α-颗粒释放经动脉放射栓塞剂(αTARE) [225Ac]Ac-DOTA-TDA-Lipiodol®抗肝脏肿瘤药代动力学、剂量学及疗效评价

IF 4.4 Q1 CHEMISTRY, INORGANIC & NUCLEAR EJNMMI Radiopharmacy and Chemistry Pub Date : 2023-08-14 DOI:10.1186/s41181-023-00205-3
Anders Josefsson, Angel G. Cortez, Harikrishnan Rajkumar, Joseph D. Latoche, Ambika P. Jaswal, Kathryn E. Day, Mohammadreza Zarisfi, Lora H. Rigatti, Ziyu Huang, Jessie R. Nedrow
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引用次数: 0

摘要

肝脏是包括结直肠癌在内的多种癌症转移性疾病的常见部位。原发性和继发性肝脏肿瘤均通过肝动脉供血,而健康的肝脏由门静脉供血。在肝细胞癌(HCC)患者中,使用钇-90玻璃或树脂微球的经动脉放射栓塞(TARE)显示出有希望的结果,副作用减少,但生存率与化疗栓塞相似。这表明需要新的抗HCC药物。靶向α治疗(TAT)是一种高效的治疗方法,由于发射α-粒子的距离短(不影响邻近的正常组织)和密集的电离轨道(高线性能量转移)。α-释放颗粒放射性同位素在HCC治疗中的应用非常有限,我们最近发表的论文开创了α-释放颗粒TARE (αTARE)领域。本研究重点从药代动力学、剂量学、稳定性和疗效等方面对α - tare -agent [225Ac]Ac-DOTA-TDA-Lipiodol®作为HCC的有效治疗剂进行了深入评价。结果[225Ac]Ac-DOTA-TDA具有高度稳定性,3天试验台稳定性≥95%放射化学纯度(RCP), 5天血清稳定性≥90% RCP。药代动力学数据显示[225Ac]Ac-DOTA-TDA-Lipiodol®在肿瘤中保留,并通过正常器官清除。此外,肿瘤和肝脏是游离子体的供给者,游离子体通过血液在肾脏中积累。剂量限制器官是肝脏,根据鼠体体重估计的最大耐受活性:728-3641 Bq/g(雄性大鼠),396-1982 Bq/g(雄性小鼠)和453-2263 Bq/g(雌性小鼠),取决于rbe值(范围1-5)。此外,[225Ac]Ac-DOTA-TDA-Lipiodol®与对照组(未治疗26天,单独使用Lipiodol®33 - 35天)相比,雄性和雌性小鼠的生存均有显著改善(中位生存期为47天)。本研究表明[225Ac]Ac-DOTA-TDA-Lipiodol®是一种稳定的化合物,可在全球范围内集中生产和分销。此外,本研究结果支持α - tre -agent [225Ac]Ac-DOTA-TDA-Lipiodol®作为治疗肝脏肿瘤的潜在治疗选择的持续评估。
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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Evaluation of the pharmacokinetics, dosimetry, and therapeutic efficacy for the α-particle-emitting transarterial radioembolization (αTARE) agent [225Ac]Ac-DOTA-TDA-Lipiodol® against hepatic tumors

Background

The liver is a common site for metastatic disease for a variety of cancers, including colorectal cancer. Both primary and secondary liver tumors are supplied through the hepatic artery while the healthy liver is supplied by the portal vein. Transarterial radioembolization (TARE) using yttrium-90 glass or resin microspheres have shown promising results with reduced side-effects but have similar survival benefits as chemoembolization in patients with hepatocellular carcinoma (HCC). This highlights the need for new novel agents against HCC. Targeted alpha therapy (TAT) is highly potent treatment due to the short range (sparing adjacent normal tissue), and densely ionizing track (high linear energy transfer) of the emitted α-particles. The incorporation of α-particle-emitting radioisotopes into treatment of HCC has been extremely limited, with our recent publication pioneering the field of α-particle-emitting TARE (αTARE). This study focuses on an in-depth evaluation of the αTARE-agent [225Ac]Ac-DOTA-TDA-Lipiodol® as an effective therapeutic agent against HCC regarding pharmacokinetics, dosimetry, stability, and therapeutic efficacy.

Results

[225Ac]Ac-DOTA-TDA was shown to be a highly stable with bench-top stability at ≥ 95% radiochemical purity (RCP) over a 3-day period and serum stability was ≥ 90% RCP over 5-days. The pharmacokinetic data showed retention in the tumor of [225Ac]Ac-DOTA-TDA-Lipiodol® and clearance through the normal organs. In addition, the tumor and liver acted as suppliers of the free daughters, which accumulated in the kidneys supplied via the blood. The dose limiting organ was the liver, and the estimated maximum tolerable activity based on the rodents whole-body weight: 728–3641 Bq/g (male rat), 396–1982 Bq/g (male mouse), and 453–2263 Bq/g (female mouse), depending on an RBE-value (range 1–5). Furthermore, [225Ac]Ac-DOTA-TDA-Lipiodol® showed significant improvement in survival for both the male and female mice (median survival 47-days) compared with controls (26-days untreated, and 33–35-days Lipiodol® alone).

Conclusions

This study shows that [225Ac]Ac-DOTA-TDA-Lipiodol® is a stable compound allowing for centralized manufacturing and distribution world-wide. Furthermore, the result of this study support the continue development of evaluation of the αTARE-agent [225Ac]Ac-DOTA-TDA-Lipiodol® as a potential treatment option for treating hepatic tumors.

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CiteScore
7.20
自引率
8.70%
发文量
30
审稿时长
5 weeks
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