Targeted radionuclide therapy: how to correlate microdosimetry with biological effects

This thesis focuses on the improvement of current computational dosimetry approaches for in vitro and in vivo TRT treatment in order to correlate microdosimetry with biological effects. The creation of such computational frameworks and the investigation of the radiobiology of dose-response in TRT in cells and in small animals will lead ultimately to a better understanding of this treatment modality to increase the predictive power of dosimetry. In this first chapter we introduced NET and PCa, the concept of TRT focusing primarily on PRRT, how dosimetry can assist the development of TRT and how it can be implemented on a preclinical level for correlation with the biological end-points of interest. In the second chapter we built a more refined dosimetry model for in vitro cell experiments with 177Lu-DOTATATE, accounting for realistic cell geometries and detailed uptake kinetics. As we questioned the validity of the LQ model at very low dose rates, we tried to gain a more fundamental understanding by modelling the mechanisms of such radiation induced DNA damage in the third chapter. Here, we highlighted the need for a microdosimetric framework able to explain the biological effects linked to the DNA damage biomarkers. In the fourth chapter, we moved to organ-level dosimetry confirming that distinct differences can be found between cellular dose and average tumor dose, which might impact clinical tumor dosimetry evaluation for 177Lu-targeted therapy. By accounting for this difference, we could establish good correlations with several biological endpoints (i.e. DSBs and tumor volume reduction) showing, once again, different sensitivity parameters for cells exposed to 177Lu-DOTATATE with respect to EBRT. In the fifth chapter we showed how dose-response correlations can be used for TRT treatment planning, hypothesizing the use of different radionuclides and evaluating the impact on healthy organs (i.e. kidney and bone marrow) and tumor volumetric response. By comparing the therapeutic efficacy of several radionuclides, we confirmed the great potential of alpha-particle emitters. Hence, in the seventh chapter we extended our work to targeted alpha therapy evaluating and comparing the binding characteristics and therapeutic efficacy of 225Ac-PSMA-I&T and 177Lu-PSMA-I&T in vitro. Our results indicated that 225Ac-PSMA-I&T has a 4.3x higher RBE compared to 177Lu-PSMA-I&T. Chapter 8 provides the summary and concluding remarks.