Palm Stig, Enmon Richard M, Matei Cornelia, Kolbert Katherine S, Xu Su, Zanzonico Pat B, Finn Ronald L, Koutcher Jason A, Larson Steven M, Sgouros George
Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
J Nucl Med. 2003 Jul;44(7):1148-55.
Preclinical biodistribution and pharmacokinetics of investigational radiopharmaceuticals are typically obtained by longitudinal animal studies. These have required the sacrifice of multiple animals at each time point. Advances in small-animal imaging have made it possible to evaluate the biodistribution of radiopharmaceuticals across time in individual animals, in vivo. MicroPET and MRI-based preclinical biodistribution and localization data were obtained and used to assess the therapeutic potential of (90)Y-trastuzumab monoclonal antibody (mAb) (anti-HER2/neu) against ovarian carcinoma.
Female nude mice were inoculated intraperitoneally with 5.10(6) ovarian carcinoma cells (SKOV3). Fourteen days after inoculation, 12-18 MBq (86)Y-labeled trastuzumab mAb was injected intraperitoneally. Tumor-free mice, injected with (86)Y-trastuzumab, and tumor-bearing mice injected with labeled, irrelevant mAb or (86)Y-trastuzumab + 100-fold excess unlabeled trastuzumab were used as controls. Eight microPET studies per animal were collected over 72 h. Standard and background images were collected for calibration. MicroPET images were registered with MR images acquired on a 1.5-T whole-body MR scanner. For selected time points, 4.7-T small-animal MR images were also obtained. Images were analyzed and registered using software developed in-house. At completion of imaging, suspected tumor lesions were dissected for histopathologic confirmation. Blood, excised normal organs, and tumor nodules were measured by gamma-counting. Tissue uptake was expressed relative to the blood concentration (percentage of injected activity per gram of tissue [%IA/g]/%IA/g blood). (86)Y-Trastuzumab pharmacokinetics were used to perform (90)Y-trastuzumab dosimetry.
Intraperitoneal injection of mAb led to rapid blood-pool uptake (5-9 h) followed by tumor localization (26-32 h), as confirmed by registered MR images. Tumor uptake was greatest for (86)Y-trastuzumab (7 +/- 1); excess unlabeled trastuzumab yielded a 70% reduction. Tumor uptake for the irrelevant mAb was 0.4 +/- 0.1. The concentration in normal organs relative to blood ranged from 0 to 1.4 across all studies, with maximum uptake in spleen. The absorbed dose to the kidneys was 0.31 Gy/MBq (90)Y-trastuzumab. The liver received 0.48 Gy/MBq, and the spleen received 0.56 Gy/MBq. Absorbed dose to tumors varied from 0.10 Gy/MBq for radius = 0.1 mm to 3.7 Gy/MBq for radius = 5 mm.
For all injected compounds, the relative microPET image intensity of the tumor matched the subsequently determined (86)Y uptake. Coregistration with MR images confirmed the position of (86)Y uptake relative to various organs. Radiolabeled trastuzumab mAb was shown to localize to sites of disease with minimal normal organ uptake. Dosimetry calculations showed a strong dependence on tumor size. These results demonstrate the usefulness of combined microPET and MRI for the evaluation of novel therapeutics.
研究用放射性药物的临床前生物分布和药代动力学通常通过纵向动物研究获得。这需要在每个时间点处死多只动物。小动物成像技术的进步使得在个体动物体内随时间评估放射性药物的生物分布成为可能。获得了基于微型正电子发射断层扫描（MicroPET）和磁共振成像（MRI）的临床前生物分布和定位数据，并用于评估（90）Y-曲妥珠单抗单克隆抗体（mAb）（抗HER2/neu）对卵巢癌的治疗潜力。
雌性裸鼠腹腔接种5×10⁶个卵巢癌细胞（SKOV3）。接种后14天，腹腔注射12 - 18 MBq（86）Y标记的曲妥珠单抗mAb。将注射了（86）Y-曲妥珠单抗的无瘤小鼠、注射了标记的无关mAb的荷瘤小鼠或注射了（86）Y-曲妥珠单抗+100倍过量未标记曲妥珠单抗的荷瘤小鼠用作对照。在72小时内对每只动物进行8次微型正电子发射断层扫描研究。收集标准图像和背景图像进行校准。微型正电子发射断层扫描图像与在1.5-T全身磁共振扫描仪上采集的磁共振图像进行配准。对于选定的时间点，还获得了4.7-T小动物磁共振图像。使用内部开发的软件对图像进行分析和配准。成像结束后，解剖疑似肿瘤病变进行组织病理学确认。通过γ计数测量血液、切除的正常器官和肿瘤结节。组织摄取以相对于血液浓度表示（每克组织注射活性的百分比[%IA/g]/%IA/g血液）。（86）Y-曲妥珠单抗的药代动力学用于进行（90）Y-曲妥珠单抗的剂量测定。
腹腔注射mAb导致快速的血池摄取（5 - 9小时），随后是肿瘤定位（26 - 32小时），这通过配准的磁共振图像得到证实。（86）Y-曲妥珠单抗的肿瘤摄取最大（7±1）；过量的未标记曲妥珠单抗使摄取减少70%。无关mAb的肿瘤摄取为0.4±0.1。在所有研究中正常器官相对于血液的浓度范围为0至1.4，脾脏摄取最高。肾脏对（90）Y-曲妥珠单抗的吸收剂量为0.31 Gy/MBq。肝脏接受0.48 Gy/MBq，脾脏接受0.56 Gy/MBq。肿瘤的吸收剂量从半径为0.1 mm时的0.10 Gy/MBq到半径为5 mm时的3.7 Gy/MBq不等。
对于所有注射的化合物，肿瘤的相对微型正电子发射断层扫描图像强度与随后测定的（86）Y摄取相匹配。与磁共振图像的联合配准证实了（86）Y摄取相对于各种器官的位置。放射性标记的曲妥珠单抗mAb显示定位于疾病部位，正常器官摄取极少。剂量测定计算显示对肿瘤大小有很强的依赖性。这些结果证明了微型正电子发射断层扫描和磁共振成像联合用于评估新型治疗方法的有用性。
