The pretargeted radioimmunotherapy approach (PRIT) decouples the administration of tumor targeting monoclonal antibodies (mAbs) from that of the radiolabeled ligand. This multistep strategy allows delivery of high doses of radiation to tumor cells while minimizing nonspecific normal tissue irradiation. In this study, we evaluated the potential of pretargeted α-particle radioimmunotherapy based on the inverse electron demand Diels–Alder (IEDDA) reaction between trans-cyclooctene (TCO) and tetrazine (Tz). Two tetrazine based chelators, DOTA-Tz and TCMC-Tz, were synthesized and compared for their radiolabeling efficiency with ²¹²Pb, radiochemical stability, and in vivo pharmacokinetics. Dosimetry was determined from pretargeted biodistribution studies. The PRIT study was carried out in LS174T tumor bearing mice pretargeted with CC49-TCO mAb. After removing unbound mAbs from the blood using two doses of clearing agent, mice were treated with various doses of (0, 2.78, 4.63, 7.40, and 2 × 2.78 MBq) of ²¹²Pb-DOTA-Tz. ²¹²Pb-DOTA-Tz displayed better in vivo biodistribution than ²¹²Pb-TCMC-Tz and was selected for PRIT study. All the mouse groups receiving treatment displayed a dose dependent reduction in tumor size, while the control groups showed exponential tumor growth. Treatment with 2.78, 4.63, and 2 × 2.78 MBq of ²¹²Pb-DOTA-Tz resulted in statistically significant improvement in median survival (26, 35, and 39 days, respectively). Groups receiving 7.40 MBq of ²¹²Pb-DOTA-Tz and 0.55 MBq of direct labeled CC49 exhibited acute radiation associated toxicity. This study successfully demonstrated that pretargeted ²¹²Pb α-particle therapy resulted in reduced tumor growth rates and improved survival with minimal normal tissue toxicity.

中文翻译：

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无金属环加成化学驱动的α粒子辐射预靶向放射免疫疗法

预靶向放射免疫疗法（PRIT）使肿瘤靶向单克隆抗体（mAb）的管理与放射标记配体的管理脱钩。这种多步骤策略允许将高剂量的放射线递送至肿瘤细胞，同时将非特异性正常组织的放射线降至最低。在这项研究中，我们基于反式环辛烯（TCO）和四嗪（Tz）之间的电子反需求Diels–Alder（IEDDA）反应，评估了预靶向α粒子放射免疫疗法的潜力。合成了两种基于四嗪的螯合剂DOTA-Tz和TCMC-Tz，并用²¹²比较了它们的放射性标记效率铅，放射化学稳定性和体内药代动力学。剂量测定是根据预先确定的生物分布研究确定的。PRIT研究是在预先靶向CC49-TCO mAb的LS174T荷瘤小鼠中进行的。使用两种剂量的清除剂从血液中去除未结合的mAb后，用各种剂量的（0、2.78、4.63、7.40和2×2.78 MBq）²¹² Pb-DOTA-Tz处理小鼠。²¹² Pb-DOTA-Tz在体内的生物分布优于²¹² Pb-TCMC-Tz，并被选择用于PRIT研究。所有接受治疗的小鼠组均显示出肿瘤大小的剂量依赖性减小，而对照组则显示出指数级的肿瘤生长。用2.78、4.63和2×2.78 MBq的^212处理Pb-DOTA-Tz导致中位生存期（分别为26、35和39天）的统计显着改善。接收的7.40 MBq的组²¹²的Pb-DOTA-TZ和直接标记的CC49 0.55 MBq的表现出急性辐射相关的毒性。这项研究成功地证明了针对性的²¹² Pbα粒子预靶向治疗可降低肿瘤的生长速度并提高生存率，同时将正常组织毒性降至最低。