O., Kenup-Hernandes H.O., Ricci-Junior E., Diniz Filho J.F.S., dos Santos C.C., Alencar L.M.R., Attia M.F., et al. Nanomicelles of Radium Dichloride [223Ra]RaCl2 Co-Loaded with Radioactive Gold [198Au]Au Nanoparticles for Targeted Alpha–Beta Radionuclide Therapy of Osteosarcoma. Polymers. 2022;14:1405. doi: 10.3390/polym14071405. PubMed DOI PMC

Pijeira M.S.O., Viltres H., Kozempel J., Sakmár M., Vlk M., İlem-Özdemir D., Ekinci M., Srinivasan S., Rajabzadeh A.R., Ricci-Junior E., et al. Radiolabeled nanomaterials for biomedical applications: Radiopharmacy in the era of nanotechnology. EJNMMI Radiopharm. Chem. 2022;7:8. doi: 10.1186/s41181-022-00161-4. PubMed DOI PMC

Gaweda W., Pruzynski M., Cedrowska E., Rodak M., Majokwska-Pilip A., Gawel D., Bruchertseifer F., Morgenstern A., Bilewicz A. Traztuzumab modified barium ferrite magnetic nanoparticles labeled with radium-223: A new potential radiobioconjuagte for alpha radioimmunotherapy. Nanomaterials. 2020;10:2067. doi: 10.3390/nano10102067. PubMed DOI PMC

Pellico J., Gawne P.J., De Rosales R.T.M. Radiolabelling of nanomaterials for medical imaging and therapy. Chem. Soc. Rev. 2021;5:3355–3423. doi: 10.1039/D0CS00384K. PubMed DOI

Toro-González M., Dame A.N., Mirzadeh S., Rojas J.V. Encapsulation and retention of 225Ac, 223Ra, 227Th, and decay daughters in zircon-type gadolinium vanadate nanoparticles. Radiochim. Acta. 2020;108:967–977. doi: 10.1515/ract-2019-3206. DOI

Salvanou E.A., Stellas D., Tsoukalas C., Mavroidi B., Paravatou-Petsotas M., Kalogeropoulos N., Xanthopoulos S., Denat F., Laurent G., Bazzi R., et al. A Proof-of-Concept Study on the Therapeutic Potential of Au Nanoparticles Radiolabeled with the Alpha-Emitter Actinium-225. Pharmaceutics. 2020;12:188. doi: 10.3390/pharmaceutics12020188. PubMed DOI PMC

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., Nykl E., Nykl P., Sakmár M., Vlk M., Kozempel J. Hydroxyapatite and Titanium Dioxide Nanoparticles: Radiolabelling and In Vitro Stability of Prospective Theranostic Nanocarriers for 223Ra and 99mTc. Nanomaterials. 2020;10:1632. doi: 10.3390/nano10091632. PubMed DOI PMC

Arazi L., Cooks T., Schmidt M., Keisari Y., Kelson I. Treatment of solid tumors by interstitial release of recoiling short-lived alpha emitters. Phys. Med. Biol. 2007;52:5025–5042. doi: 10.1088/0031-9155/52/16/021. PubMed DOI

Nishri Y., Vatarescu M., Luz I., Epstein L., Dumančić M., Del Mare S., Shai A., Schmidt M., Deutsch L., Den R.B., et al. Diffusing alpha-emitters radiation therapy in combination with temozolomide or bevacizumab in human glioblastoma multiforme xenografts. Front. Oncol. 2022;12:888100. doi: 10.3389/fonc.2022.888100. PubMed DOI PMC

Krolicki L., Bruchertseifer F., Kunikowska J., Koziara H., Krolicki B., Jakucinski M., Pawlak D., Apostolidis C., Mirzadeh S., Rola R., et al. Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with 213Bi-substance P analogue. Eur. J. Nucl. Med. Mol. Imaging. 2018;45:1636–1644. doi: 10.1007/s00259-018-4015-2. PubMed DOI PMC

Gorin J.-B., Guilloux Y., Morgenstern A., Chérel M., Davodeau F., Gaschet J. Using α radiation to boost cancer immunity? OncoImmunology. 2014;3:e954925. doi: 10.4161/21624011.2014.954925. PubMed DOI PMC

Confino H., Schmidt M., Efrati M., Hochman I., Umansky V., Kelson I., Keisari Y. Inhibition of mouse breast adenocarcinoma growth by ablation with intratumoral alpha-irradiation combined with inhibitors of immunosuppression and CpG. Cancer Immunol. Immunother. 2016;65:1149–1158. doi: 10.1007/s00262-016-1878-6. PubMed DOI PMC

Gorin J.-B., Ménager J., Gouard S., Maurel C., Guilloux Y., Faivre-Chauvet A., Morgenstern A., Bruchertseifer F., Chérel M., Davodeau F., et al. Antitumor Immunity Induced after α Irradiation. Neoplasia. 2014;16:319–328. doi: 10.1016/j.neo.2014.04.002. 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

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

Live Chart of Nuclides, IAEA Vienna Austria. [(accessed on 22 December 2022)]. Available online: https://www-nds.iaea.org/relnsd/vcharthtml/VChartHTML.html.

Holzwarth U., Ojea Jimenez I., Calzolai L. A random walk approach to estimate the confinement of α-particle emitters in nanoparticles for targeted radionuclide therapy. EJNMMI Radiopharm. Chem. 2018;3:9. doi: 10.1186/s41181-018-0042-3. PubMed DOI PMC

Kelly J.M., Amor-Coarasa A., Sweeney E., Wilson J., Cusey P.W., Babich J.W. A suitable time point for quantifying the radiochemical purity of 225Ac-labeled radiopharmaceuticals. EJNMMI Radiopharm. Chem. 2021;6:38. doi: 10.1186/s41181-021-00151-y. PubMed DOI PMC

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