Theranostics of osteosarcoma and lung metastasis with new integrin α<sub>v</sub>β<sub>3</sub> receptor targeted radiotracers_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

SUI Jisheng ^1,2 , SHAO Guoqiang ³ , ZHANG Lulu ³ , ZHANG Pengjun ³ , BU Ting ³ , YAO Qingqiang ^1,2 ,  WANG Liming ^1,2

1. Department of Orthopedics, Affiliated Nanjing Hospital (the First Hospital of Nanjing), Nanjing Medical University , Nanjing Jiangsu, 210006, P.R.China;
2. Digital Medical Institute, Nanjing Medical University, Nanjing Jiangsu, 210006, P.R.China;
3. Department of Nuclear Medicine, Affiliated Nanjing Hospital (the First Hospital of Nanjing), Nanjing Medical University , Nanjing Jiangsu, 210006, P.R.China;

Corresponding author：

WANG Liming, Email: limingwang99@yahoo.com

Keywords：

Osteosarcoma; lung metastasis; Integrin α_vβ₃; targeted endotheranostics

DOI：

10.7507/1002-1892.201808014

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the value of integrin α_vβ₃ targeted microPET/CT imaging with ⁶⁸Ga-NODAGA-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 α_vβ₃ 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-RGD₂. Biodistribution study of ⁶⁸Ga-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-NODAGA-RGD₂ 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-RGD₂ 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-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 ⁶⁸Ga-NODAGA-RGD₂ 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-RGD₂ in lung metastasis was similar with ⁶⁸Ga-NODAGA-RGD₂. The number and size of osteosarcoma metastasis decreased at 2 weeks after ¹⁷⁷Lu-NODAGA-RGD₂ administration and integrin targeting specificity was confirmed by pathology examination.Conclusion ⁶⁸Ga-NODAGA-RGD₂ was potential for positive imaging and early detection of osteosarcoma and metastasis. Targeted radiotherapy with ¹⁷⁷Lu-NODAGA-RGD₂ was one potential alternative for osteosarcoma lung metastasis.

Citation： SUI Jisheng, SHAO Guoqiang, ZHANG Lulu, ZHANG Pengjun, BU Ting, YAO Qingqiang, WANG Liming. Theranostics of osteosarcoma and lung metastasis with new integrin α_vβ₃ receptor targeted radiotracers. Chinese Journal of Reparative and Reconstructive Surgery, 2019, 33(2): 170-176. doi: 10.7507/1002-1892.201808014 Copy

