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目的:构建靶向整合素αn vβn 3诊疗一体化放射性分子n 177Lu－伊文思蓝(EB)－精氨酸－甘氨酸－天冬氨酸(RGD)并探讨其用于非小细胞肺癌(NSCLC)－患者来源异种移植瘤(PDX)模型显像及治疗的效果。n 方法:将RGD肽与白蛋白结合基团EB相连接，构建特异性靶向整合素αn vβn 3的EB－RGD，并经螯合剂1，4，7，10－四氮杂环十二烷－1，4，7，10－四乙酸(DOTA)偶联完成靶向分子n 177Lu标记。构建68只NSCLC－PDX模型鼠，取28只注射n 177Lu－EB－RGD或n 177Lu－RGD行microSPECT显像和生物分布研究；另行n 177Lu－EB－RGD放射靶向治疗实验：取PDX模型鼠40只，分为生理盐水组(A组)、18.5 MBq n 177Lu－RGD组(B组)、18.5 MBq n 177Lu－EB－RGD组(C组)、29.6 MBq n 177Lu－EB－RGD组(D组)，每组10只，观察治疗后50 d内模型鼠肿瘤体积变化情况。2组间比较采用两独立样本n t检验。n 结果:177Lu－EB－RGD的标记率在95%以上，比活度为(55±14) GBq/μmol，其体外稳定性好，放化纯大于95%。注射n 177Lu－EB－RGD后4～96 h，NSCLC－PDX模型鼠肿瘤清晰可见，注射后4、24、72、96 h的肿瘤/肌肉摄取比值(T/M)分别为7.34±0.67、14.63±3.82、15.69±3.58及15.99±5.42；生物分布结果示n 177Lu－EB－RGD摄取[每克组织百分注射剂量率(%ID/g)]与SPECT显像结果一致，且4 h时的n 177Lu－EB－RGD在肿瘤中的摄取明显高于n 177Lu－RGD[(10.15±1.17)与(3.30±1.47) %ID/g；n t＝18.60，n P<0.05]。n 177Lu－EB－RGD治疗后，A组与B组模型鼠的肿瘤体积均快速增加；而C组与D组肿瘤体积呈持续降低趋势，在第28天时C组与D组肿瘤均已肉眼不可见，且在随后的监测时间内未见复发。n 结论:177Lu－EB－RGD能靶向αn vβn 3阳性的NSCLC－PDX模型，显像效果好，对肿瘤生长有明显抑制作用，有望为晚期靶向治疗耐药或无效的肺癌患者提供新的治疗策略。n “,”Objective:To develop a novel α n vβn 3-targeted theranostic agent n 177Lu-Evans blue (EB)-Arg-Gly-Asp (RGD) and evaluate its value for SPECT imaging and targeted radionuclide therapy in the non-small cell lung cancer (NSCLC)-patient-derived xenografts (PDX).n Methods:The α n vβn 3-targeted molecule RGD was conjugated with the albumin binding moiety EB to obtain EB-RGD, and EB-RGD was further conjugated with the chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) for n 177Lu radiolabeling. NSCLC-PDX mice models (n n=68) were established. n 177Lu-EB-RGD SPECT imaging, biodistribution study were performed in 28 PDX mice models after being injected with n 177Lu-EB-RGD or n 177Lu-RGD. Targeted radionuclide therapy were subsequently performed in NSCLC-PDX mice models, saline group (group A), 18.5 MBq n 177Lu-RGD group (group B), 18.5 MBq n 177Lu-EB-RGD group (group C), 29.6 MBq n 177Lu-EB-RGD group (group D), n n=10 in each group; tumor volumes of PDX mice models in each group were observed within 50 d. Differences between 2 groups were compared using independent-sample n t test.n Results:177Lu-EB-RGD was radiolabeled at a specific activity of (55±14) GBq/μmol, with a radiochemical yield of more than 95% and a radiochemical purity of more than 95%. Regarding the SPECT imaging, tumors in NSCLC-PDX mice were clearly observed from 4 to 96 h post-injection and the tumor to muscle ratio (T/M) reached 7.34±0.67, 14.63±3.82, 15.69±3.58 and 15.99±5.42 at 4, 24, 72, 96 h post-injection, respectively. Biodistribution study further confirmed the findings from SPECT imaging, and the tumor uptake ofn 177Lu-EB-RGD were markedly increased compared to n 177Lu-RGD 4 h post-injection ((10.15±1.17) n vs (3.30±1.47) percent injection dose per gram (%ID/g); n t=18.60, n P<0.05). Regarding targeted radiotherapy, the tumor volumes were quickly increased within 50 d after treatment in group A and B, while the tumor volumes were decreased in group C and D, until the tumors in group C and D disappeared at the 28th day after initial treatment with no sign of recurrence during the observation period.n Conclusions:177Lu-EB-RGD can target α n vβn 3-positive NSCLC-PDX with intense tumor to background ratio and strong tumor inhibition efficacy. The preclinical data suggests that n 177Lu-EB-RGD may be an effective new treatment option for advanced NSCLC patients with resistance or ineffective results for targeted therapy.n