Theranostic Cu-DOTHA-PSMA Allows Low Toxicity Radioligand Therapy in Mice Prostate Cancer Model

Overview

Journal Front Oncol

Specialty Oncology

Date 2023 Feb 6

PMID 36741017

Authors

Marie-Christine Milot

Ophelie Belissant-Benesty

Veronique Dumulon-Perreault

Samia Ait-Mohand

Sameh Geha

Patrick O Richard

Etienne Rousseau

Brigitte Guerin

Affiliations

Soon will be listed here.

Abstract

Introduction: We have previously shown that copper-64 (Cu)-DOTHA-PSMA can be used for positron emission tomography (PET) imaging of prostate cancer. Owing to the long-lasting, high tumoral uptake of Cu-DOTHA-PSMA, the objective of the current study was to evaluate the therapeutic potential of Cu-DOTHA-PSMA .

Methods: LNCaP tumor-bearing NOD- (NRG) mice were treated with an intraveinous single-dose of Cu-DOTHA-PSMA at maximal tolerated injected activity, Cu-DOTHA-PSMA at equimolar amount (control) or lutetium-177 (Lu)-PSMA-617 at 120 MBq to assess their impact on survival. Weight, well-being and tumor size were followed until mice reached 62 days post-injection or ethical limits. Toxicity was assessed through weight, red blood cells (RBCs) counts, pathology and dosimetry calculations.

Results: Survival was longer with Cu-DOTHA-PSMA than with Cu-DOTHA-PSMA ( < 0.001). Likewise, survival was also longer when compared to Lu-PSMA-617, although it did not reach statistical significance ( = 0.09). RBCs counts remained within normal range for the Cu-DOTHA-PSMA group. Cu-DOTHA-PSMA treated mice showed non-pathological fibrosis and no other signs of radiation injury. Human extrapolation of dosimetry yielded an effective dose of 3.14 × 10 mSv/MBq, with highest organs doses to gastrointestinal tract and liver.

Discussion: Collectively, our data showed that Cu-DOTHA-PSMA-directed radioligand therapy was effective for the treatment of LNCaP tumor-bearing NRG mice with acceptable toxicity and dosimetry. The main potential challenge is the hepatic and gastrointestinal irradiation.

Citing Articles

Zirconium 89 and Copper 64 for ImmunoPET: From Antibody Bioconjugation and Radiolabeling to Molecular Imaging.

Badier L, Quelven I Pharmaceutics. 2024; 16(7).

PMID: 39065579 PMC: 11279968. DOI: 10.3390/pharmaceutics16070882.

Preclinical Evaluation of a Cu-Based Theranostic Approach in a Murine Model of Multiple Myeloma.

Metivier C, Saec P, Gaschet J, Chauvet C, Marionneau-Lambot S, Hofgaard P Pharmaceutics. 2023; 15(7).

PMID: 37514004 PMC: 10385603. DOI: 10.3390/pharmaceutics15071817.

References

Warnier M, Roudbaraki M, Derouiche S, Delcourt P, Bokhobza A, Prevarskaya N . CACNA2D2 promotes tumorigenesis by stimulating cell proliferation and angiogenesis. Oncogene. 2015; 34(42):5383-94. DOI: 10.1038/onc.2014.467. View

Sampath S, Schultheiss T, Wong J . Dose response and factors related to interstitial pneumonitis after bone marrow transplant. Int J Radiat Oncol Biol Phys. 2005; 63(3):876-84. DOI: 10.1016/j.ijrobp.2005.02.032. View

Tomayko M, Reynolds C . Determination of subcutaneous tumor size in athymic (nude) mice. Cancer Chemother Pharmacol. 1989; 24(3):148-54. DOI: 10.1007/BF00300234. View

Pearson T, Shultz L, Miller D, King M, Laning J, Fodor W . Non-obese diabetic-recombination activating gene-1 (NOD-Rag1 null) interleukin (IL)-2 receptor common gamma chain (IL2r gamma null) null mice: a radioresistant model for human lymphohaematopoietic engraftment. Clin Exp Immunol. 2008; 154(2):270-84. PMC: 2612717. DOI: 10.1111/j.1365-2249.2008.03753.x. View

Afshar-Oromieh A, Hetzheim H, Kratochwil C, Benesova M, Eder M, Neels O . The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions. J Nucl Med. 2015; 56(11):1697-705. DOI: 10.2967/jnumed.115.161299. View

Milot M, Benesty O, Dumulon-Perreault V, Ait-Mohand S, Richard P, Rousseau E . Cu-DOTHA-PSMA, a Novel PSMA PET Radiotracer for Prostate Cancer with a Long Imaging Time Window. Pharmaceuticals (Basel). 2022; 15(8). PMC: 9412875. DOI: 10.3390/ph15080996. View

