The last decade has seen rapid growth in the use of theranostic radionuclides for the treatment and imaging of a wide range of cancers. Radionuclide therapy and imaging rely on a radiolabeled vector to specifically target cancer cells. Radionuclides that emit β particles have thus far dominated the field of targeted radionuclide therapy (TRT), mainly because the longer range (μm–mm track length) of these particles offsets the heterogeneous expression of the molecular target. Shorter range (nm–μm track length) α- and Auger electron (AE)-emitting radionuclides on the other hand provide high ionization densities at the site of decay which could overcome much of the toxicity associated with β-emitters. Given that there is a growing body of evidence that other sensitive sites besides the DNA, such as the cell membrane and mitochondria, could be critical targets in TRT, improved techniques in detecting the subcellular distribution of these radionuclides are necessary, especially since many β-emitting radionuclides also emit AE. The successful development of TRT agents capable of homing to targets with subcellular precision demands the parallel development of quantitative assays for evaluation of spatial distribution of radionuclides in the nm–μm range. In this review, the status of research directed at subcellular targeting of radionuclide theranostics and the methods for imaging and quantification of radionuclide localization at the nanoscale are described.
Purpose. Molecular Radiotherapy (MRT) using 177 Lu-DOTATATE is a most effective therapy for the treatment of somatostatin receptor expressing neuroendocrine tumors (NETs). Despite its frequent and successful use in the clinic, little or no radiobiological considerations are taken into account at the time of treatment planning or delivery, and upon positive uptake of octreotide-based PET/SPECT imaging, treatment is usually administered as a standard dose and number of cycles without adjustment for peptide uptake, dosimetry, or radiobiological and DNA damage effects in the tumor. Here, we visualize and quantify the extent of DNA damage response following 177 Lu-DOTATATE therapy using SPECT imaging with 111 In-anti-γH2AX-TAT. This work is a proof-of-principle study of this in vivo non-invasive biodosimeter with beta-emitting therapeutic radiopharmaceuticals. Methods. Six cell lines were exposed to external beam radiotherapy (EBRT) or 177 Lu-DOTATATE, after which the number of γH2AX foci and clonogenic survival were measured. Mice bearing CA20948 somatostatin receptor positive tumor xenografts were treated with 177 Lu-DOTATATE or sham-treated, and co-injected with 111 In-anti-γH2AX-TAT, 111 In-IgG-TAT control, or vehicle. Results. Clonogenic survival following EBRT was cell line specific, indicating varying levels of intrinsic radiosensitivity. In vitro, cell lines treated with 177 Lu-DOTATATE, clonogenic survival decreased and γH2AX foci increased in cells expressing high levels of somatostatin receptor subtype 2 (SST2). Ex vivo measurements revealed a partial correlation between 177 Lu-DOTATATE uptake and γH2AX foci induction between different regions of CA20948 xenograft tumors, suggesting different parts of the tumor may react differentially to 177 Lu-DOTATATE irradiation. Conclusion. 111 In-anti-γH2AX-TAT allows monitoring of DNA damage following 177 Lu-DOTATATE therapy, and reveals heterogeneous damage responses.
<b>Introduction:</b> <sup>135</sup>La has favorable nuclear and chemical properties for Auger-based targeted internal radiotherapy. Here we present detailed investigations of the production, emissions, imaging characteristics, and dosimetry related to <sup>135</sup>La therapy. <b>Methods and Results:</b> <sup>135</sup>La was produced by 16.5 MeV proton irradiation of metallic <sup>nat</sup>Ba on a medical cyclotron, and was isolated and purified by trap-and-release on weak cation-exchange resin. The average production rate was 407 ± 19 MBq/µA (saturation activity, n = 3), and the radionuclidic purity was 98% at 20 h post irradiation. Chemical separation recovered > 98 % of the <sup>135</sup>La with an effective molar activity of 70 ±20 GBq/µmol. To better assess cellular and organ dosimetry of this nuclide, we have recalculated the X-ray and Auger emission spectra using a Monte Carlo model accounting for effects of multiple vacancies during the Auger cascade. The generated Auger spectrum was used to recalculate cellular S-factors. <b>Conclusion:</b> <sup>135</sup>La was produced with high specific activity, reactivity, radionuclidic purity, and yield. The emission spectrum and the dosimetry are favorable for internal radionuclide therapy. .
