Preclinical investigation of [149Tb]Tb-DOTATATE and [149Tb]Tb-DOTA-LM3 for tumor-targeted alpha therapy

IF 8.6 1区 医学 Q1 RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING
Ana Katrina Mapanao, Sarah D. Busslinger, Avni Mehta, Kristel Kegler, Chiara Favaretto, Pascal V. Grundler, Zeynep Talip, Ulli Köster, Karl Johnston, Roger Schibli, Nicholas P. van der Meulen, Cristina Müller
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引用次数: 0

Abstract

Purpose

Terbium-149 is a short-lived α-particle emitter, potentially useful for tumor-targeted therapy. The aim of this study was to investigate terbium-149 in combination with the somatostatin receptor (SSTR) agonist DOTATATE and the SSTR antagonist DOTA-LM3. The radiopeptides were evaluated to compare their therapeutic efficacy in vitro and in vivo.

Methods

Terbium-149 was produced at ISOLDE/CERN and chemically purified at the Paul Scherrer Institute. Radiolabeling of somatostatin analogues with [149Tb]TbCl3 was performed under standard labeling conditions at pH 4.5. Cell viability (MTT) and survival assays (colony forming) assays were performed after 16–18 h exposure of SSTR-positive AR42J rat pancreatic tumor cells to various activity concentrations of [149Tb]Tb-DOTATATE and [149Tb]Tb-DOTA-LM3. DNA double-strand breaks were determined using immunofluorescence imaging of γ-H2A.X and 53BP1. Therapy studies were performed with AR42J tumor-bearing mice injected with 1 × 5 MBq or 2 × 5 MBq of the respective radiopeptide. The tolerability of up to 40 MBq [149Tb]Tb-DOTATATE or 40 MBq [149Tb]Tb-DOTA-LM3 was assessed with regard to undesired effects to the bone marrow and kidneys in immunocompetent mice without tumors.

Results

The radiolabeling of peptides was achieved at molar activities of up to 20 MBq/nmol at ≥ 98% radiochemical purity. AR42J cell viability was reduced in an activity-dependent manner, with [149Tb]Tb-DOTA-LM3 being slightly more potent than [149Tb]Tb-DOTATATE (EC50: 0.5 vs. 1.2 kBq/mL). Both radiopeptides induced a similar number of γ-H2A.X and 53BP1 foci per nuclei, which indicated DNA damage in AR42J tumor cells. Injection of tumor-bearing mice with 1 × 5 MBq radiopeptide resulted in median survival times of 16.5 days and 19 days for [149Tb]Tb-DOTATATE and [149Tb]Tb-DOTA-LM3, respectively, as compared to only 8 days for untreated control mice. Application of 2 × 5 MBq of the radiopeptides further extended the median survival times to 30 days and 29 days, respectively. The blood cell counts and values for blood plasma biomarkers of treated mice without tumors were similar to those of untreated controls. Renal accumulation of [99mTc]Tc-DMSA was similar in all mice, indicating normal kidney function.

Conclusion

149Tb-based radiopeptides effectively reduced the viability of tumor cells in vitro as well as the tumor growth in mice without causing relevant adverse events, irrespective of whether the SSTR agonist or antagonist was employed. These data encourage further preclinical application of terbium-149 to evaluate its potential in combination with other tumor-targeting agents.

Graphical Abstract

[149Tb]Tb-DOTATATE和[149Tb]Tb-DOTA-LM3用于肿瘤靶向α治疗的临床前研究
目的铽-149是一种寿命短的α粒子发射器,在肿瘤靶向治疗中具有潜在的应用价值。本研究的目的是研究铽-149与生长抑素受体(SSTR)激动剂DOTATATE和SSTR拮抗剂DOTA-LM3联合使用的效果。对放射性多肽进行体外和体内治疗效果的比较。方法铯-149在ISOLDE/CERN生产,在Paul Scherrer研究所进行化学纯化。在标准标记条件下,pH为4.5,用[149Tb]TbCl3放射标记生长抑素类似物。将sstr阳性AR42J大鼠胰腺肿瘤细胞暴露于不同活性浓度的[149Tb]Tb-DOTATATE和[149Tb]Tb-DOTA-LM3中16-18 h后,进行细胞活力(MTT)和存活(集落形成)测定。用γ-H2A免疫荧光成像检测DNA双链断裂。X和53BP1。对AR42J荷瘤小鼠分别注射1 × 5 MBq或2 × 5 MBq的放射肽进行治疗研究。在没有肿瘤的免疫功能小鼠中,评估了高达40 MBq [149Tb]Tb-DOTA-LM3或40 MBq [149Tb]Tb-DOTA-LM3对骨髓和肾脏的不良影响。结果在≥98%的放射化学纯度下,肽的摩尔活性可达20 MBq/nmol。AR42J细胞活力呈活性依赖性降低,[149Tb]Tb-DOTA-LM3的效力略高于[149Tb]Tb-DOTATATE (EC50: 0.5 vs. 1.2 kBq/mL)。两种放射性多肽诱导了相似数量的γ-H2A。X和53BP1每核聚焦,提示AR42J肿瘤细胞DNA损伤。向荷瘤小鼠注射1 × 5 MBq放射肽,[149Tb]Tb-DOTATATE和[149Tb]Tb-DOTA-LM3的中位生存时间分别为16.5天和19天,而未治疗的对照组小鼠仅为8天。使用2 × 5 MBq的放射性多肽进一步延长了中位生存时间,分别为30天和29天。治疗后无肿瘤小鼠的血细胞计数和血浆生物标志物值与未治疗对照组相似。所有小鼠肾脏中[99mTc]Tc-DMSA的积累相似,表明肾功能正常。结论无论使用SSTR激动剂还是拮抗剂,基于149tb的放射性多肽均能有效降低体外肿瘤细胞活力和小鼠肿瘤生长,且未引起相关不良事件。这些数据鼓励进一步临床前应用铽-149,以评估其与其他肿瘤靶向药物联合的潜力。图形抽象
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来源期刊
CiteScore
15.60
自引率
9.90%
发文量
392
审稿时长
3 months
期刊介绍: The European Journal of Nuclear Medicine and Molecular Imaging serves as a platform for the exchange of clinical and scientific information within nuclear medicine and related professions. It welcomes international submissions from professionals involved in the functional, metabolic, and molecular investigation of diseases. The journal's coverage spans physics, dosimetry, radiation biology, radiochemistry, and pharmacy, providing high-quality peer review by experts in the field. Known for highly cited and downloaded articles, it ensures global visibility for research work and is part of the EJNMMI journal family.
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