[225Ac]Ac-DOTA-C595作为胰腺癌放射免疫疗法的进展:体外评价、剂量学评估和检测器校准

IF 4.4 Q1 CHEMISTRY, INORGANIC & NUCLEAR EJNMMI Radiopharmacy and Chemistry Pub Date : 2023-09-07 DOI:10.1186/s41181-023-00209-z

Ashleigh Hull, William Hsieh, Artem Borysenko, William Tieu, Dylan Bartholomeusz, Eva Bezak

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引用次数: 0

摘要

背景:胰腺导管腺癌(PDAC)是一种侵袭性恶性肿瘤，放射免疫治疗可能对其有益。此前，[177Lu]Lu-DOTA-C595已被开发为一种β -发射放射免疫偶联物，用于靶向PDAC上过表达的癌症特异性粘蛋白1表位(MUC1-CE)。然而，使用诸如锕-225 (Ac-225)之类的α -发射放射性核素可以增强治疗效果。α粒子的短程和高线性能量传递提供了密集的细胞损伤，并可以克服与PDAC治疗相关的典型障碍，如缺氧。尽管α -发射器增加了细胞毒性，但它们的临床应用可能因其复杂的衰变链、反冲能量和短程阻碍辐射检测而变得复杂。在本研究中，我们通过一系列体外实验开发并评估了[225Ac]Ac-DOTA-C595作为抗PDAC的α放射免疫疗法，并对Ac-225的临床应用进行了初步剂量学评估和交叉校准检测器。结果在MUC1-CE表达强烈的细胞中，[225Ac]Ac-DOTA-C595的细胞结合和内化速度最快。在暴露于[225Ac]Ac-DOTA-C595后1小时内，超过99%的PDAC细胞yH2AX表达阳性，表明存在高度的DNA损伤。克隆实验进一步证明了[225Ac]Ac-DOTA-C595的细胞毒性呈浓度依赖性。在低浓度[225Ac]Ac-DOTA-C595中，MUC1-CE表达强的细胞比MUC1-CE表达弱的细胞存活率低，但在高浓度下，无论MUC1-CE表达如何，细胞系之间的存活率都是相似的。考虑α粒子，对[225Ac]Ac-DOTA-C595的1 kBq剂量率进行了剂量学评估。经探测器测量和计算证实，1 kBq Ac-225的总吸收估计提供17.5毫戈瑞/小时的剂量率。结论[225Ac]Ac-DOTA-C595可靶向并诱导表达MUC1-CE的PDAC细胞的治疗作用。

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Development of [225Ac]Ac-DOTA-C595 as radioimmunotherapy of pancreatic cancer: in vitro evaluation, dosimetric assessment and detector calibration

Background

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy which may benefit from radioimmunotherapy. Previously, [¹⁷⁷Lu]Lu-DOTA-C595 has been developed as a beta-emitting radioimmunoconjugate to target cancer-specific mucin 1 epitopes (MUC1-CE) overexpressed on PDAC. However, the therapeutic effect may be enhanced by using an alpha-emitting radionuclide such as Actinium-225 (Ac-225). The short range and high linear energy transfer of alpha particles provides dense cellular damage and can overcome typical barriers related to PDAC treatment such as hypoxia. Despite the added cytotoxicity of alpha-emitters, their clinical implementation can be complicated by their complex decay chains, recoil energy and short-range impeding radiation detection. In this study, we developed and evaluated [²²⁵Ac]Ac-DOTA-C595 as an alpha-emitting radioimmunotherapy against PDAC using a series of in vitro experiments and conducted a preliminary dosimetric assessment and cross-calibration of detectors for the clinical implementation of Ac-225.

Results

Cell binding and internalisation of [²²⁵Ac]Ac-DOTA-C595 was rapid and greatest in cells with strong MUC1-CE expression. Over 99% of PDAC cells had positive yH2AX expression within 1 h of [²²⁵Ac]Ac-DOTA-C595 exposure, suggesting a high level of DNA damage. Clonogenic assays further illustrated the cytotoxicity of [²²⁵Ac]Ac-DOTA-C595 in a concentration-dependent manner. At low concentrations of [²²⁵Ac]Ac-DOTA-C595, cells with strong MUC1-CE expression had lower cell survival than cells with weak MUC1-CE expression, yet survival was similar between cell lines at high concentrations irrespective of MUC1-CE expression. A dosimetric assessment was performed to estimate the dose-rate of 1 kBq of [²²⁵Ac]Ac-DOTA-C595 with consideration to alpha particles. Total absorption of 1 kBq of Ac-225 was estimated to provide a dose rate of 17.5 mGy/h, confirmed via both detector measurements and calculations.