Compared to external beam radiotherapy, targeted radionuclide therapy (TRT) allows for systemic radiation treatment of metastatic lesions. Published work on recent strategies to improve patient management and response to TRT through individualising patient treatment, modifying treatment pharmacokinetics and increasing anticancer potency are discussed in this review, with a special focus on the application of clinically evaluated radiolabelled ligands and peptides in the treatment of neuroendocrine and prostate cancers.
To benchmark a Monte Carlo model of the Auger cascade that has been developed at the Australian National University (ANU) against the literature data. The model is applicable to any Auger-electron emitting radionuclide with nuclear structure data in the format of the Evaluated Nuclear Structure Data File (ENSDF). Schönfeld's algorithms and the BrIcc code were incorporated to obtain initial vacancy distributions due to electron capture (EC) and internal conversion (IC), respectively. Atomic transition probabilities were adopted from the Evaluated Atomic Data Library (EADL) for elements with atomic number, Z = 1-100. Atomic transition energies were evaluated using a relativistic Dirac-Fock method. An energy-restriction protocol was implemented to eliminate energetically forbidden transitions from the simulations. Calculated initial vacancy distributions and average energy spectra of I,I, and I were compared with the literature data. In addition, simulated kinetic energy spectra and frequency distributions of the number of emitted electrons and photons of the three iodine radionuclides are presented. Some examples of radiation spectra of individual decays are also given. Good agreement with the published data was achieved except for the outer-shell Auger and Coster-Kronig transitions. Nevertheless, the model needs to be compared with experimental data in a future study.
Excited states in 58,60,62 Ni were populated via inelastic proton scattering at the Australian National University as well as via inelastic neutron scattering at the University of Kentucky Accelerator Laboratory. The Super-e electron spectrometer and the CAESAR Compton-suppressed HPGe array were used in complementary experiments to measure conversion coefficients and δ(E2/M 1) mixing ratios, respectively, for a number of 2 + → 2 + transitions. The data obtained were combined with lifetimes and branching ratios to determine E0, M 1, and E2 transition strengths between 2 + states. The E0 transition strengths between 0 + states were measured using internal conversion electron spectroscopy and compare well to previous results from internal pair formation spectroscopy. The E0 transition strengths between the lowest-lying 2 + states were found to be consistently large for the isotopes studied.
The aim of this study was to investigate the impact of decay data provided by the newly developed stochastic atomic relaxation model BrIccEmis on dose point kernels (DPKs - radial dose distribution around a unit point source) and S-values (absorbed dose per unit cumulated activity) of 14 Auger electron (AE) emitting radionuclides, namely Ga,Br, Zr,Nb, Tc,In, Sn,Sb, I,I, I,La, Pt andTl. Radiation spectra were based on the nuclear decay data from the medical internal radiation dose (MIRD) RADTABS program and the BrIccEmis code, assuming both an isolated-atom and condensed-phase approach. DPKs were simulated with the PENELOPE Monte Carlo (MC) code using event-by-event electron and photon transport. S-values for concentric spherical cells of various sizes were derived from these DPKs using appropriate geometric reduction factors. The number of Auger and Coster-Kronig (CK) electrons and x-ray photons released per nuclear decay (yield) from MIRD-RADTABS were consistently higher than those calculated using BrIccEmis. DPKs for the electron spectra from BrIccEmis were considerably different from MIRD-RADTABS in the first few hundred nanometres from a point source where most of the Auger electrons are stopped. S-values were, however, not significantly impacted as the differences in DPKs in the sub-micrometre dimension were quickly diminished in larger dimensions. Overestimation in the total AE energy output by MIRD-RADTABS leads to higher predicted energy deposition by AE emitting radionuclides, especially in the immediate vicinity of the decaying radionuclides. This should be taken into account when MIRD-RADTABS data are used to simulate biological damage at nanoscale dimensions.
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