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

IF 2.5 4区医学 Q2 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Molecular Imaging and Biology Pub Date : 2025-09-02 DOI:10.1007/s11307-025-02046-9

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

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引用次数: 0

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.

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PSMA-1-DOTA可能是前列腺癌有效的靶向放射治疗。

目的：虽然psma靶向放射配体治疗（RLT）治疗终末期前列腺癌的疗效显著，但α-释放的RLT往往导致严重的唾液腺毒性，限制了其使用。人们尝试了各种策略来减轻这种副作用，但收效甚微。因此，本研究引入了一种新的psma靶向配体，其结合特性比现有配体更有利。方法：比较PSMA-1- dota与PSMA-11和PSMA I&T的结合亲和力。在同一周内用微pet /CT比较[68 Ga]Ga- psma -1- dota、[68 Ga]Ga- psma -11和[68 Ga]Ga- psma I&T对异种移植小鼠模型唾液腺、肾脏和PC3pip肿瘤细胞的摄取情况。同样的小鼠模型分别用[177Lu]Lu-PSMA-1-DOTA或[177Lu]Lu-PSMA-617处理。采用[68 Ga]Ga- psma -1- dota技术对1例转移性去势抵抗性前列腺癌患者进行了慈悲应用PET成像研究。结果：发现PSMA-1- dota与PSMA的结合亲和力约为其他PSMA靶向配体的4倍。微pet /CT成像显示，与其他psma放射配体相比，[68 Ga]Ga- psma -1- dota的肾脏、摄食量明显降低，唾液和泪腺摄食量也很少。临床前疗效研究表明，[177Lu]Lu-PSMA-1-DOTA对肿瘤生长的抑制作用与[177Lu]Lu-PSMA-617相当，表明其可能通过避免对唾液腺的损伤来增加靶向RLT的治疗窗口期。体位PET成像证实患者唾液腺对[68 Ga]Ga- psma -1- dota的摄取减少，表明其作为psma阳性前列腺癌患者α-或β-放射核素RLT的靶向药物的潜在用途。结论：PSMA-1-DOTA显示唾液腺摄取减少，同时有效靶向psma表达肿瘤，从而潜在地避免口干症的副作用，并可能使psma靶向RLT成为前列腺癌的一线治疗方法，而不是目前作为最后手段使用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Imaging and Biology 医学-核医学

CiteScore

6.90

自引率

3.20%

发文量

审稿时长

3 months

期刊介绍： Molecular Imaging and Biology (MIB) invites original contributions (research articles, review articles, commentaries, etc.) on the utilization of molecular imaging (i.e., nuclear imaging, optical imaging, autoradiography and pathology, MRI, MPI, ultrasound imaging, radiomics/genomics etc.) to investigate questions related to biology and health. The objective of MIB is to provide a forum to the discovery of molecular mechanisms of disease through the use of imaging techniques. We aim to investigate the biological nature of disease in patients and establish new molecular imaging diagnostic and therapy procedures. Some areas that are covered are: Preclinical and clinical imaging of macromolecular targets (e.g., genes, receptors, enzymes) involved in significant biological processes. The design, characterization, and study of new molecular imaging probes and contrast agents for the functional interrogation of macromolecular targets. Development and evaluation of imaging systems including instrumentation, image reconstruction algorithms, image analysis, and display. Development of molecular assay approaches leading to quantification of the biological information obtained in molecular imaging. Study of in vivo animal models of disease for the development of new molecular diagnostics and therapeutics. Extension of in vitro and in vivo discoveries using disease models, into well designed clinical research investigations. Clinical molecular imaging involving clinical investigations, clinical trials and medical management or cost-effectiveness studies.