Helena Koniar, Luke Wharton, Aidan Ingham, Ana Paulina Morales Oliver, Helen Merkens, Cristina Rodríguez-Rodríguez, Peter Kunz, Valery Radchenko, Hua Yang, Arman Rahmim, Carlos Uribe, Paul Schaffer
{"title":"Preclinical Evaluation of <sup>226</sup>Ac as a Theranostic Agent: Imaging, Dosimetry, and Therapy.","authors":"Helena Koniar, Luke Wharton, Aidan Ingham, Ana Paulina Morales Oliver, Helen Merkens, Cristina Rodríguez-Rodríguez, Peter Kunz, Valery Radchenko, Hua Yang, Arman Rahmim, Carlos Uribe, Paul Schaffer","doi":"10.2967/jnumed.124.267999","DOIUrl":null,"url":null,"abstract":"<p><p><sup>226</sup>Ac (t<sub>½</sub> = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. <sup>226</sup>Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, <sup>226</sup>Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical <sup>226</sup>Ac-radiopharmaceutical for its theranostic efficacy and present the first <sup>226</sup>Ac-targeted α-therapy study. <b>Methods:</b> <sup>226</sup>Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [<sup>226</sup>Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. <b>Results:</b> We present quantitative SPECT images of the in vivo biodistribution of [<sup>226</sup>Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [<sup>226</sup>Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. <b>Conclusion:</b> This study highlights the theranostic potential of <sup>226</sup>Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched <sup>225</sup>Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of <sup>226</sup>Ac-radiopharmaceuticals.</p>","PeriodicalId":94099,"journal":{"name":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of nuclear medicine : official publication, Society of Nuclear Medicine","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.2967/jnumed.124.267999","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
Abstract
226Ac (t½ = 29.37 h) has been proposed as a theranostic radioisotope leveraging both its diagnostic γ-emissions and therapeutic α-emissions. 226Ac emits 158 and 230 keV γ-photons ideal for quantitative SPECT imaging and acts as an in vivo generator of 4 high-energy α-particles. Because of these nuclear decay properties, 226Ac has potential to act as a standalone theranostic isotope. In this proof-of-concept study, we evaluated a preclinical 226Ac-radiopharmaceutical for its theranostic efficacy and present the first 226Ac-targeted α-therapy study. Methods:226Ac was produced at TRIUMF and labeled with the chelator-peptide bioconjugate crown-TATE. [226Ac]Ac-crown-TATE was selected to target neuroendocrine tumors in male NRG mice bearing AR42J tumor xenografts for SPECT imaging, biodistribution, and therapy studies. A preclinical SPECT/CT scanner acquired quantitative images reconstructed from both the 158 and the 230 keV emissions. Mice in the biodistribution study were euthanized at 1, 3, 5, 24, and 48 h after injection, and internal radiation dosimetry was derived for the tumor and organs of interest to establish appropriate therapeutic activity levels. Mice in the therapy study were administered 125, 250, or 375 kBq treatments and were monitored for tumor size and body condition. Results: We present quantitative SPECT images of the in vivo biodistribution of [226Ac]Ac-crown-TATE, which showed agreement with ex vivo measurements. Biodistribution studies demonstrated high uptake (>30%IA/g at 5 h after injection) and retention in the tumor, with an estimated mean absorbed dose coefficient of 222 mGy/kBq. [226Ac]Ac-crown-TATE treatments significantly extended the median survival from 7 d in the control groups to 16, 24, and 27 d in the 125, 250, and 375 kBq treatment groups, respectively. Survival was prolonged by slowing tumor growth, and no weight loss or toxicities were observed. Conclusion: This study highlights the theranostic potential of 226Ac as a standalone therapeutic isotope in addition to its demonstrated diagnostic capabilities to assess dosimetry in matched 225Ac-radiopharmaceuticals. Future studies will investigate maximum dose and toxicity to further explore the therapeutic potential of 226Ac-radiopharmaceuticals.