Division of Nuclear Medicine, Department of Radiology, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0243, United States.
Bioconjug Chem. 2011 Dec 21;22(12):2539-45. doi: 10.1021/bc200366t. Epub 2011 Nov 3.
While (188)Re has been used successfully in mice for tumor radiotherapy by MORF/cMORF pretargeting, previous radiolabeling of the amine-derivatized cMORF with (90)Y, a longer physical half-life nuclide, was not very successful. After developing a method involving a prepurification heating step during conjugation that increases labeling efficiency and label stability, the biodistribution of (90)Y-DOTA-Bn-SCN-cMORF ((90)Y-DOTA-cMORF) was measured in normal mice and in MORF-CC49 pretargeted mice that bear LS174T tumors. Absorbed radiation doses were then estimated and compared to those estimated for (188)Re. The pharmacokinetics of the (90)Y-DOTA-cMORF in normal mice and in the pretargeted nude mice was similar to that observed previously with (99m)Tc- and (188)Re-MAG(3)-cMORFs. While the (90)Y-DOTA-cMORF cleared rapidly from normal tissues, tumor clearance was very slow and tumor radioactivity accumulation was constant for at least 7 days such that the tumor/blood (T/B) ratio increased linearly from 6 to 25 over this period. Therefore, by extrapolation, normal tissue toxicities following administration of therapeutic doses of (90)Y may be comparable to that observed for (188)Re in which the T/B increased from 5 to 20. In conclusion, radiolabeling of DOTA-cMORF with (90)Y was improved by introducing a prepurification heating step during conjugation. The (90)Y-DOTA-cMORF provided a similar T/B ratio and biodistribution to that of (188)Re-MAG(3)-cMORF and was retained well in the tumor pretargeted with MORF-CC49. Because of the longer physical half-life, the T/NT absorbed radiation dose ratios were improved in most organs and especially in blood.
虽然（188）Re 通过 MORF/cMORF 预靶向成功用于小鼠肿瘤放射治疗，但之前用（90）Y（一种物理半衰期较长的核素）对胺衍生的 cMORF 进行放射性标记效果并不理想。在开发了一种在连接过程中涉及预纯化加热步骤的方法后，该方法提高了标记效率和标记稳定性，然后测量了（90）Y-DOTA-Bn-SCN-cMORF（（90）Y-DOTA-cMORF）在正常小鼠和携带 LS174T 肿瘤的 MORF-CC49 预靶向小鼠中的生物分布。然后估计吸收剂量并与（188）Re 估计的剂量进行比较。（90）Y-DOTA-cMORF 在正常小鼠和预靶向裸鼠中的药代动力学与之前用（99m）Tc-和（188）Re-MAG（3）-cMORF 观察到的相似。虽然（90）Y-DOTA-cMORF 从正常组织中快速清除，但肿瘤清除非常缓慢，肿瘤放射性积累至少在 7 天内保持恒定，使得肿瘤/血液（T/B）比值在此期间从 6 线性增加到 25。因此，通过推断，（90）Y 治疗剂量给药后的正常组织毒性可能与（188）Re 观察到的毒性相当，其中 T/B 从 5 增加到 20。总之，通过在连接过程中引入预纯化加热步骤，（90）Y 标记 DOTA-cMORF 的效果得到了改善。（90）Y-DOTA-cMORF 提供了与（188）Re-MAG（3）-cMORF 相似的 T/B 比值和生物分布，并且在 MORF-CC49 预靶向的肿瘤中保持良好。由于物理半衰期较长，大多数器官特别是血液中的 T/NT 吸收辐射剂量比得到改善。
