Liu Guozheng, Dou Shuping, He Jiang, Liu Xinrong, Rusckowski Mary, Hnatowich Donald J
Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655-0243, USA.
Eur J Nucl Med Mol Imaging. 2007 Feb;34(2):237-46. doi: 10.1007/s00259-006-0222-3.
Pretargeting with phosphorodiamidate morpholino oligomers (MORFs) involves administration of a MORF-conjugated anti-tumor antibody such as MN14 as a pretargeting agent before that of the radiolabeled complementary MORF (cMORF) as the effector. The dosages of the pretargeting agent and effector, the pretargeting interval, and the detection time are the four pretargeting variables. The goal of this study was to develop a semiempirical description capable of predicting the biodistribution of the radiolabeled effector in pretargeted mice and then to compare predictions with experimental results from pretargeting studies in tumored animals in which the pretargeting interval and the detection time were both fixed but the dosages of both the effector and the pretargeting agent were separately varied.
Pretargeting studies in LS174T tumored mice were performed using the anti-CEA antibody MN14 conjugated with MORF and the cMORF radiolabeled with (99m)Tc. A description was developed based on our previous observations in the same mouse model of the blood and tumor levels of MORF-MN14, accessibility of MORF-MN14 to labeled cMORF, the tumor accumulation of labeled cMORF relative to MORF-MN14 levels therein, and the kidney accumulation of labeled cMORF. The predicted values were then compared with the experimental values.
The predicted biodistribution of the radiolabeled effector and the experimental data were in gratifying agreement in normal organs, suggesting that the description of the pretargeting process was reliable. The tumor accumulations occasionally fell outside two standard deviations of that predicted, but after tumor size correction, good agreement between predicted and experimental values was observed here as well.
A semiempirical description of the biodistribution of labeled cMORF was capable of predicting the biodistribution of the radiolabeled effector in the pretargeted tumored mouse model, demonstrating that the underlying pretargeting concepts are correct. We believe that the approach described herein may be applied to any of the alternative pretargeting approaches and animal tumor models currently under investigation. Furthermore, appreciation of the concepts may provide a rationale for selecting dosages and timings in human pretargeting studies as an alternative to pure empirical means.
用磷酰二胺吗啉代寡聚物（MORF）进行预靶向涉及在给予放射性标记的互补MORF（cMORF）作为效应物之前，先给予一种MORF偶联的抗肿瘤抗体，如MN14作为预靶向剂。预靶向剂和效应物的剂量、预靶向间隔以及检测时间是四个预靶向变量。本研究的目的是建立一种半经验描述方法，能够预测放射性标记的效应物在预靶向小鼠体内的生物分布，然后将预测结果与在荷瘤动物中进行的预靶向研究的实验结果进行比较，在这些研究中，预靶向间隔和检测时间均固定，但效应物和预靶向剂的剂量分别变化。
使用与MORF偶联的抗CEA抗体MN14和用（99m）Tc放射性标记的cMORF进行LS174T荷瘤小鼠的预靶向研究。基于我们之前在同一小鼠模型中对MORF - MN14的血液和肿瘤水平、MORF - MN14与标记的cMORF的可及性、标记的cMORF相对于其中MORF - MN14水平的肿瘤蓄积以及标记的cMORF的肾脏蓄积的观察，建立了一种描述方法。然后将预测值与实验值进行比较。
在正常器官中，放射性标记效应物的预测生物分布与实验数据吻合良好，表明预靶向过程的描述是可靠的。肿瘤蓄积偶尔会超出预测值的两个标准差，但在进行肿瘤大小校正后，此处预测值与实验值之间也观察到了良好的一致性。
标记的cMORF生物分布的半经验描述能够预测预靶向荷瘤小鼠模型中放射性标记效应物的生物分布，表明潜在的预靶向概念是正确的。我们认为本文所述方法可应用于目前正在研究的任何替代预靶向方法和动物肿瘤模型。此外，理解这些概念可为在人体预靶向研究中选择剂量和时间提供理论依据，以替代单纯的经验方法。
