Biodistribution study of 211Pb progeny released from intravenously applied 223Ra labelled TiO2 nanoparticles in a mouse model

Abstract

Background

Targeted alpha therapy is one of the most powerful therapeutical modalities available in nuclear medicine. It's therapeutic potency is based on the nuclides that emit one or several alpha particles providing strong and highly localized therapeutic effects. However, some of these radionuclides, like e.g. ²²³Ra or ²²⁵Ac decay in cascades, where the radioactive progeny originating from the consecutive alpha-decays may leave the original vector and cause unwanted irradiation of non-target organs. This progeny, even if partially retained in target tissues by internalization processes, typically do not follow the fate of originally targeted radiopharmaceutical and potentially spread over body following their own biodistribution. In this study we aimed to estimate ²¹¹Pb/²¹¹Bi progeny fate from the ²²³Ra surface-labelled TiO₂ nanoparticles in vitro and the fate of ²¹¹Pb in vivo in a mice model.

Results

In vitro stability studies have shown significant differences between the release of the mother ²²³Ra and its progeny (²¹¹Pb, ²¹¹Bi) in all the biological matrices that have been tested. The lowest released activities were measured in saline, resulting in less than 5 % of released activity for all nuclides. Contrary to that, the highest released activity of ²²³Ra of up to 10 % within 48 h was observed in 5 % solution of albumin. The released activity of its progeny; the ²¹¹Pb and ²¹¹Bi was in the range of 20–40 % in this test medium. Significantly higher released activities of ²¹¹Pb and ²¹¹Bi compared to ²²³Ra by at least 10 % was observed in each biological medium, except saline, where no significant differences were observed. The in vivo biodistribution studies results in a mice model, show similar pattern, where it was found that even after accumulation of nanoparticles in target tissues, approximately 10 % of ²¹¹Pb is continuously released into the blood stream within 24 h, followed by its natural accumulation in kidneys.

Conclusion

This study confirms our assumption that the progeny formed in a chain alpha decay of a certain nuclide, in this case the ²²³Ra, can be released from its original vector, leave the target tissue, relocate and could be deposited in non-target organs. We did not observe complete progeny wash-out from its original target tissues in our model. This indicates strong dependence of the progeny hot atom fate after its release from the original radiopharmaceutical preparation on multiple factors, like their internalization and retention in cells, cell membranes, extracellular matrices, protein binding, etc. We hypothesize, that also the primary tumour or metastasis size, their metabolic activity may significantly influence progeny fate in vivo, directly impacting the dose delivered to non-target tissues and organs. Therefore a bottom-up approach should be followed and detailed pre-/clinical studies on the release and biodistribution of radioactive progeny originating from the chain alpha emitters should be preferably performed.