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European Journal of Nuclear Medicine and Molecular Imaging
Published in: European Journal of Nuclear Medicine and Molecular Imaging 3/2023

Open Access 08-11-2022 | Prostate Cancer | Original Article

Targeted α-therapy using astatine (211At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound

Authors: Tadashi Watabe, Kazuko Kaneda-Nakashima, Yoshifumi Shirakami, Yuichiro Kadonaga, Kazuhiro Ooe, Yang Wang, Hiromitsu Haba, Atsushi Toyoshima, Jens Cardinale, Frederik L. Giesel, Noriyuki Tomiyama, Koichi Fukase

Published in: European Journal of Nuclear Medicine and Molecular Imaging | Issue 3/2023

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Abstract

Purpose

Targeted α-therapy (TAT) for prostate-specific membrane antigen (PSMA) is a promising treatment for metastatic castration-resistant prostate cancer (CRPC). Astatine is an α-emitter (half-life=7.2 h) that can be produced by a 30-MeV cyclotron. This study evaluated the treatment effect of 211At-labeled PSMA compounds in mouse xenograft models.

Methods

Tumor xenograft models were established by subcutaneous transplantation of human prostate cancer cells (LNCaP) in NOD/SCID mouse. [211At]PSMA1, [211At]PSMA5, or [211At]PSMA6 was administered to LNCaP xenograft mice to evaluate biodistribution at 3 and 24 h. The treatment effect was evaluated by administering [211At]PSMA1 (0.40 ± 0.07 MBq), [211At]PSMA5 (0.39 ± 0.03 MBq), or saline. Histopathological evaluation was performed for the at-risk organs at 3 and 6 weeks after administration.

Results

[211At]PSMA5 resulted in higher tumor retention compared to [211At]PSMA1 and [211At]PSMA6 (30.6 ± 17.8, 12.4 ± 4.8, and 19.1 ± 4.5 %ID/g at 3 h versus 40.7 ± 2.6, 8.7 ± 3.5, and 18.1 ± 2.2%ID/g at 24 h, respectively), whereas kidney excretion was superior in [211At]PSMA1 compared to [211At]PSMA5 and [211At]PSMA6. An excellent treatment effect on tumor growth was observed after [211At]PSMA5 administration. [211At]PSMA1 also showed a substantial treatment effect; however, the tumor size was relatively larger compared to that with [211At]PSMA5. In the histopathological evaluation, regenerated tubules were detected in the kidneys at 3 and 6 weeks after the administration of [211At]PSMA5.

