New radiopharmaceuticals must undergo extensive pre-clinical evaluation to assess their efficacy and safety before they are tested in humans. Following in vitro evaluation in cells, in vivo animal studies are performed on relevant biological models to further assess stability, biodistribution, efficacy and potential toxicity.
In targeted radionuclide therapy, treatment-related biological effects such as tumor control and normal tissue toxicity show a dependence on the amount of radiation absorbed dose [Gy] received by tissue due to the ionizing radiations emitted by the radionuclide. Determining the dose-toxicity relationship at preclinical level is particularly important to assess the safety profile and determine the maximum tolerated absorbed dose of a therapeutic regime with a radiopharmaceutical. Pharmacokinetic and dosimetry data from preclinical radiobiological studies may then be used to guide the design of phase I clinical trials (first in-human testing), in particular to inform the amount of activity that may be administered to patients.
Accurate dosimetry of mouse tissues in targeted radionuclide therapy requires accurately knowing the amount of radionuclide activity and its spatial distribution in tissues and its variation over time (pharmacokinetics). Two methods are typically used to assess the pharmacokinetics in mice: ex vivo gamma counting of dissected organs following sacrifice of multiple mice at different time points, and in vivo longitudinal radionuclide imaging. Conventional whole-organ ex-vivo biodistribution methods are limited as they require animal sacrifice, introduce pharmacokinetics inter-variability from the different animals used at different time points and do not provide information on the potentially heterogeneous uptake (retention) distribution of radiopharmaceutical at sub-organ level.
Instead, preclinical Single Photon Emission Computed Tomography (micro SPECT) imaging can be used to perform in vivo longitudinal pharmacokinetic studies using the same animal. With this technique it is possible to evaluate the pharmacokinetics required for tissue dosimetry on the same animal used for long-term toxicity studies, limiting the effects of mice inter-variability on the evaluation of the absorbed dose-toxicity relationship. However, micro SPECT also presents a unique set of challenges. The limited spatial resolution of the imaging system affects the accuracy of activity quantification in small tissues due to partial volume effect (PVE). The impact of thi physical effect depends on the size and shape of the imaged tissue: small tissues and tissues with a refined shape are more difficult to image and quantify than large bulky tissues. Additionally, the accuracy of activity quantification is also dependent on the regions of interest (ROI) used for image quantification (regions of the SPECT image whose “intensity” is used to determine the tissue activity, after applying an appropriate calibration factor). Thus ROI settings (drawing method, size, shape) need to be optimized for the specific imaging task to enable accurate tissue activity quantification.
This project focuses on the quantification of a radiopharmaceutical radiolabeled with Iodine-131 in murine kidney tissues. Radiopharmaceuticals are often cleared from the body through renal excretion. During this process a significant amount of the (untargeted) radiopharmaceutical may be retained in the kidneys, increasing the risk of radiation-induced nephrotoxicity during radiopharmaceutical therapy.