Document Type
Article
Publication Date
9-2-2025
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 [⁶⁸Ga]Ga-PSMA-1-DOTA, [⁶⁸Ga]Ga-PSMA-11 and [⁶⁸Ga]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 [⁶⁸Ga]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 [⁶⁸Ga]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 [⁶⁸Ga]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, prostate cancer, PSMA, targeted radioligand therapy
Language
English
Publication Title
Molecular Imaging and Biology
Grant
5R01CA260847-02
Rights
© The Author(s) 2025. This is an Open Access work distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Wang, X., sergeeva, O., Sergeev, M. et al. PSMA-1-DOTA Potentially for Effective Targeted Radioligand Therapy of Prostate Cancer. Mol Imaging Biol 27, 785–796 (2025). https://doi.org/10.1007/s11307-025-02046-9
Manuscript Version
Final Publisher Version