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

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2025年9月2日

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Xinning Wang,
Olga sergeeva,
Maxim Sergeev,
Lifang Zhang,
Zoey Lockwood,
Patrick Wojtylak,
Riley Sangster,
David Reichert,
Marc Berridge,
Wolfgang Weber,
Zhenghong Lee,
James P. Basilion

摘要

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.