整合素α_vβ_3受体靶向显像骨肉瘤和诊治肺转移的初步研究  

Theranostics of osteosarcoma and lung metastasis with new integrin α_vβ_3 receptor targeted radiotracers

作　　者：隋吉生[1,2] 邵国强[3] 张露露[3] 张朋俊 卜婷 姚庆强[1,2] 王黎明[1,2] SUI Jisheng;SHAO Guoqiang;ZHANG Lulu;ZHANG Pengjun;BU Ting;YAO Qingqiang;WANG Liming(Department of Orthopedics,Affiliated Nanjing Hospital (the First Hospital of Nanjing),Nanjing Medical University,Nanjing Jiangsu, 210006,P.R.China;Digital Medical Institute,Nanjing Medical University,Nanjing ]iangsu,210006,P.R.China;Department of Nuclear Medicine,Affiliated Nanjing Hospital (the First Hospital of Nanjing),Nanjing Medical University,Nanjing Jiangsu,210006,P.R.China)

机构地区：[1]南京医科大学附属南京医院(南京市第一医院)骨科,南京210006 [2]南京医科大学数字医学研究所,南京210006 [3]南京医科大学附属南京医院(南京市第一医院)核医学科,南京210006

出　　处：《中国修复重建外科杂志》2019年第2期170-176,共7页Chinese Journal of Reparative and Reconstructive Surgery

基　　金：国家自然科学基金资助项目(81202032);江苏省青年医学重点人才项目(QNRC2016075);南京市科技发展计划项目(201715030)~~

摘　　要：目的初步探讨整合素α_vβ_3受体靶向显像诊断骨肉瘤及肺转移病灶及其靶向内放射性治疗肺转移病灶的价值。方法一步法制备^(68)Ga-NODAGA-RGD_2和^(177)Lu-NODAGA-RGD_2,体外检测其放射性比活度、放射性化学纯度(Radio-HPLC法)和整合素α_vβ_3受体靶向特异性。取41只裸鼠经皮下、胫骨髓腔及尾静脉注射MG63人骨肉瘤细胞,分别构建皮下骨肉瘤(n=21)、原位骨肉瘤(n=5)以及骨肉瘤肺转移(n=15)模型。3种骨肉瘤动物模型于尾静脉注射^(68)Ga-NODAGA-RGD_2, 1 h后行^(68)Ga-NODAGA-RGD_2 microPET/CT显像;皮下骨肉瘤模型注射后10、60、120 min,取重要脏器及肿瘤组织,行^(68)Ga-NODAGA-RGD_2生物学分布研究。骨肉瘤肺转移灶模型于细胞注射后7周经尾静脉注射^(177)Lu-NODAGA-RGD_2,观察其靶向治疗骨肉瘤肺转移效果。同时,取原位骨肉瘤模型胫骨骨肉瘤组织以及骨肉瘤肺转移模型的荷瘤肺组织行组织学及免疫组织化学染色观察。结果体外稳定性实验显示,^(68)Ga-NODAGA-RGD_2体外合成后1、4、8 h,放射性化学纯度分别为98.5%±0.3%、98.3%±0.5%、97.9%±0.4%。^(177)Lu-NODAGA-RGD_2体外合成后1、7、14 d,放射性化学纯度分别为99.3%±0.7%、98.7%±1.2%、96.0%±2.8%。^(68)Ga-NODAGA-RGD_2及^(177)Lu-NODAGA-RGD_2整合素α_vβ_3受体结合实验半抑制浓度率值分别为(5.0±1.1)、(6.5±0.8) nmol/L。microPET-CT显像,皮下骨肉瘤模型及原位骨肉瘤模型均可见明显^(68)Ga-NODAGA-RGD_2浓聚;骨肉瘤肺转移模型在转移灶1～2mm时即可见^(68)Ga-NODAGA-RGD_2浓聚。生物学分布实验显示,皮下骨肉瘤模型中^(68)Ga-NODAGA-RGD_2血液中清除迅速,肌肉、正常骨骼摄取极少,注入120 min时达峰值,为(3.85±0.84)%ID/g。骨肉瘤肺转移灶模型注射^(177)Lu-NODAGA-RGD_2后显示其在肺转移灶浓聚,第2周病灶数量和大小明显降低。组织学及免疫组织化学染色结果显示肿瘤形成及其整合素受体靶向性。结论^(68)Ga-NODAGObjective To investigate the value of integrin αvβ3 targeted microPET/CT imaging with 68GaNODAGA-RGD2 as radiotracer for the detection of osteosarcoma and theranostics of osteosarcoma lung metastasis.Methods The 68Ga-NODAGA-RGD2 and 177Lu-NODAGA-RGD2 were prepared via one-step method and their stability and integrin αvβ3 binding specificity were investigated in vitro. Forty-one nude mice were injected with human MG63 osteosarcoma to established the animal model bearing subcutaneous osteosarcoma(n=21), osteosarcoma in tibia(n=5), and osteosarcoma pulmonary metastatic(n=15). The microPET-CT imaging was carried out in 3 animal models at1 hour after tail vein injection of 68Ga-NODAGA-RGD2. Biodistribution study of 68 Ga-NODAGA-RGD2 was performed in animal model bearing subcutaneous osteosarcoma at 10, 60, and 120 minutes. The animal model bearing pulmonary metastatic osteosarcoma was injected with 177Lu-NODAGA-RGD2 at 7 weeks after model establishment to observe the therapeutic effect of pulmonary metastatic osteosarcoma. Histological and immunohistochemistry examinations were also done to confirm the establishment of animal model and integrin β3 expression in animal models bearing subcutaneous osteosarcoma and bearing pulmonary metastatic osteosarcoma. Results 68Ga-NODAGA-RGD2 and 177Lu-NODAGARGD2 had good stability in vitro with the 50% inhibitory concentration value of(5.0±1.1) and(6.5±0.8) nmol/L,respectively. The radiochemical purity of 68 Ga-NODAGA-RGD2 at 1,4, and 8 hours was 98.5%±0.3%,98.3%±0.5%,and97.9%±0.4%;while the radiochemical purity of 177Lu-NODAGA-RGD2 at 1,7, and 14 days was 99.3%±0.7%,98.7%±1.2%,and 96.0%±2.8%. 68Ga-NODAGA-RGD2 microPET-CT showed that the accumulation of 68Ga-NODAGA-RGD2 in animal models bearing subcutaneous osteosarcoma and osteosarcoma in tibia and in lung metastasis as small as 1-2 mm in diameter of animal model bearing pulmonary metastatic osteosarcoma. Biodistribution study of 68 Ga-NODAGA-RGD2 in animal model bearing subcutaneous osteosarcoma revealed rapid clear

关 键 词：骨肉瘤 肺转移 整合素ΑVΒ3 靶向诊疗 

分 类 号：R738.1[医药卫生—肿瘤]