Conclusion

TAT using [211At]PSMA5 resulted in excellent tumor growth suppression with minimal side effects in the normal organs. [211At]PSMA5 should be considered a new possible TAT for metastatic CRPC, and translational prospective trials are warranted.
Appendix
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Literature
1.
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.CrossRef
2.
Barocas DA, Alvarez J, Resnick MJ, Koyama T, Hoffman KE, Tyson MD, et al. Association between radiation therapy, surgery, or observation for localized prostate cancer and patient-reported outcomes after 3 years. JAMA. 2017;317(11):1126–40.CrossRef
3.
Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. 2015;4(3):365–80.
4.
Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65(11):1180–92.CrossRef
5.
Mori K, Mostafaei H, Pradere B, Motlagh RS, Quhal F, Laukhtina E, et al. Apalutamide, enzalutamide, and darolutamide for non-metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis. Int J Clin Oncol. 2020;25(11):1892–900.CrossRef
6.
Angelergues A, Efstathiou E, Gyftaki R, Wysocki PJ, Lainez N, Gonzalez I, et al. Results of the FLAC European database of metastatic castration-resistant prostate cancer patients treated wth docetaxel, cabazitaxel, and androgen receptor-targeted agents. Clin Genitourin Cancer. 2018;16(4):e777–e84.CrossRef
7.
Giesel FL, Knorr K, Spohn F, Will L, Maurer T, Flechsig P, et al. Detection efficacy of (18)F-PSMA-1007 PET/CT in 251 patients with biochemical recurrence of prostate cancer after radical prostatectomy. J Nucl Med. 2019;60(3):362–8.CrossRef
8.
Sprute K, Kramer V, Koerber SA, Meneses M, Fernandez R, Soza-Ried C, et al. Diagnostic accuracy of (18)F-PSMA-1007 PET/CT imaging for lymph node staging of prostate carcinoma in primary and biochemical recurrence. J Nucl Med. 2021;62(2):208–13.CrossRef
9.
Watabe T, Uemura M, Soeda F, Naka S, Ujike T, Hatano K, et al. High detection rate in [(18)F]PSMA-1007 PET: interim results focusing on biochemical recurrence in prostate cancer patients. Ann Nucl Med. 2021;35(4):523–8.CrossRef
10.
FDA approves Pluvicto/Locametz for metastatic castration-resistant prostate cancer. J Nucl Med. 2022;63:13N.
11.
Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091–103.CrossRef
12.
Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for PSMA-targeted alpha-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57(12):1941–4.CrossRef
13.
Feuerecker B, Tauber R, Knorr K, Heck M, Beheshti A, Seidl C, et al. Activity and adverse events of Actinium-225-PSMA-617 in advanced metastatic castration-resistant prostate cancer after failure of Lutetium-177-PSMA. Eur Urol. 2021;79(3):343–50.CrossRef
14.
Nagatsu K, Suzuki H, Fukada M, Ito T, Ichinose J, Honda Y, et al. Cyclotron production of (225)Ac from an electroplated (226)Ra target. Eur J Nucl Med Mol Imaging. 2021;49(1):279–89.CrossRef
15.
Zalutsky MR, Pruszynski M. Astatine-211: production and availability. Curr Radiopharm. 2011;4(3):177–85.CrossRef
16.
Watabe T, Kaneda-Nakashima K, Liu Y, Shirakami Y, Ooe K, Toyoshima A, et al. Enhancement of (211)At uptake via the sodium iodide symporter by the addition of ascorbic acid in targeted α-therapy of thyroid cancer. J Nucl Med. 2019;60(9):1301–7.CrossRef
17.
Watabe T, Kaneda-Nakashima K, Shirakami Y, Liu Y, Ooe K, Teramoto T, et al. Targeted alpha therapy using astatine ((211)At)-labeled phenylalanine: a preclinical study in glioma bearing mice. Oncotarget. 2020;11(15):1388–98.CrossRef
18.
Kaneda-Nakashima K, Zhang Z, Manabe Y, Shimoyama A, Kabayama K, Watabe T, et al. α-emitting cancer therapy using (211) At-AAMT targeting LAT1. Cancer Sci. 2021;112(3):1132–40.CrossRef
19.
Watabe T, Hosono M, Kinuya S, Yamada T, Yanagida S, Namba M, et al. Manual on the proper use of sodium astatide ([(211)At]NaAt) injections in clinical trials for targeted alpha therapy (1st edition). Ann Nucl Med. 2021;35(7):753–66.CrossRef
20.
Shirakami Y, Watabe T, Obata H, Kaneda K, Ooe K, Liu Y, et al. Synthesis of [(211)At]4-astato-L-phenylalanine by dihydroxyboryl-astatine substitution reaction in aqueous solution. Sci Rep. 2021;11(1):12982.CrossRef
21.
Cardinale J, Schafer M, Benesova M, Bauder-Wust U, Leotta K, Eder M, et al. Preclinical evaluation of (18)F-PSMA-1007, a new prostate-specific membrane antigen ligand for prostate cancer imaging. J Nucl Med. 2017;58(3):425–31.CrossRef
22.
Soeda F, Watabe T, Naka S, Liu Y, Horitsugi G, Neels OC, et al. Impact of (18)F-PSMA-1007 uptake in prostate cancer using different peptide concentrations: preclinical PET/CT study on mice. J Nucl Med. 2019;60(11):1594–9.CrossRef
23.
Watabe T, Kaneda-Nakashima K, Ooe K, Liu Y, Kurimoto K, Murai T, et al. Extended single-dose toxicity study of [(211)At]NaAt in mice for the first-in-human clinical trial of targeted alpha therapy for differentiated thyroid cancer. Ann Nucl Med. 2021;35(6):702–18.CrossRef
24.
Al-Ahmadie HA, Olgac S, Gregor PD, Tickoo SK, Fine SW, Kondagunta GV, et al. Expression of prostate-specific membrane antigen in renal cortical tumors. Mod Pathol. 2008;21(6):727–32.CrossRef
25.
Ikeda H, Hayashi Y, Takahashi N, Watabe T, Kanai Y, Shinohara A, et al. Application of astatine-210: evaluation of astatine distribution and effect of pre-injected iodide in whole body of normal rats. Appl Radiat Isot. 2018;139:251–5.CrossRef
26.
27.
Jaggi JS, Seshan SV, McDevitt MR, LaPerle K, Sgouros G, Scheinberg DA. Renal tubulointerstitial changes after internal irradiation with alpha-particle-emitting actinium daughters. J Am Soc Nephrol. 2005;16(9):2677–89.CrossRef
28.
Kiess AP, Minn I, Vaidyanathan G, Hobbs RF, Josefsson A, Shen C, et al. (2S)-2-(3-(1-carboxy-5-(4-211At-astatobenzamido)pentyl)ureido)-pentanedioic acid for PSMA-targeted α-particle radiopharmaceutical therapy. J Nucl Med. 2016;57(10):1569–75.CrossRef
29.
Kratochwil C, Apostolidis L, Rathke H, Apostolidis C, Bicu F, Bruchertseifer F, et al. Dosing (225)Ac-DOTATOC in patients with somatostatin-receptor-positive solid tumors: 5-year follow-up of hematological and renal toxicity. Eur J Nucl Med Mol Imaging. 2021;49(1):54–63.CrossRef
30.
Giesel FL, Hadaschik B, Cardinale J, Radtke J, Vinsensia M, Lehnert W, et al. F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients. Eur J Nucl Med Mol Imaging. 2017;44(4):678–88.CrossRef
Metadata
Title
Targeted α-therapy using astatine (211At)-labeled PSMA1, 5, and 6: a preclinical evaluation as a novel compound
Authors
Tadashi Watabe
Kazuko Kaneda-Nakashima
Yoshifumi Shirakami
Yuichiro Kadonaga
Kazuhiro Ooe
Yang Wang
Hiromitsu Haba
Atsushi Toyoshima
Jens Cardinale
Frederik L. Giesel
Noriyuki Tomiyama
Koichi Fukase
Publication date
08-11-2022
Publisher
Springer Berlin Heidelberg
Published in
European Journal of Nuclear Medicine and Molecular Imaging / Issue 3/2023
Print ISSN: 1619-7070
Electronic ISSN: 1619-7089
DOI
https://doi.org/10.1007/s00259-022-06016-z

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