Milenic Diane E, Baidoo Kwamena E, Kim Young-Seung, Barkley Rachel, Brechbiel Martin W
Radioimmune & Inorganic Chemistry Section, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD, USA.
Dalton Trans. 2017 Oct 31;46(42):14591-14601. doi: 10.1039/c7dt01819c.
Identification of the appropriate combination of radionuclide, target and targeting vehicle is critical for successful radioimmunotherapy. For the treatment of disseminated peritoneal diseases such as pancreatic or ovarian cancer, α-emitting radionuclides have been proposed for targeted radiation therapy. This laboratory has taken a systematic approach investigating targeted α-radiation therapy, allowing comparisons to now be made between At, Th, Bi and Pb. Herein, trastuzumab radiolabeled with At and Th was evaluated for therapeutic efficacy in the LS-174T i.p. tumor model. A dose escalation study was conducted with each radioimmunoconjugate (RIC). Therapeutic benefit was realized with At-trastuzumab with doses of 20, 30 and 40 μCi. At doses >40 μCi, toxicity was observed with greater weight loss and 2-fold higher decrease in the platelet counts. Following a second study comparing the effect of 20, 30 and 40 μCi of At-trastuzumab, 30 μCi was selected as the dose for future studies. A parallel study was performed evaluating 0.25, 0.5, 1.0, 2.0 and 5.0 μCi of Th-trastuzumab. The 0.5 and 1.0 μCi injected dose resulted in a therapeutic response; a lower degree of weight loss was experienced by the mice in the 0.5 μCi cohort. When the data is normalized for comparing At, Th, Bi and Pb, the choice of radionuclide for RIT is perhaps not entirely based on simple therapeutic efficacy, other factors may play a role in choosing the "right" radionuclide.
确定放射性核素、靶点和靶向载体的合适组合对于成功进行放射免疫治疗至关重要。对于治疗诸如胰腺癌或卵巢癌等播散性腹膜疾病，已提出使用发射α粒子的放射性核素来进行靶向放射治疗。本实验室采用系统方法研究靶向α放射治疗，从而能够对砹、钍、铋和铅进行比较。在此，评估了用砹和钍标记的曲妥珠单抗在LS-174T腹腔肿瘤模型中的治疗效果。对每种放射免疫缀合物（RIC）进行了剂量递增研究。使用20、30和40 μCi剂量的砹-曲妥珠单抗实现了治疗益处。在剂量>40 μCi时，观察到毒性，体重减轻更明显，血小板计数下降两倍。在第二项比较20、30和40 μCi砹-曲妥珠单抗效果的研究之后，选择30 μCi作为未来研究的剂量。进行了一项平行研究，评估0.25、0.5、1.0、2.0和5.0 μCi的钍-曲妥珠单抗。注射0.5和1.0 μCi剂量产生了治疗反应；0.5 μCi组的小鼠体重减轻程度较低。当对砹、钍、铋和铅的数据进行归一化以进行比较时，放射免疫治疗中放射性核素的选择可能并非完全基于简单的治疗效果，其他因素可能在选择“正确”的放射性核素中起作用。
