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. 2019 Feb 15;33(2):170-176.
doi: 10.7507/1002-1892.201808014.

[Theranostics of osteosarcoma and lung metastasis with new integrin α vβ 3 receptor targeted radiotracers]

[Article in Chinese]
Jisheng Sui  1 , Guoqiang Shao  2 , Lulu Zhang  2 , Pengjun Zhang  2 , Ting Bu  2 , Qingqiang Yao  1 , Liming Wang  3
Affiliations

[Theranostics of osteosarcoma and lung metastasis with new integrin α vβ 3 receptor targeted radiotracers]

[Article in Chinese]
Jisheng Sui et al. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. .

Abstract
in English, Chinese

Objective: To investigate the value of integrin α vβ 3 targeted microPET/CT imaging with 68Ga-NODAGA-RGD 2 as radiotracer for the detection of osteosarcoma and theranostics of osteosarcoma lung metastasis.

Methods: The 68Ga-NODAGA-RGD 2 and 177Lu-NODAGA-RGD 2 were prepared via one-step method and their stability and integrin α vβ 3 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 at 1 hour after tail vein injection of 68Ga-NODAGA-RGD 2. Biodistribution study of 68Ga-NODAGA-RGD 2 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-RGD 2 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 β 3 expression in animal models bearing subcutaneous osteosarcoma and bearing pulmonary metastatic osteosarcoma.

Results: 68Ga-NODAGA-RGD 2 and 177Lu-NODAGA-RGD 2 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 68Ga-NODAGA-RGD 2 at 1, 4, and 8 hours was 98.5%±0.3%, 98.3%±0.5%, and 97.9%±0.4%; while the radiochemical purity of 177Lu-NODAGA-RGD 2 at 1, 7, and 14 days was 99.3%±0.7%, 98.7%±1.2%, and 96.0%±2.8%. 68Ga-NODAGA-RGD 2 microPET-CT showed that the accumulation of 68Ga-NODAGA-RGD 2 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 68Ga-NODAGA-RGD 2 in animal model bearing subcutaneous osteosarcoma revealed rapid clearance from blood with tumor peak uptake of (3.85±0.84) %ID/g at 120 minutes. The distribution of 177Lu-NODAGA-RGD 2 in lung metastasis was similar with 68Ga-NODAGA-RGD 2. The number and size of osteosarcoma metastasis decreased at 2 weeks after 177Lu-NODAGA-RGD 2 administration and integrin targeting specificity was confirmed by pathology examination.

Conclusion: 68Ga-NODAGA-RGD 2 was potential for positive imaging and early detection of osteosarcoma and metastasis. Targeted radiotherapy with 177Lu-NODAGA-RGD 2 was one potential alternative for osteosarcoma lung metastasis.

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 68Ga-NODAGA-RGD 2 和 177Lu-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 68Ga-NODAGA-RGD 2，1 h 后行 68Ga-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 68Ga-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 177Lu-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， 68Ga-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%。 177Lu-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%。 68Ga-NODAGA-RGD 2 及 177Lu-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 68Ga-NODAGA-RGD 2 浓聚；骨肉瘤肺转移模型在转移灶 1～2 mm 时即可见 68Ga-NODAGA-RGD 2 浓聚。生物学分布实验显示，皮下骨肉瘤模型中 68Ga-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 177Lu-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: 68Ga-NODAGA-RGD 2 显像可有效探测骨肉瘤及其肺转移灶，为 177Lu-NODAGA-RGD 2 用于骨肉瘤肺转移的靶向治疗提供实验依据。.

Keywords: Integrin αvβ3; Osteosarcoma; lung metastasis; targeted endotheranostics.

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Figures

图 1
图 1
Radio-HPLC results Radio-HPLC 检测
图 2
图 2
68Ga-NODAGA-RGD2 microPET-CT images 68Ga-NODAGA-RGD2 microPET-CT 显像观察
图 3
图 3
Investigation of therapeutic effect of 177Lu-NODAGA-RGD2 for animal model bearing pulmonary metastatic osteosarcoma 177Lu-NODAGA-RGD2靶向治疗前后骨肉瘤肺转移模型观察
图 4
图 4
Histological observation (HE×20) 组织学观察（HE×20）
图 5
图 5
Immunohistochemistry observation of tumor tissues from animal model bearing osteosarcoma in tibia（×100） 原位骨肉瘤模型免疫组织化学染色观察（×100）
See this image and copyright information in PMC

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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）