66P - Exploring the radiobiology and dosimetry of targeted alpha therapy as a tool to optimize its clinical application: A preclinical study

Background

The use of molecular radionuclide therapy (MRT), such as targeted alpha therapy, is an emerging option for cancer treatment. The first alpha-emitter approved for therapeutic use was radium-223 (Ra-223), indicated for metastatic castration-resistant prostate cancer (mCRPC), with exclusive bone metastasis. However, treatment outcomes are below expectations. There are some limitations, such as precise dosimetry, that could be addressed to improve clinical outcomes. In fact, there is no inclusion of radiobiology and molecular dosimetry data obtained in preclinical studies into MRT planning as occur for radiotherapy. Moreover, there is a lack of these data for MRT. Thus, the aim of this study was to develop preclinical studies to access radiobiology and dosimetry for MRT, namely for Ra-223.

Methods

Preclinical studies were conducted using metastatic PCa cells or spheroids, to better mimic tumor architecture, as cellular models of mCRPC. Radiobiological endpoints, such as viability, survival and death, were measured 7days post-irradiation of cellular models with increasing activities of Ra-223 (0-7040 Bq/mL) for 24h. The size, geometry and cell distribution of each cellular model were analyzed by confocal microscopy and values were used in combination with radiobiological and kinetics endpoints to perform cell dosimetry using MIRDcell V3.

Results

The exposure to increasing activities of Ra-223 induces a decrease in viability, survival with increasing of cell death for both cellular models, with biological effects depending on the cell model characteristics. These effects are less evident when evaluated in spheroids, when exposed to the same activities of Ra-223. These biological data were validated with dosimetric calculations that confirm differences in absorbed doses depending not only on initial activity but also on cellular model characteristics.

Conclusions

The radiobiological and dosimetric studies showed that radiation effects for Ra-223 are dependent on molecular and structural characteristics of the cellular model, being the spheroids more representative of tumor architecture and better to conduct translational preclinical studies for MRT, as well as to obtain precise dosimetry.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

This research was funded by the Foundation for Science And Technology (FCT), Portugal, through the Strategic Projects UIDB/04539/2020, UIDP/04539/2020, and by COMPETE-FEDER, reference number POCI-01-0145-FEDER-007440. Scholarship grants from FCT and European Social Funding to I.A.M. (SFRH/BD/136973/2018).

Disclosure

All authors have declared no conflicts of interest.