Quantification of 131Iodine-labelled radiopharmaceuticals in mouse tissues using preclinical Single Photon Emission Computed Tomography (micro SPECT)

SCK•CEN Mentor

Saldarriaga Vargas Clarita, csvargas@sckcen.be, +32 (0)14 33 88 14

Expert group

Research in Dosimetric Applications

Introduction

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.

Objective

This project aims to develop a protocol for image quantification of small animal SPECT imaging, to enable more reproducible and accurate tissue activity measurements in preclinical studies based on Iodine-131.

The accuracy and reproducibility associated with the assessment of the pharmacokinetics of a 131I-labelled radiopharmaceutical in mice will be investigated for longitudinal micro SPECT quantitative imaging, and will be compared against conventional ex vivo biodistribution studies based on external gamma counting. The impact of different activity quantification methods and the variability of mouse pharmacokinetics on tissue absorbed dose calculations will be assessed.

Proposed workplan

The project will be performed in collaboration with the In vivo Cellular and Molecular Imaging (ICMI) lab of the Vrije Universiteit Brussel.

  • Perform image quantification on SPECT images of mice obtained at different time points after injection of the 131I-labelled radiopharmaceutical. Derive time-dependent activity curves and calculate total (time-integrated) cumulated activity in kidney tissues.
    • Evaluate the influence of ROI settings on SPECT quantification.
    • Assess the influence of different time-activity curve fitting methods on the calculation of the total cumulated activity.
    • Evaluate the reproducibility in the assessment of mouse pharmacokinetics taking into account mouse inter-variability.
    • Investigate the feasibility of 131I activity quantification in main kidney sub-regions (renal cortex and medulla).
  • Assess the accuracy of SPECT-based activity quantification using as a reference whole tissue activity data from ex vivo gamma counting measurements.
    • Identify optimal ROI settings for accurate and reproducible SPECT-based activity quantification of the kidneys.
  • Evaluate the reproducibility in the assessment of mouse pharmacokinetics using gamma counting, taking into account mouse inter-variability: compare kidney activities of different mice at selected time points (covering different kidney-to-medium activity ratios).
  • Calculate the radiation absorbed dose to kidney tissues based on the cumulated tissue activities previously determined with different quantification methods and available S-values (coefficients of tissue absorbed dose per radionuclide decay).
  • Write a scientific report summarizing the work performed during the internship. Present final results in a scientific meeting at SCK•CEN.

 

Estimated duration of the project: 4 to 8 months.

Other requirements: The candidate must have good command of English language.

The minimum diploma level of the candidate needs to be

Academic bachelor , Professional bachelor