Fendler W, Stuparu A, Evans-Axelsson S, Luckerath K, Wei L, Kim W . Establishing Lu-PSMA-617 Radioligand Therapy in a Syngeneic Model of Murine Prostate Cancer. J Nucl Med. 2017; 58(11):1786-1792. PMC: 6944167. DOI: 10.2967/jnumed.117.193359. View

Kuo H, Merkens H, Zhang Z, Uribe C, Lau J, Zhang C . Enhancing Treatment Efficacy of Lu-PSMA-617 with the Conjugation of an Albumin-Binding Motif: Preclinical Dosimetry and Endoradiotherapy Studies. Mol Pharm. 2018; 15(11):5183-5191. DOI: 10.1021/acs.molpharmaceut.8b00720. View

Engle J . The Production of Ac-225. Curr Radiopharm. 2018; 11(3):173-179. DOI: 10.2174/1874471011666180418141357. View

10.

Seitzer K, Seifert R, Kessel K, Roll W, Schlack K, Boegemann M . Lutetium-177 Labelled PSMA Targeted Therapy in Advanced Prostate Cancer: Current Status and Future Perspectives. Cancers (Basel). 2021; 13(15). PMC: 8371469. DOI: 10.3390/cancers13153715. View

11.

Yoshii Y, Yoshimoto M, Matsumoto H, Tashima H, Iwao Y, Takuwa H . Integrated treatment using intraperitoneal radioimmunotherapy and positron emission tomography-guided surgery with Cu-labeled cetuximab to treat early- and late-phase peritoneal dissemination in human gastrointestinal cancer xenografts. Oncotarget. 2018; 9(48):28935-28950. PMC: 6034757. DOI: 10.18632/oncotarget.25649. View

12.

Jin Z, Furukawa T, Degardin M, Sugyo A, Tsuji A, Yamasaki T . αVβ3 Integrin-Targeted Radionuclide Therapy with 64Cu-cyclam-RAFT-c(-RGDfK-)4. Mol Cancer Ther. 2016; 15(9):2076-85. DOI: 10.1158/1535-7163.MCT-16-0040. View

13.

Lewis J, Lewis M, Cutler P, Srinivasan A, Schmidt M, Schwarz S . Radiotherapy and dosimetry of 64Cu-TETA-Tyr3-octreotate in a somatostatin receptor-positive, tumor-bearing rat model. Clin Cancer Res. 1999; 5(11):3608-16. View

14.

Banerjee S, Kumar V, Lisok A, Chen J, Minn I, Brummet M . Lu-labeled low-molecular-weight agents for PSMA-targeted radiopharmaceutical therapy. Eur J Nucl Med Mol Imaging. 2019; 46(12):2545-2557. PMC: 8068522. DOI: 10.1007/s00259-019-04434-0. View

15.

Bouchelouche K, Choyke P, Capala J . Prostate specific membrane antigen- a target for imaging and therapy with radionuclides. Discov Med. 2010; 9(44):55-61. PMC: 3410553. View

16.

Duan H, Iagaru A, Mari Aparici C . Radiotheranostics - Precision Medicine in Nuclear Medicine and Molecular Imaging. Nanotheranostics. 2022; 6(1):103-117. PMC: 8671964. DOI: 10.7150/ntno.64141. View

17.

Juzeniene A, Stenberg V, Bruland O, Larsen R . Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer. Cancers (Basel). 2021; 13(4). PMC: 7918517. DOI: 10.3390/cancers13040779. View

18.

Ahmedova A, Todorov B, Burdzhiev N, Goze C . Copper radiopharmaceuticals for theranostic applications. Eur J Med Chem. 2018; 157:1406-1425. DOI: 10.1016/j.ejmech.2018.08.051. View

19.

Benesova M, Bauder-Wust U, Schafer M, Klika K, Mier W, Haberkorn U . Linker Modification Strategies To Control the Prostate-Specific Membrane Antigen (PSMA)-Targeting and Pharmacokinetic Properties of DOTA-Conjugated PSMA Inhibitors. J Med Chem. 2016; 59(5):1761-75. DOI: 10.1021/acs.jmedchem.5b01210. View

20.

Jadon R, Higgins E, Hanna L, Evans M, Coles B, Staffurth J . A systematic review of dose-volume predictors and constraints for late bowel toxicity following pelvic radiotherapy. Radiat Oncol. 2019; 14(1):57. PMC: 6448293. DOI: 10.1186/s13014-019-1262-8. View