Preclinical evaluation of [225Ac]Ac-PSMA-617 and in vivo effect comparison in combination with [177Lu]Lu-PSMA-617 for prostate cancer

IF 3.6 4区医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING

Nuclear medicine and biology Pub Date : 2025-06-06 DOI:10.1016/j.nucmedbio.2025.109032

E. Savio, L. Reyes, J. Giglio, L. Alfaya, G. Falasco, L. Urrutia, M. Bentura, K. Zirbesegger, F. Arredondo, P. Duarte, J.P. Gambini, R. Dapueto

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引用次数: 0

Abstract

Introduction

The interest in targeted alpha therapy (TAT) has grown in the recent years as it can provide new treatment options for advanced- and late-stage cancer. In this sense, the use of actinium-225 is rising showing promising results. Even more, combining alpha and beta (lutetium-177) radionuclides might help to minimize actinium adverse effects, while preserving treatment efficacy. Preclinical studies of actinium-225-PSMA-targeting tracers for advanced prostate cancer and the “cocktail” combination with lutetium-177-PSMA needs to be further explored.

Methods

In vitro properties of [²²⁵Ac]Ac-PSMA-617 using the human prostatic cancer cell lines, LNCaP (PSMA+) and PC3 (PSMA-) were investigated by means of antiproliferative, binding, cytotoxicity and clonogenic studies. In vivo de-escalated treatment protocols of actinium-225/lutetium-177-PSMA-617 “cocktail”-regimens were also assessed in order to improve the tolerability of ²²⁵Ac-PSMA-617 TAT. A four-branch study with ([¹⁷⁷Lu]Lu-PSMA-617 and [²²⁵Ac]Ac-PSMA-617) or its combination was successfully performed in a xenographic nude mice model bearing prostate cancer. Tumour growth was monitored by external caliper measurements and PET-CT imaging with [¹⁸F]F-AlF-PSMA-11 over two months.

Results

Specific dose-dependent inhibition proliferation of [²²⁵Ac]Ac-PSMA-617 was observed in LNCaP cells (IC₅₀ = 0.14 KBq/mL) whereas an antiproliferative effect in PC3 cells required an activity concentration two orders of magnitude higher (IC₅₀ = 15.5 KBq/mL). In autoradiography binding studies, [²²⁵Ac]Ac-PSMA-617 had significant higher affinity for LNCaP cells, compared to PC3 cells, which probed to be specific under blocking conditions. Cytotoxicity assay evidenced a 200-fold higher toxicity in LNCaP cells. The percentage of colony survival significantly decreased in LNCaP cells treated with 1 KBq/mL and 10 KBq/mL, as compared to PC3 cells treated with the same activity concentrations. The co-administration of both beta and alpha therapeutical radiopharmaceuticals to xenographic nude mice model bearing prostate cancer showed the best results in terms of survival, growth rates and absence of tumour at the endpoint of the study.

Conclusion

This study shows that PSMA radioisotope therapy (RIT) and TAT combined therapy could improve patient management by delaying disease progression.

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[225Ac]Ac-PSMA-617的临床前评价及与[177Lu]Lu-PSMA-617联合治疗前列腺癌的体内效果比较

近年来，人们对靶向α治疗（TAT）的兴趣日益浓厚，因为它可以为晚期和晚期癌症提供新的治疗选择。从这个意义上说，锕-225的使用正在增加，显示出令人鼓舞的结果。更重要的是，结合α和β（镥-177）放射性核素可能有助于减少锕的副作用，同时保持治疗效果。晚期前列腺癌的actinium-225- psma靶向示踪剂的临床前研究以及与luteinium -177- psma的“鸡尾酒”联合治疗还有待进一步探索。方法利用人前列腺癌细胞LNCaP （PSMA+）和PC3 （PSMA-）对[225Ac]Ac-PSMA-617进行体外抗增殖、结合、细胞毒性和克隆性研究。为了提高225Ac-PSMA-617 TAT的耐受性，还评估了锕-225/镥-177- psma -617“鸡尾酒”方案的体内降级治疗方案。用（[177Lu]Lu-PSMA-617和[225Ac]Ac-PSMA-617）或其组合在前列腺癌裸鼠模型中成功进行了四分支研究。肿瘤生长监测通过外卡尺测量和PET-CT成像[18F]F-AlF-PSMA-11超过两个月。结果[225Ac]Ac-PSMA-617在LNCaP细胞中具有特异性的剂量依赖性抑制增殖作用（IC50 = 0.14 KBq/mL），而在PC3细胞中则需要高2个数量级的活性浓度（IC50 = 15.5 KBq/mL）。在放射自显影结合研究中，[225Ac]Ac-PSMA-617对LNCaP细胞的亲和力明显高于PC3细胞，而PC3细胞在阻断条件下具有特异性。细胞毒性实验证明LNCaP细胞毒性高200倍。与PC3细胞相比，1 KBq/mL和10 KBq/mL处理LNCaP细胞的集落存活率显著降低。在研究结束时，对患有前列腺癌的裸鼠模型同时给予β和α治疗性放射性药物，在存活率、生长率和肿瘤消失方面显示出最好的结果。结论PSMA放射性同位素治疗（RIT）和TAT联合治疗可通过延缓疾病进展改善患者管理。

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

Nuclear medicine and biology 医学-核医学

CiteScore

6.00

自引率

9.70%

发文量

479

审稿时长

51 days

期刊介绍： Nuclear Medicine and Biology publishes original research addressing all aspects of radiopharmaceutical science: synthesis, in vitro and ex vivo studies, in vivo biodistribution by dissection or imaging, radiopharmacology, radiopharmacy, and translational clinical studies of new targeted radiotracers. The importance of the target to an unmet clinical need should be the first consideration. If the synthesis of a new radiopharmaceutical is submitted without in vitro or in vivo data, then the uniqueness of the chemistry must be emphasized. These multidisciplinary studies should validate the mechanism of localization whether the probe is based on binding to a receptor, enzyme, tumor antigen, or another well-defined target. The studies should be aimed at evaluating how the chemical and radiopharmaceutical properties affect pharmacokinetics, pharmacodynamics, or therapeutic efficacy. Ideally, the study would address the sensitivity of the probe to changes in disease or treatment, although studies validating mechanism alone are acceptable. Radiopharmacy practice, addressing the issues of preparation, automation, quality control, dispensing, and regulations applicable to qualification and administration of radiopharmaceuticals to humans, is an important aspect of the developmental process, but only if the study has a significant impact on the field. Contributions on the subject of therapeutic radiopharmaceuticals also are appropriate provided that the specificity of labeled compound localization and therapeutic effect have been addressed.