• Citer

Modeling of kidney absorbed dose heterogeneity and toxicity in radiopharmaceutical therapy with 161Tb and 177Lu radiolabeled peptides

par Andersson, Michelle
Président du jury Verhoeven, Caroline
Promoteur Reynaert, Nick
Co-Promoteur Levillain, Hugo
Publication Non publié, 2026-02-27

Thèse de doctorat

• Accès en ligne
• Détails
• Contenu
• Statistiques

Résumé :

Radiopharmaceutical therapy (RPT) is emerging as a rapidly expanding treatment modality for several malignancies, exemplified by the widespread use of [177Lu]Lu-DOTA-TATE for neuroendocrine tumors, and the recent regulatory approval of [177Lu]Lu-PSMA-617 for specific prostate cancers. With interest in novel radionuclides, such as terbium-161 (161Tb), and introducing RPT into a larger patient cohort for established treatments increasing, potential adverse effects become of greater importance to consider. The kidneys are a primary organ at risk in RPT due to their role in the excretion and potential retention of radiopharmaceuticals, and nephrotoxicity has been consistently identified as a dose-limiting factor. Accurate prediction of nephrotoxicity in RPT across radiopharmaceuticals is confounded by the current inability to consider absorbed dose heterogeneity at a biologically relevant scale. The influence of non-uniform absorbed dose distribution on potential nephrotoxicity becomes highly relevant to investigate as interest in radionuclides resulting in localized irradiation of tissues continue to increase. In order to improve understanding of the underlying mechanisms leading to renal impairment following RPT, preclinical studies are of great value, enabling controlled investigations of improved dosimetry and the potential influence on accurate prediction of renal adverse effects in RPT, preclinical studies offer. This thesis aimed to develop a preclinical nephron substructure-level dosimetry framework and a mechanistic normal tissue complication probability (NTCP) model to improve prediction of radiation-induced nephrotoxicity in RPT. In Chapter II, a computational multi-nephron model was developed based on 3D microscopy data of murine renal tissues. The model considered the three different nephron types present in murine kidneys and their respective main substructures, enabling absorbed dose calculations using Monte Carlo radiation transport simulations. The influence of considering substructural differences in absorbed dose was investigated in Chapter III for [161Tb]Tb- and [177Lu]Lu-DOTA-TATE by defining a nephron substructure-level dosimetry framework for comparison of absorbed dose heterogeneity between the radiopharmaceuticals. The influence of the differences in absorbed dose heterogeneity between 161Tb and 177Lu on radiation-induced nephropathy was investigated in a preclinical nephrotoxicity experiment in Chapter IV. By matching absorbed doses to selected substructures between [161Tb]Tb- and [177Lu]Lu-DOTA-TATE, the influence of differences in absorbed dose heterogeneity between radiopharmaceuticals was investigated. Finally, a radiobiologically based, mechanistic NTCP model for nephrotoxicity, adapted to RPT-specific absorbed dose heterogeneity was formulated in Chapter V.