Radiation dosimetry to support the preclinical investigation and further development of radiopharmaceutical therapy

Radiopharmaceutical therapy (RPT) is an exciting and promising field of nuclear medicine which is currently experiencing tremendous progress. The number and variety of novel radioligands being developed and tested in preclinical and clinical settings is growing. As a consequence, the impact of molecular imaging and radiotherapeutics on healthcare is increasingly expanding by addressing unmet clinical needs in the diagnosis and treatment of cancer and other medical conditions. Novel approaches are being investigated to further improve the safety and efficacy of RPT and support the implementation of personalized medicine. More specifically, the use of more localized and cytotoxic forms of radiation are being evaluated to improve the therapeutic efficacy of radiopharmaceuticals. Approaches exploiting diagnostic and therapeutic properties of radiopharmaceuticals (i.e., theranostic approaches) are increasingly being used to personalize RPT. Patient dosimetry is becoming an essential tool for treatment optimization, as the amount of absorbed dose of radiation is the main factor driving the biological response of therapy with radiopharmaceuticals. Overall, there is an increasing interest in developing and implementing tools for accurate and practical tissue dosimetry, in establishing a solid knowledge basis on absorbed dose–effect relationships of irradiations with radiopharmaceuticals, and in advancing biophysical modelling of the radiobiological phenomena relevant in RPT. The aim of these efforts is to set a framework for predicting clinical endpoints of disease control and undesired radiotoxicity in normal tissues which can be used for treatment planning and optimization. As this field continues to grow and mature, preclinical radiopharmaceutical research on laboratory animals will be essential for further developing and optimizing RPT. Prior to first tests in humans, radiopharmaceuticals must undergo a thorough investigation of their efficacy and safety on living organisms so as to anticipate on their potential behavior in humans and provide insight to support the design of clinical trials. Additionally, preclinical studies on laboratory animals are invaluable for investigating fundamental as well as clinically relevant research questions which are difficult or impossible to investigate in a clinical setting. In particular, knowledge on the radiobiological and biophysical basis of tissue response upon irradiations with radiopharmaceuticals may be best obtained in animal systems, where a controlled, systematic and thorough study of the radiopharmaceutical activity and absorbed dose distribution, diverse biological endpoints of local tissue effects, and clinically relevant endpoints of response is possible. This kind of quantitative investigations require appropriate methods which allow a meaningful and reliable assessment of the quantities used for analyzing radiobiological outcomes. This will improve the correlations between input parameters (e.g., amount of radiopharmaceutical administered) and output variables (e.g., endpoints of biological effect) upon which sound conclusions with an increased translatability to applications in humans can be formulated. The developments addressed in the PhD thesis relate to the accuracy evaluation or improvement of methods used (i) for activity quantification of radiopharmaceuticals prior to administration in humans or laboratory animals, (ii) for radiopharmaceutical activity quantification in tissues of laboratory mice, and (iii) for absorbed dose estimations of radiopharmaceuticals in mouse kidney tissues. Through six different chapters, this thesis shows how these topics are important for using radiation dosimetry and dose–response modelling as tools for evaluating the safety of novel radiopharmaceuticals during the preclinical development phase and/or for individualized treatment optimization in clinical applications. Chapter I introduces various topics which relate to and set the background for the subsequent chapters of the thesis manuscript. Both in clinical and preclinical settings, accurate measurement of radiopharmaceutical activity before administration is important to ensure that patients and laboratory animals receive the appropriate amount of radiopharmaceutical suitable for the intended application. Chapter II presents a study in which the accuracy of activity measurements using radionuclide activity calibrators was evaluated in the context of nuclear medicine theranostics. In order to acquire accurate drug pharmacokinetic information, as required for tissue dosimetry, the imaging technique micro–SPECT (small-animal single-photon emission computed tomography) must be quantitative to allow an accurate assessment of radioligand activity in the relevant tissues over time post-administration. Therefore, Chapter III investigates the feasibility of using micro-SPECT for determining the mouse-specific pharmacokinetics of a 131I-labelled single-domain antibody in kidneys. Evaluating the distribution of absorbed dose within major organs at risk is becoming increasingly important, as the distribution of radiopharmaceuticals is often not uniform in tissues and charged particles with a short penetration path are increasingly being considered in RPT. Preclinical radiopharmaceutical analyses, such as toxicity studies, require the use of dedicated dosimetry methods adapted to the tissue morphology of laboratory animals. This PhD project specifically focuses on nephrotoxicity and mouse kidney dosimetry. Therefore, Chapter IV, describes the development of a realistic multi-region model of a mouse kidney to support the preclinical evaluation of potential nephrotoxicity in RPT. The developed model was used to create a database of S values (coefficients of absorbed dose in target tissue per radionuclide decay in source tissue) for various kidney tissue regions and for a wide range of beta and alpha emitters of interest in RPT. Chapter V of the thesis manuscript focuses on revising the heterogeneity of absorbed dose distribution in human kidney tissues and the dose–response modelling of nephrotoxicity in RPT with beta- particle emitters. Lastly, in Chapter VI the content of previous chapters is discussed further, detailed research perspectives to address some identified challenges to progress in this field are proposed, and the general conclusion of the PhD project is formulated.