Development of computational model for renal dosimetry in preclinical radiopharmaceutical therapy

Introduction

Radiation-induced kidney toxicity (nephrotoxicity) has shown to be a dose-limiting factor during peptide receptor radionuclide therapy using beta-emitting radiolabeled somatostatin analogs 90Y-DOTATOC and 177Lu-DOTATATE for the treatment of somatostatin receptor-positive neuroendocrine tumors.
A subject that is key for a better understanding and modelling of nephrotoxicity in radiopharmaceutical therapy and that requires further investigation is the influence of absorbed dose heterogeneity in the biological response of the kidney. Radiopharmaceutical uptake is often not uniform in kidney tissues. Small molecules such as radiolabeled peptides often show an increased retention in the proximal tubules of the renal cortex and outer medulla. This results in a corresponding non-uniform distribution of absorbed dose across renal regions and even the small substructures within them, particularly for therapeutic radionuclides emitting charged-particle radiation with low tissue penetration range (< 100 um) like alphas and betas/electrons with a low energy (< 50 keV). 
 
The preclinical investigation of kidney toxicity in the presence of absorbed dose heterogeneity is precluded by the limited accuracy of the reference S values (coefficients of absorbed dose per radionuclide activity in source tissue) used for absorbed dose calculations in mouse kidneys. In particular, computational anatomical models with multiple compartments of the different kidney substructures are needed to model non-uniform distributions of radionuclides and be able to calculate the radiation dose absorbed in different kidney tissues.
For radiopharmaceutical therapy, the S-values for kidneys currently available are considering either uniform organ activity, or uniform activity on tissue level. In order to accurately calculate the absorbed dose to kidneys in preclinical radiopharmaceutical therapy, the development of more detailed anatomical models for S-value calculation is of great interest. 

Objectives

This project aims to further develop a computational multi-region anatomical model of murine kidney tissues for preclinical radiopharmaceutical dosimetry. The candidate will be working on an existing preliminary model which is being developed based on 3D multiphoton microscopy data (Blanc et al. 2021. https://doi.org/10.1016/j.kint.2020.09.032). The objective is to finalize the segmentation (3D Slicer software) of the different microscopic substructures of nephrons from murine kidneys. Once the 3D model is finalized, the student will perform Monte Carlo radiation transport simulations (GATE simulation toolkit) to calculate S values for the different tissue regions for a variety of radionuclides of medical interest. 
This project will be supporting an ongoing PhD study (https://www.sckcen.be/en/thesis-ongoing/modelling-dose-response-nephrotoxicity-preclinical-targeted-radionuclide-therapy-161tb-and-177lu-radiolabeled-peptides-0a899ade-9897-eb11-80d4-ecf4bbc6e827). The student will learn how to use the relevant software during the internship. 

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