碘伪载体提高[2111at]YF2的治疗指标：减少肾脏、唾液腺和泪腺积聚的简单策略

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

Nuclear medicine and biology Pub Date : 2025-05-11 DOI:10.1016/j.nucmedbio.2025.109028

Truc T. Huynh, Yutian Feng, Rebecca L. Banks, Ganesan Vaidyanathan, Michael R. Zalutsky

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引用次数: 0

摘要

低分子量（LMW） psma靶向药物已经取得了成功；然而，它们对正常组织如肾脏、唾液腺和泪腺的脱靶毒性可能是剂量限制的。在此，我们评估了非放射性碘伪载体碘YF2对异种移植小鼠正常组织摄取[2111at]YF2的影响。通过评估LMW PSMA靶向药物与小鼠和人PSMA的结合，研究了这些研究对临床转化的潜在影响。方法[2111at]YF2合成方法。每组5只皮下移植PSMA+ PC3 PIP的小鼠接受[2111at]YF2与不同剂量的碘YF2 （0-2 nmol）共同静脉注射，并在注射后1小时（p.i）评估其生物分布。在另一项研究中，单独使用[2111at]YF2和与1.5 nmol碘YF2共同使用[2111at]YF2在1和8小时的生物分布进行了评估。对[131I]YF2和其他几种LMW药物进行了基于球珠的放射性配体结合试验，以比较它们与人和小鼠PSMA的结合。结果1 h时，碘YF2浓度为0、0.05和0.1 nmol时，肾脏对[211At]YF2的摄取无显著差异(p >；0.05)，但联合给药2.0 nmol碘YF2显著降低肾脏积累量(p <；0.0001)。[211At]YF2与0.1 nmol碘YF2共注射1 h时，唾液和泪腺摄取也有所减少(p <；0.05)。一项随访研究显示，与单独使用[2111at]YF2的46.5±7.7%的ID/g相比，使用1.5 nmol碘的[2111at]YF2在8小时的肾脏摄取为1.8±0.4% ID/g。肿瘤摄取无显著差异(p >；[211At]YF2在1 h时（17.1±8.8% ID/g）；[211At]YF2加1.5 nmol碘YF2(12.8±2.7% ID/g, 1h)；14.1±3.2% ID/g （8 h）。基于微球的放射性配体结合实验显示，[131I]YF2与人类PSMA（94.1±0.1%）和小鼠PSMA（92.5±0.2%）的结合率最高，两者之间差异很小，而[177Lu]PSMA-617与人类PSMA的结合率最高，为90.5±0.3%，与小鼠PSMA的结合率为60.9±1.4%。结论口服碘化YF2可减少[2111at]YF2在正常组织中的蓄积，但对肿瘤的摄取无明显影响。在某些情况下，LMW PSMA靶向药物与人类和小鼠PSMA的结合存在显著差异，这表明，特别是对于某些药物，应用小鼠数据预测人类剂量学必须谨慎进行。

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Enhancing the therapeutic index of [211At]YF2 with iodo pseudo carrier: A simple strategy for reducing accumulation in kidneys, salivary and lacrimal glands

Introduction

Low-molecular-weight (LMW) PSMA-targeted agents have enjoyed success; however, their off-target toxicity in normal tissues such as kidneys, salivary gland and lacrimal gland can be dose limiting. Herein, we have evaluated the effect of co-administration of the non-radioactive iodo pseudo carrier, iodo YF2, on the normal tissue uptake of [²¹¹At]YF2 in xenografted mice. The potential implications for clinical translation of these studies were investigated by evaluating the binding of LMW PSMA-targeted agents to murine and human PSMA.

Methods

[²¹¹At]YF2 was synthesized following established protocols. Groups of 5 mice bearing subcutaneous PSMA+ PC3 PIP xenografts received [²¹¹At]YF2 co-injected with varying i.v. doses of iodo YF2 (0–2 nmol), and the biodistribution was evaluated at 1 h post injection (p.i.). In another study, the biodistribution of [²¹¹At]YF2 alone and [²¹¹At]YF2 co-administered with 1.5 nmol iodo YF2 was evaluated at 1 and 8 h p.i. Bead-based radioligand binding assays were conducted for [¹³¹I]YF2 and several other LMW agents to compare their binding to human and murine PSMA.

Results

At 1 h, no significant difference was seen in kidney uptake of [²¹¹At]YF2 at iodo YF2 concentrations of 0, 0.05 and 0.1 nmol (p > 0.05), but renal accumulations significantly reduced by co-administering 2.0 nmol iodo YF2 (p < 0.0001). Decreases in salivary and lacrimal gland uptake also were observed at 1 h for [²¹¹At]YF2 co-injected with 0.1 nmol iodo YF2 (p < 0.05). A follow-up study revealed a kidney uptake of 1.8 ± 0.4 % ID/g for [²¹¹At]YF2 with 1.5 nmol iodo YF2, compared to 46.5 ± 7.7 % ID/g for [²¹¹At]YF2 alone at 8 h. Tumor uptake showed no significant difference (p > 0.05) between [²¹¹At]YF2 alone (17.1 ± 8.8 % ID/g at 1 h; 13.6 ± 5.3 % ID/g at 8 h) and [²¹¹At]YF2 plus 1.5 nmol iodo YF2 (12.8 ± 2.7 % ID/g at 1 h; 14.1 ± 3.2 % ID/g at 8 h). Bead-based radioligand binding assays showed that [¹³¹I]YF2 has the highest binding fractions to both human PSMA (94.1 ± 0.1 %) and murine PSMA (92.5 ± 0.2 %) with minimal differences between the two, while [¹⁷⁷Lu]PSMA-617 had the greatest species-dependent disparity with a binding fraction of 90.5 ± 0.3 % to human PSMA and 60.9 ± 1.4 % to murine PSMA.

Conclusions

Co-administration of iodo YF2 reduced kidney uptake of [²¹¹At]YF2 and decreased accumulation in normal tissues with no significant change in tumor uptake. In some cases, there was a significant difference in binding to human and murine PSMA among LMW PSMA-targeted agents suggesting that particularly for some agents, applying mouse data to predict human dosimetry must be done with caution.

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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.