Microdosimetric approaches for optimizing proton therapy and targeted radionuclide therapy

Hadron therapy and targeted radionuclide therapy have emerged as advanced clinical approaches for cancer treatment. Their main goal is to increase radiation doses to tumors while minimizing toxicity to healthy tissues. Proper characterization of radiation quality is thus crucial to ensure safe and effective tumor treatment. For this reason, microdosimetry has been employed. It helps to better understand the relationship between energy deposition and biological effects. It also identifies suitable quantities for characterizing and quantifying radiation quality. In spite of its potential, more technological and methodological improvements are needed for clinical use. Both the development of reliable solid-state microdosimeters suitable for clinical beams and the definition of biological models that connect physical quantities to therapeutic outcomes remain crucial elements in the research field. Within this context, this PhD work contributes to the microdosimetric characterization of radiation using a combined experimental and modeling approach, also supporting improved understanding of biological effects and more effective quality assurance strategies. Integrating experimental and Monte Carlo modeling approaches, the first part of the research concerns the DIODE (Diamond Integrated devices fOr haDronthErapy) project. This work presents the development and experimental characterization of DIODE, an innovative detection system based on single-crystal synthetic diamond designed to perform simultaneous dosimetric and microdosimetric measurements in clinical hadron therapy beams. Tests conducted at the Proton Therapy Center in Trento with a 70 MeV proton beam confirmed the device's excellent linearity with dose and its ability to accurately estimate LET and RBE variations (with RBE values between ~1.1 and ~1.8), providing results consistent with literature data and Monte Carlo simulations. One of the key aspects of this project concerns the characterization of the so-called "border effect", a typical challenge for solid-state microdosimeters linked to incomplete charge collection at the edges of the sensitive volume. Through IBIC (Ion Beam Induced Charge) analysis and Geant4 simulations, it has been quantified that this effect can cause significant variations in microdosimetric quantities, up to 40\% for $\bar{y}_F$ and 20\% for $\bar{y}_D$. Therefore, understanding and mitigating this phenomenon is essential to ensure the accuracy of clinical measurements. Overall, the DIODE system is an advanced and reliable tool for real-time beam quality assessment and optimization of biologically based treatment plans in modern ion therapy. At the same time, the SEGNAR (Synergic Effects of Gold Nanorods and Radiopharmaceuticals) project analyzed the biological efficacy of $^{99m}$Tc conjugated to gold nanorods (AuNRs). Through Geant4-DNA simulations and the Monte Carlo temporal - Microdosimetric Kinetic Model (MCt-MKM), it was demonstrated that the dose enhancement due to the presence of gold is minimal (6-7 orders of magnitude lower than the radionuclide alone). However, the study of the synergistic effect of the $^{99m}$Tc-AuNR system revealed that the co-localization of multiple sources for AuNR lead to a dose enhancement, making the dose distribution extremely heterogeneous. Despite the increase in local dose, the synergistic effect is limited by the low dose rate (6-hour half-life of $^{99m}$Tc), which allows cellular repair mechanisms to actively intervene during irradiation, reducing the formation of sublethal lesions. The study demonstrates that the fundamental role of gold nanorods lies in their function as carriers capable of positioning the radionuclide as close as possible to the cell nucleus in order to exploit the high LET of Auger electrons and maximize DNA damage. Finally, this thesis presents a new standard for quality assurance for proton therapy by reducing uncertainties in radiobiological calculations performed by the Treatment Planning Systems (TPS) and improving their robustness. New innovative perspectives in theranostics are introduced as the results of the combined usage of $^{99m}$Tc and nanoparticles that could be further converted and used with other toxic radiopharmaceuticals using specially designed nanomaterials.