Bauer David, De Gregorio Roberto, Pratt Edwin C, Bell Abram, Michel Alexa, Lewis Jason S
Department of Radiology and the Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Brigham Young University-Idaho, Rexburg, ID 83440, USA.
bioRxiv. 2024 Apr 28:2024.04.25.591165. doi: 10.1101/2024.04.25.591165.
The radionuclide pair cerium-134/lanthanum-134 (Ce/La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (Ac). The unique properties of Ce offer perspectives for developing innovative in vivo investigations not possible with Ac. In this work, Ac- and Ce-labeled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, Ce/La has limitations to the setting of quantitative positron emission tomography imaging.
The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG-Tz) were radiolabelled with Ac or Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The Ac and Ce-labeled mcp-PEG-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody.
In vitro and in vivo studies with both Ac and Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of Ce's PET-compatible daughter La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing Ac-labelled tracers are not quantitatively represented by Ce PET imaging.
When employing slow-internalizing vectors, Ce might not be an ideal match for Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of La. However, this same characteristic makes it possible to estimate the redistribution of Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment.
放射性核素对铈 - 134/镧 - 134（Ce/La）最近被提议作为治疗性α发射体锕 - 225（Ac）的合适诊断对应物。Ce的独特性质为开展用Ac无法实现的创新体内研究提供了前景。在本研究中，使用内化型和慢内化型癌症模型直接比较了Ac和Ce标记的示踪剂，以评估它们在体内的可比性、子代迁移情况以及作为临床转化的匹配诊疗对的潜力。尽管Ce/La在化学上是很好的匹配，但在定量正电子发射断层扫描成像方面存在局限性。
前体PSMA - 617和基于大分子的四嗪共轭物（mcp - PEG - Tz）用Ac或Ce进行放射性标记，并使用标准（放射）化学方法在体外和体内进行比较。在无胸腺裸鼠中进行生物分布研究和正电子发射断层扫描（PET）成像，在PC3/PIP（工程改造为高表达前列腺特异性膜抗原的PC3）前列腺癌小鼠模型中评估放射性标记的PSMA - 617示踪剂。基于反式环辛烯修饰的5B1单克隆抗体的预靶向策略，在BxPC - 3胰腺肿瘤模型中研究了Ac和Ce标记的mcp - PEG - Tz。
对Ac和Ce标记示踪剂进行的体外和体内研究得出了可比的结果，证实了这一诊疗对的匹配药代动力学。然而，对Ce标记前体的PET成像表明，由于Ce的PET兼容子代La的重新分布，定量高度依赖于示踪剂的内化。因此，基于内化载体如PSMA - 617的放射性示踪剂适用于这一诊疗对，而慢内化的Ac标记示踪剂在Ce PET成像中无法进行定量显示。
当使用慢内化载体时，由于La在体内的重新分布导致肿瘤摄取被低估，Ce可能不是Ac的理想匹配物。然而，这一相同特性使得无创估计Ac子代的重新分布成为可能。在未来的研究中，这种独特的PET体内发生器将进一步用于研究示踪剂内化、受体转运以及肿瘤微环境的进展。