1.	Xie L, Ji T, Guo W. Anti-angiogenesis target therapy for advanced osteosarcoma (Review). Oncol Rep, 2017, 38(2): 625-636.
2.	Bielack SS, Hecker-Nolting S, Blattmann C, et al. Advances in the management of osteosarcoma.(2016-11-25).[2018-01-04] https://f1000research.com/articles/5-2767/v1.
3.	Baczyk M, Czepczyński R, Milecki P, et al. 89Sr versus 153Sm-EDTMP: comparison of treatment efficacy of painful bone metastases in prostate and breast carcinoma. Nucl Med Commun, 2007, 28(4): 245-250.
4.	Tome Y, Kimura H, Sugimoto N, et al. The disintegrin echistatin in combination with doxorubicin targets high-metastatic human osteosarcoma overexpressing ανβ3 integrin in chick embryo and nude mouse models. Oncotarget, 2016, 7(52): 87031-87036.
5.	Sprague JE, Kitaura H, Zou W, et al. Noninvasive imaging of osteoclasts in parathyroid hormone-induced osteolysis using a 64culabeled rgd peptide. J Nucl Med, 2007, 48(2): 311-318.
6.	Shi J, Zhou Y, Chakraborty S, et al. Evaluation of in-labeled cyclic RGD peptides: effects of peptide and linker multiplicity on their tumor uptake, excretion kinetics and metabolic stability. Theranostics, 2011, 1: 322-340.
7.	Dijkgraaf I, Yim CB, Franssen GM, et al. PET imaging of αvβ3 integrin expression in tumours with ⁶⁸Ga-labelled mono-, di- and tetrameric RGD peptides. Eur J Nucl Med Mol Imaging, 2011, 38(1): 128-137.
8.	Auzzas L, Zanardi F, Battistini L, et al. Targeting alphavbeta3 integrin: design and applications of mono- and multifunctional RGD-based peptides and semipeptides. Curr Med Chem, 2010, 17(13): 1255-1299.
9.	Zhao ZQ, Yang Y, Fang W, et al. Comparison of biological properties of ^99mTc-labeled cyclic RGD Peptide trimer and dimer useful as SPECT radiotracers for tumor imaging. Nucl Med Biol, 2016, 43(11): 661-669.
10.	杨晓, 李思, 向尚, 等. RNA干扰降低唾液酸酶3表达对骨肉瘤MG-63细胞增殖和凋亡影响的实验研究. 中国修复重建外科杂志, 2018, 32(7): 887-892.
11.	吴凡, 方向, 郎志刚, 等. 人工全股骨置换术治疗股骨恶性肿瘤. 中国修复重建外科杂志, 2019, 33(1): 18-22.
12.	Zhao K, Yang SY, Geng J, et al. Combination of anginex gene therapy and radiation decelerates the growth and pulmonary metastasis of human osteosarcoma xenografts. Cancer Med, 2018, 7(6): 2518-2529.
13.	Zhang Y, Zvi YS, Batko B, et al. Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma. Sci Rep, 2018, 8(1): 14294.
14.	Fang Z, Sun Y, Xiao H, et al. Targeted osteosarcoma chemotherapy using RGD peptide-installed doxorubicin-loaded biodegradable polymeric micelle. Biomed Pharmacother, 2017, 85: 160-168.
15.	Chang R, Sun L, Webster TJ, et al. Selective inhibition of MG-63 osteosarcoma cell proliferation induced by curcumin-loaded self-assembled arginine-rich-RGD nanospheres. Int J Nanomedicine, 2015, 10: 3351-3365.
16.	Bhang HE, Gabrielson KL, Laterra J, et al. Tumor-specific imaging through progression elevated gene-3 promoter-driven gene expression. Nat Med, 2011, 17(1): 123-129.
17.	Shokri B, Zarghi A, Shahhoseini S, et al. Design, synthesis and biological evaluation of ketoprofen conjugated to RGD/NGR for targeted cancer therapy. Iran J Pharm Res, 2018, 17(4): 1297-1305.
18.	Cheng Y, Ji Y. RGD-modified polymer and liposome nanovehicles: Recent research progress for drug delivery in cancer therapeutics. Eur J Pharm Sci, 2018, 128: 8-17.
19.	Kumar C, Korde A, Kumari KV, et al. Cellular toxicity and apoptosis studies in osteocarcinoma cells, a comparison of 177Lu-EDTMP and Lu-EDTMP. Curr Radiopharm, 2013, 6(3): 146-151.
20.	Karimi Ghodoosi E, D’Alessandria C, Li Y, et al. The effect of attenuation map, scatter energy window width, and volume of interest on the calibration factor calculation in quantitative ¹⁷⁷Lu SPECT imaging: Simulation and phantom study. Phys Med, 2018, 56: 74-80.
21.	Hippeläinen E, Tenhunen M, Mäenpää H, et al. Quantitative accuracy of ¹⁷⁷Lu SPECT reconstruction using different compensation methods: phantom and patient studies. EJNMMI Res, 2016, 6(1): 16.

