2. Academic Validation
  3. PSMA-1-DOTA Potentially for Effective Targeted Radioligand Therapy of Prostate Cancer

PSMA-1-DOTA Potentially for Effective Targeted Radioligand Therapy of Prostate Cancer

  • Mol Imaging Biol. 2025 Sep 2. doi: 10.1007/s11307-025-02046-9.
Xinning Wang 1,  Olga Sergeeva 2,  Maxim Sergeev 3,  Lifang Zhang 1,  Zoey Lockwood 3,  Patrick Wojtylak 4,  Riley Sangster 5,  David Reichert 5,  Marc Berridge 5,  Wolfgang Weber 6,  Zhenghong Lee 7 8 9,  James P Basilion 10 11
Affiliations

Affiliations

  • 1 Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA.
  • 2 Radiology, Case Western Reserve University, Cleveland, OH, USA.
  • 3 Chemistry, Case Western Reserve University, Cleveland, OH, USA.
  • 4 Nuclear Medicine, Radiology, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.
  • 5 3D Imaging, LCC, Little Rock, AR, USA.
  • 6 Klinikum Rechts Der Isar, Nuklearmedizin, Technische Universität München (TUM), München, Germany.
  • 7 Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA. zxl11@case.edu.
  • 8 Radiology, Case Western Reserve University, Cleveland, OH, USA. zxl11@case.edu.
  • 9 Chemistry, Case Western Reserve University, Cleveland, OH, USA. zxl11@case.edu.
  • 10 Biomedical Engineering, Case Western Reserve University, Cleveland, OH, USA. jxb206@case.edu.
  • 11 Radiology, Case Western Reserve University, Cleveland, OH, USA. jxb206@case.edu.
PMID: 40897948 DOI: 10.1007/s11307-025-02046-9
Abstract

Purpose: While PSMA-targeted radioligand therapy (RLT) has shown remarkable efficacy for treating end-stage prostate Cancer, the α-emitting RLT often results in severe salivary gland toxicity, limiting its use. Various strategies to mitigate this side effect have been attempted with limited success. Accordingly, this study introduced a new PSMA-targeting ligand with more favorable binding characteristics than the existing ligands.

Procedures: The binding affinity of PSMA-1-DOTA to PSMA was compared with that of PSMA-11 and PSMA I&T. Comparison of uptake in the salivary glands, kidneys and PC3pip tumor cells in the xenograft mouse models between [68 Ga]Ga-PSMA-1-DOTA, [68 Ga]Ga-PSMA-11 and [68 Ga]Ga-PSMA I&T was conducted with microPET/CT within the same week. The same mouse models were treated with [177Lu]Lu-PSMA-1-DOTA or [177Lu]Lu-PSMA-617. A compassionate use PET imaging study on a patient with metastatic castration-resistant prostate Cancer was performed using [68 Ga]Ga-PSMA-1-DOTA.

Results: The binding affinity of PSMA-1-DOTA to PSMA was found to be approximately four times greater than Other PSMA-targeted ligands. Imaging with microPET/CT revealed significantly lower kidney, uptake and little salivary and lacrimal gland uptake with [68 Ga]Ga-PSMA-1-DOTA compared to Other PSMA-radioligands. Preclinical efficacy studies demonstrated that [177Lu]Lu-PSMA-1-DOTA inhibited tumor growth comparable to that with [177Lu]Lu-PSMA-617, suggesting its potential to enhance the therapeutic window of targeted RLT by avoiding damage to the salivary glands. The compassionate use PET imaging confirmed the reduced salivary gland uptake of [68 Ga]Ga-PSMA-1-DOTA in the patient, indicating its potential utility as a targeting agent for RLT with α- or β-emitting radionuclides in patients with PSMA-positive prostate Cancer.

Conclusion: PSMA-1-DOTA shows reduced uptake in salivary glands while effectively targeting PSMA-expressing tumors, thus potentially avoiding the side effects of xerostomia, and possibly moving PSMA-targeted RLT to a more frontline therapy for prostate Cancer rather than the current use as a last resort.

Keywords

Dry mouth; PSMA; Prostate cancer; Targeted radioligand therapy.

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