Yang Xing, Minn Il, Rowe Steven P, Banerjee Sangeeta Ray, Gorin Michael A, Brummet Mary, Lee Hye Soo, Koo Soo Min, Sysa-Shah Polina, Mease Ronnie C, Nimmagadda Sridhar, Allaf Mohamad E, Pomper Martin G
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
The James Buchanan Brady Urological Institute and Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Oncotarget. 2015 Oct 20;6(32):33733-42. doi: 10.18632/oncotarget.5254.
We developed a new scaffold for radionuclide-based imaging and therapy of clear cell renal cell carcinoma (ccRCC) targeting carbonic anhydrase IX (CAIX). Compound XYIMSR-01, a DOTA-conjugated, bivalent, low-molecular-weight ligand, has two moieties that target two separate sites on CAIX, imparting high affinity. We synthesized [111In]XYIMSR-01 in 73.8-75.8% (n = 3) yield with specific radioactivities ranging from 118 - 1,021 GBq/μmol (3,200-27,600 Ci/mmol). Single photon emission computed tomography of [111In]XYIMSR-01 in immunocompromised mice bearing CAIX-expressing SK-RC-52 tumors revealed radiotracer uptake in tumor as early as 1 h post-injection. Biodistribution studies demonstrated 26% injected dose per gram of radioactivity within tumor at 1 h. Tumor-to-blood, muscle and kidney ratios were 178.1 ± 145.4, 68.4 ± 29.0 and 1.7 ± 1.2, respectively, at 24 h post-injection. Retention of radioactivity was exclusively observed in tumors by 48 h, the latest time point evaluated. The dual targeting strategy to engage CAIX enabled specific detection of ccRCC in this xenograft model, with pharmacokinetics surpassing those of previously described radionuclide-based probes against CAIX.
我们开发了一种用于透明细胞肾细胞癌（ccRCC）基于放射性核素的成像和治疗的新型支架，其靶向碳酸酐酶IX（CAIX）。化合物XYIMSR-01是一种与DOTA共轭的二价低分子量配体，有两个靶向CAIX上两个不同位点的部分，具有高亲和力。我们以73.8 - 75.8%（n = 3）的产率合成了[111In]XYIMSR-01，比活度范围为118 - 1,021 GBq/μmol（3,200 - 27,600 Ci/mmol）。在携带表达CAIX的SK-RC-52肿瘤的免疫受损小鼠中进行的[111In]XYIMSR-01单光子发射计算机断层扫描显示，注射后1小时肿瘤中就有放射性示踪剂摄取。生物分布研究表明，注射后1小时肿瘤内每克放射性活度为注射剂量的26%。注射后24小时，肿瘤与血液、肌肉和肾脏的比率分别为178.1±145.4、68.4±29.0和1.7±1.2。在评估的最晚时间点48小时时，仅在肿瘤中观察到放射性活度的滞留。针对CAIX的双靶向策略能够在该异种移植模型中特异性检测ccRCC，其药代动力学优于先前描述的针对CAIX的基于放射性核素的探针。
