Integrin α vβ 3 receptor targeted theragnostics of osteosarcoma and lung metastasis with ⁶⁸Ga/177Lu-RGD2

To investigate the value of integrin α vβ 3 targeted micro PET/CT imaging with 68Ga-NODAGARGD 2 as radiotracer for the detection of osteosarcoma and theranostics of osteosarcoma lung metastasis. 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. 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. 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. (author)