Abstract：
OBJECTIVE: The radionuclide pair cerium-134/lanthanum-134 (134Ce/134La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (225Ac). The unique properties of 134Ce offer perspectives for developing innovative in vivo investigations that are not possible with 225Ac. In this work, 225Ac- and 134Ce-labelled 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, 134Ce/134La has limitations to the setting of quantitative positron emission tomography imaging.
METHODS: The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with 225Ac or 134Ce 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 225Ac and 134Ce-labelled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody.
RESULTS: In vitro and in vivo studies with both 225Ac and 134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the 134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of 134Ce\'s PET-compatible daughter 134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing 225Ac-labelled tracers are not quantitatively represented by 134Ce PET imaging.
CONCLUSIONS: When employing slow-internalizing vectors, 134Ce might not be an ideal match for 225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of 134La. However, this same characteristic makes it possible to estimate the redistribution of 225Ac\'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.
METHODS: The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG8-Tz) were radiolabelled with 225Ac or 134Ce 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 225Ac and 134Ce-labelled mcp-PEG8-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody.
RESULTS: In vitro and in vivo studies with both 225Ac and 134Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the 134Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of 134Ce\'s PET-compatible daughter 134La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing 225Ac-labelled tracers are not quantitatively represented by 134Ce PET imaging.
CONCLUSIONS: When employing slow-internalizing vectors, 134Ce might not be an ideal match for 225Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of 134La. However, this same characteristic makes it possible to estimate the redistribution of 225Ac\'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.
摘要：
目的：最近提出了放射性核素对铈-134/镧-134（134Ce/134La）作为治疗性α-发射体i-225（225Ac）的合适诊断对应物。134Ce的独特特性为开发225Ac无法进行的创新体内研究提供了前景。在这项工作中,使用内化和缓慢内化癌症模型直接比较225Ac和134Ce标记的示踪剂，以评估其体内可比性，后代蜿蜒，并有可能作为临床翻译的匹配治疗对。尽管是一场出色的化学赛，134Ce/134La对定量正电子发射断层成像的设置具有局限性。
方法:用225Ac或134Ce对前体PSMA-617和基于macropa的四嗪-缀合物(mcp-PEG8-Tz)进行放射性标记,并使用标准(放射性)化学方法在体外和体内进行比较。在无胸腺裸鼠中采用生物分布研究和正电子发射断层扫描（PET）成像，在PC3/PIP(经工程改造表达高水平前列腺特异性膜抗原的PC3)前列腺癌小鼠模型中评估了放射性标记的PSMA-617示踪剂.在BxPC-3胰腺肿瘤模型中研究了225Ac和134Ce标记的mcp-PEG8-Tz，该模型利用了基于反式环辛烯修饰的5B1单克隆抗体的预靶向策略。
结果：使用225Ac和134Ce标记的示踪剂进行的体外和体内研究得出了可比的结果，证实了这对theranostic的匹配药代动力学。然而,134Ce标记前体的PET成像表明，由于134Ce的PET相容子134La的重新分布，定量高度依赖于示踪剂内化。因此,基于PSMA-617等内化载体的放射性示踪剂适用于这种治疗对，而缓慢内化的225Ac标记的示踪剂不能通过134CePET成像定量表示。
结论：当使用慢内化载体时，134Ce可能不是225Ac的理想匹配,因为由134La的体内再分布引起的肿瘤摄取的低估。然而,同样的特征使得非侵入性地估计225Ac后代的再分布成为可能。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，受体的贩运，和肿瘤微环境的进展。
方法:用225Ac或134Ce对前体PSMA-617和基于macropa的四嗪-缀合物(mcp-PEG8-Tz)进行放射性标记,并使用标准(放射性)化学方法在体外和体内进行比较。在无胸腺裸鼠中采用生物分布研究和正电子发射断层扫描（PET）成像，在PC3/PIP(经工程改造表达高水平前列腺特异性膜抗原的PC3)前列腺癌小鼠模型中评估了放射性标记的PSMA-617示踪剂.在BxPC-3胰腺肿瘤模型中研究了225Ac和134Ce标记的mcp-PEG8-Tz，该模型利用了基于反式环辛烯修饰的5B1单克隆抗体的预靶向策略。
结果：使用225Ac和134Ce标记的示踪剂进行的体外和体内研究得出了可比的结果，证实了这对theranostic的匹配药代动力学。然而,134Ce标记前体的PET成像表明，由于134Ce的PET相容子134La的重新分布，定量高度依赖于示踪剂内化。因此,基于PSMA-617等内化载体的放射性示踪剂适用于这种治疗对，而缓慢内化的225Ac标记的示踪剂不能通过134CePET成像定量表示。
结论：当使用慢内化载体时，134Ce可能不是225Ac的理想匹配,因为由134La的体内再分布引起的肿瘤摄取的低估。然而,同样的特征使得非侵入性地估计225Ac后代的再分布成为可能。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，受体的贩运，和肿瘤微环境的进展。
