靶向HER2的177Lu标记亲和体核素药物的构建及其在荷瘤鼠中的评估  

Construction of 177Lu-labeled affibody radiopharmaceutical targeting HER2 and its evaluation in tumor xenografts

作　　者：刘嘉月 郭晓轶 朱华[1] 杨志[1] Liu Jiayue;Guo Xiaoyi;Zhu Hua;Yang Zhi(Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Key Laboratory for Research and Evaluation of Radiopharmaceuticals(National Medical Products Administration),Department of Nuclear Medicine,Peking University Cancer Hospital&Institute,Beijing 100142,China)

机构地区：[1]北京大学肿瘤医院暨北京市肿瘤防治研究所核医学科、国家药监局放射性药物研究与评价重点实验室、恶性肿瘤发病机制及转化研究教育部重点实验室,北京100142

出　　处：《中华核医学与分子影像杂志》2024年第6期324-329,共6页Chinese Journal of Nuclear Medicine and Molecular Imaging

基　　金：首都卫生发展科研专项(2022-2Z-2154)。

摘　　要：目的:制备一种基于亲和体的靶向人表皮生长因子受体2(HER2)的放射性核素治疗药物177Lu-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸(DOTA)-HER2-BCH,初步评估其在HER2阳性肿瘤模型中的生物分布、治疗效果及安全性,探讨其用于HER2阳性肿瘤治疗的可行性。方法:采用盐酸-乙酸钠缓冲体系完成177Lu标记。采用放射性高效液相色谱对标记产物进行质量控制并监测体外稳定性。在HER2阳性NCI-N87荷瘤鼠模型中进行生物分布实验,以及177Lu-DOTA-HER2-BCH放射性核素治疗及曲妥珠单克隆抗体(简称单抗)治疗。对治疗后小鼠正常器官行组织学分析。采用重复测量方差分析及Bonferroni法分析数据。结果:成功获得放射性标记产率>80%、放化纯>98%、体外稳定性良好的177Lu-DOTA-HER2-BCH。生物分布数据显示,177Lu-DOTA-HER2-BCH靶向性好,肿瘤摄取高且滞留时间长,注射后4、24、48和96 h的肿瘤摄取值分别为(11.93±0.46)、(8.65±0.40)、(5.89±0.69)和(3.26±0.36)每克组织百分注射剂量率(%ID/g)。治疗实验示,177Lu-DOTA-HER2-BCH治疗可明显抑制肿瘤生长,治疗开始后第3天,肿瘤体积明显小于对照组[平均值差值146.97 mm 3;F=4.02,P=0.016(Bonferroni法校正)],随后2组间肿瘤体积的差异随着时间的延长而增大;在整个治疗过程中,177Lu-DOTA-HER2-BCH治疗组与曲妥珠单抗治疗组间肿瘤体积差异无统计学意义[F值:0.05~61.21,均P>0.017(Bonferroni法校正)]。治疗结束后,小鼠各器官病理检测结果均未见异常。结论:177Lu-DOTA-HER2-BCH放射性核素治疗在HER2阳性荷瘤鼠中表现出良好的抑制肿瘤生长的效果,有望成为HER2阳性肿瘤的可替代治疗方式。Objective To prepare an affinity-based radionuclide therapeutic drug targeting human epidermal growth factor receptor 2(HER2),named 177Lu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid(DOTA)-HER2-BCH,and preliminarily evaluate its biodistribution,therapeutic efficacy,and safety in HER2-positive tumor models,in order to explore its feasibility as a radiopharmaceutical for treatment of HER2-positive tumor.Methods 177Lu labeling was accomplished by using a hydrochloric acid-sodium acetate buffer system.The radiochemical purity and in vitro stability of the labeled products were analyzed by radio high performance liquid chromatography.Biodistribution,177Lu-DOTA-HER2-BCH radionuclide targeting therapy,and trastuzumab therapy were performed in the HER2-positive NCI-N87 tumor-bearing mice.Repeated measures analysis of variance and Bonferroni method were utilized to analyze data.Results 177Lu-DOTA-HER2-BCH was obtained,with the radiolabeling yield>80%,radiochemical purity>98%,and good in vitro stability.Biodistribution data showed that 177Lu-DOTA-HER2-BCH was well targeted,with high tumor uptake and high retention.The tumor uptake values at 4,24,72 and 96 h post-injection were(11.93±0.46),(8.65±0.40),(5.89±0.69)and(3.26±0.36)percentage activity of injection dose per gram of tissue(%ID/g),respectively.In the treatment experiment,177Lu-DOTA-HER2-BCH significantly inhibited tumor growth.On the 3rd day,the tumor volume of mice treated with 177Lu-DOTA-HER2-BCH was significantly smaller than that of the control group(mean difference 146.97 mm^(3);F=4.02,P=0.016(Bonferroni correction method),and then differences of tumor volume between the 2 groups increased with time.The differences of tumor volume between 177Lu-DOTA-HER2-BCH and trastuzumab treatment groups were not statistically significant throughout the treatment process(F values:0.05-61.21,all P>0.017(Bonferroni correction method)).At the end of treatment,no histological abnormality was seen in all organs of the mice.Conclusion 177Lu-DOTA-HER2-BCH radionucli

关 键 词：胃肿瘤 基因 ERBB-2 同位素标记 镥 曲妥珠单抗 小鼠 裸 

分 类 号：R735.2[医药卫生—肿瘤]