Abstract
Auger electron emitters are considered to be a promising strategy for targeted radionuclide therapy of metastatic diseases, given their high linear energy transfer (LET) and short range in tissue which could potentially limit normal tissue toxicity. Particularly, Auger electron emitters that can be targeted into the DNA of tumor cells have been considered as an attractive cancer therapy in the past decade. In this study, the efficiency of induction of chromosomal damage by Auger electron emitter 123I (half-life 13.2 hours) was investigated by using the cytokinesis-block micronucleus assay. A stannylated deoxyuridine was synthesized and radiolabeled with 123I, resulting in 123IUdR that carried the Auger electron emitter across the nuclear membrane and allowed its incorporation into newly synthesized DNA. The DNA damage caused by the 123I Auger cascade was estimated by evaluating the induced micronuclei frequencies in human peripheral blood lymphocytes obtained from three different donors. The isolated lymphocytes were stimulated with phytohaemagglutinin (1 mg/mL) for 48 hours before pulse labelling with 123IUdR and the S-phase fraction was determined using flow cytometry. Geant4 Monte Carlo calculations were performed to determine the absorbed dose in cells by the Auger emitter. The relative biological effectiveness (RBE) was calculated by comparing the dose response curves for 123IUdR with the reference dose response curves, obtained by 60Co γ-ray irradiation, for lymphocytes of the same donors. This resulted in a range of individual RBE values from 3 up to 10, depending on the donor and the radiation dose. In addition, dose limiting RBE values (RBEMax) were calculated for each donor and ranged from 5 to 11, dependent on the inherent radiosensitivity of the donors. This study provides valuable information on the RBE of Auger electron emitter 123I, which is identified as a promising theranostic radionuclide for future targeted radionuclide therapy.
Highlights
The Auger effect refers to the emission of a cascade of low energy electrons, including Auger, Coster-Kronig (CK), and super-CK electrons as a result of radioactive decay by electron capture or internal conversion
The reaction progress was monitored by thin layer chromatography (TLC) and once the reaction was completed, the reaction mixture was subjected to column chromatography using ethyl acetate and hexane as mobile phase to isolate 1 as a yellow oil in 67% yield
The isotope 123I is an ideal candidate for targeted radionuclide therapy, due to its Auger decay and the opportunity to simultaneously image the tumor with SPECT imaging based on its characteristic 159 keV γ-ray, which provides the option to calculate dosimetry and treatment efficacy
Summary
The Auger effect refers to the emission of a cascade of low energy electrons, including Auger, Coster-Kronig (CK), and super-CK electrons (collectively called Auger electrons) as a result of radioactive decay by electron capture or internal conversion. Many radionuclides that are commonly used in nuclear medicine follow this decay process, including 123I, 125I, 67Ga, 99mTc, 111In, 201Tl and others as described in Ref. 6 It took many years since the discovery of Auger electrons before radiobiologists observed the extreme cytotoxic effect of Auger electron emitters, when they are incorporated into the nucleus of cells [7, 8]. Recent clinical studies have given encouraging results for targeted alpha-particle therapy (TAT) in the treatment of metastatic, castration-resistant prostate cancer and the number of promising radiopharmaceuticals for clinical TAT is growing rapidly [15, 16] While it has been a long-standing research goal, the majority of the Auger electron emitter therapy studies still remain preclinical [10]. The path length of Auger electrons is much shorter compared to α-particles, typically
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