Tools for the Advancement of Radiopharmaceutical Therapy

Abstract

Radiopharmaceutical therapy is used to treat cancers and other diseases with radiolabeled pharmaceuticals. The treatment targets specific cells, and the emitted ionizing radiation cause cytotoxic damage. Dosimetry is performed to estimate the absorbed dose from the energy deposited in the body. This requires measurement of the activity in vivo and knowledge of the retention time of the activity in tumor and organs. Preclinical trials precede clinical studies and evaluate the potential of new radiopharmaceuticals for treatment. Similarly, in vitro and in vivo experiments with radiopharmaceuticals and sources of ionizing radiation are performed to increase radiobiological knowledge, which is helpful in the optimization of radiopharmaceutical therapy. Dosimetry is also necessary for these studies to correctly quantify the biological response to ionizing radiation.
However, standard dosimetry only considers macroscopic volumes such as organs or solid tumors. Due to the short range of the emitted radiation, heterogeneous activity uptake can generate heterogeneous energy depositions. In a tumor, this means a large variation in particle tracks hitting the cell nuclei, where cells in
undertreated areas will not receive any particle tracks through the cell nucleus. Since damage to DNA in the cell nucleus is the main cause of radiation-induced cell death, this can reduce the treatment effect. Early insight into these limitations of a new radiopharmaceutical can be achieved in preclinical studies investigating
the intra-tumoral distribution of the radiopharmaceutical uptake. Paper 4 investigated the tumor control probability from the intra-tumoral distribution of 177Lu-PSMA-617 in LNCaP xenografts. Monte Carlo simulations can be used for small-scale and microscopic dosimetry, where small targets such as cells and cell
nuclei are considered. Similarly, in paper 3, simulations of an alpha particle source and cell nuclei irradiated were used to estimate the distribution of induced γ-H2AX foci in PC3 cells irradiated with an 241Am source in vitro.
In preclinical studies of therapeutic radiopharmaceuticals, xenografted animal models are followed postinjection over long periods to evaluate the treatment response. This is usually done by measuring changes in tumor size over time. In addition, molecular imaging with positron emission tomography (PET) offers an
opportunity to measure biochemical changes in vivo, such as the radiation damage response. However, as investigated in paper 1, gamma emission from the therapeutic radiopharmaceutical in the animal model can cause perturbations to the image by increasing dead-time losses and causing signal pile-up. However, as
suggested in paper 2, preclinical intra-therapeutic PET imaging can still be performed during 177Lu-labeled radiopharmaceutical therapy, with shielding attenuating the excess photons while still allowing coincidence detection of annihilation photons.

Abstract (Swedish)

Radiopharmaceutical therapy is used to treat cancers and other diseases with radiolabeled
pharmaceuticals. The treatment targets specific cells, and the emitted ionizing radiation cause cytotoxic
damage. Dosimetry is performed to estimate the absorbed dose from the energy deposited in the body.
This requires measurement of the activity in vivo and knowledge of the retention time of the activity in tumor
and organs. Preclinical trials precede clinical studies and evaluate the potential of new radiopharmaceuticals
for treatment. Similarly, in vitro and in vivo experiments with radiopharmaceuticals and sources of ionizing
radiation are performed to increase radiobiological knowledge, which is helpful in the optimization of
radiopharmaceutical therapy. Dosimetry is also necessary for these studies to correctly quantify the biological
response to ionizing radiation.
However, standard dosimetry only considers macroscopic volumes such as organs or solid tumors. Due to
the short range of the emitted radiation, heterogeneous activity uptake can generate heterogeneous energy
depositions. In a tumor, this means a large variation in particle tracks hitting the cell nuclei, where cells in
undertreated areas will not receive any particle tracks through the cell nucleus. Since damage to DNA in the
cell nucleus is the main cause of radiation-induced cell death, this can reduce the treatment effect. Early
insight into these limitations of a new radiopharmaceutical can be achieved in preclinical studies investigating
the intra-tumoral distribution of the radiopharmaceutical uptake. Paper 4 investigated the tumor control
probability from the intra-tumoral distribution of 177Lu-PSMA-617 in LNCaP xenografts. Monte Carlo
simulations can be used for small-scale and microscopic dosimetry, where small targets such as cells and cell
nuclei are considered. Similarly, in paper 3, simulations of an alpha particle source and cell nuclei irradiated
were used to estimate the distribution of induced γ-H2AX foci in PC3 cells irradiated with an 241Am source
in vitro.
In preclinical studies of therapeutic radiopharmaceuticals, xenografted animal models are followed postinjection over long periods to evaluate the treatment response. This is usually done by measuring changes in
tumor size over time. In addition, molecular imaging with positron emission tomography (PET) offers an
opportunity to measure biochemical changes in vivo, such as the radiation damage response. However, as
investigated in paper 1, gamma emission from the therapeutic radiopharmaceutical in the animal model can
cause perturbations to the image by increasing dead-time losses and causing signal pile-up. However, as
suggested in paper 2, preclinical intra-therapeutic PET imaging can still be performed during 177Lu-labeled
radiopharmaceutical therapy, with shielding attenuating the excess photons while still allowing coincidence
detection of annihilation photons.

• author: Mellhammar, Emma
• supervisor: Sven-Erik Strand; Oskar Vilhelmsson Timmermand; Magnus Dahlbom; Lars Ekblad
• opponent: Professor Bernhardt, Peter, Department of Medical Physics, University of Gothenburg
• organization: Systemic Radiation Therapy Group (research group); LUCC: Lund University Cancer Centre; Systemic radiation therapy
• publishing date: 2023
• type: Thesis
• publication status: published
• subject: Radiology, Nuclear Medicine and Medical Imaging; Cancer and Oncology
• keywords: Radiopharmaceutical therapy, Nuclear medicine, Monte Carlo simulation, Intratherapeutic preclinical PET, Alpha particles, Beta Particles, radionuclides, Radiobiology, γ-H2AX, Dosimetry
• in: Lund University, Faculty of Medicine Doctoral Dissertation Series
• issue: 2023:46
• pages: 95 pages
• defense location: Föreläsningssal Torsten Landberg, 3:e våningen, Onkologikliniken, Klinikgatan 5, Universitetssjukhuset i Lund
• defense date: 2023-04-21 09:00:00
• ISSN: 1652-8220
• ISBN: 978-91-8021-386-8
• language: English
• LU publication?: yes
• id: 12917287-9b50-4e9e-8ab1-b3edeeb77646
• date added to LUP: 2023-03-16 10:01:06
• date last changed: 2023-04-03 15:00:47