1. Xie L, Ji T, Guo W. Anti-angiogenesis target therapy for advanced osteosarcoma (Review). Oncol Rep, 2017, 38(2): 625-636.
2. Bielack SS, Hecker-Nolting S, Blattmann C, et al. Advances in the management of osteosarcoma.(2016-11-25).[2018-01-04] https://f1000research.com/articles/5-2767/v1.
3. Baczyk M, Czepczyński R, Milecki P, et al. 89Sr versus 153Sm-EDTMP: comparison of treatment efficacy of painful bone metastases in prostate and breast carcinoma. Nucl Med Commun, 2007, 28(4): 245-250.
4. Tome Y, Kimura H, Sugimoto N, et al. The disintegrin echistatin in combination with doxorubicin targets high-metastatic human osteosarcoma overexpressing ανβ3 integrin in chick embryo and nude mouse models. Oncotarget, 2016, 7(52): 87031-87036.
5. Sprague JE, Kitaura H, Zou W, et al. Noninvasive imaging of osteoclasts in parathyroid hormone-induced osteolysis using a 64culabeled rgd peptide. J Nucl Med, 2007, 48(2): 311-318.
6. Shi J, Zhou Y, Chakraborty S, et al. Evaluation of in-labeled cyclic RGD peptides: effects of peptide and linker multiplicity on their tumor uptake, excretion kinetics and metabolic stability. Theranostics, 2011, 1: 322-340.
7. Dijkgraaf I, Yim CB, Franssen GM, et al. PET imaging of αvβ3 integrin expression in tumours with ⁶⁸Ga-labelled mono-, di- and tetrameric RGD peptides. Eur J Nucl Med Mol Imaging, 2011, 38(1): 128-137.
8. Auzzas L, Zanardi F, Battistini L, et al. Targeting alphavbeta3 integrin: design and applications of mono- and multifunctional RGD-based peptides and semipeptides. Curr Med Chem, 2010, 17(13): 1255-1299.
9. Zhao ZQ, Yang Y, Fang W, et al. Comparison of biological properties of ^99mTc-labeled cyclic RGD Peptide trimer and dimer useful as SPECT radiotracers for tumor imaging. Nucl Med Biol, 2016, 43(11): 661-669.
10. 杨晓, 李思, 向尚, 等. RNA干扰降低唾液酸酶3表达对骨肉瘤MG-63细胞增殖和凋亡影响的实验研究. 中国修复重建外科杂志, 2018, 32(7): 887-892.
11. 吴凡, 方向, 郎志刚, 等. 人工全股骨置换术治疗股骨恶性肿瘤. 中国修复重建外科杂志, 2019, 33(1): 18-22.
12. Zhao K, Yang SY, Geng J, et al. Combination of anginex gene therapy and radiation decelerates the growth and pulmonary metastasis of human osteosarcoma xenografts. Cancer Med, 2018, 7(6): 2518-2529.
13. Zhang Y, Zvi YS, Batko B, et al. Down-regulation of Skp2 expression inhibits invasion and lung metastasis in osteosarcoma. Sci Rep, 2018, 8(1): 14294.
14. Fang Z, Sun Y, Xiao H, et al. Targeted osteosarcoma chemotherapy using RGD peptide-installed doxorubicin-loaded biodegradable polymeric micelle. Biomed Pharmacother, 2017, 85: 160-168.
15. Chang R, Sun L, Webster TJ, et al. Selective inhibition of MG-63 osteosarcoma cell proliferation induced by curcumin-loaded self-assembled arginine-rich-RGD nanospheres. Int J Nanomedicine, 2015, 10: 3351-3365.
16. Bhang HE, Gabrielson KL, Laterra J, et al. Tumor-specific imaging through progression elevated gene-3 promoter-driven gene expression. Nat Med, 2011, 17(1): 123-129.
17. Shokri B, Zarghi A, Shahhoseini S, et al. Design, synthesis and biological evaluation of ketoprofen conjugated to RGD/NGR for targeted cancer therapy. Iran J Pharm Res, 2018, 17(4): 1297-1305.
18. Cheng Y, Ji Y. RGD-modified polymer and liposome nanovehicles: Recent research progress for drug delivery in cancer therapeutics. Eur J Pharm Sci, 2018, 128: 8-17.
19. Kumar C, Korde A, Kumari KV, et al. Cellular toxicity and apoptosis studies in osteocarcinoma cells, a comparison of 177Lu-EDTMP and Lu-EDTMP. Curr Radiopharm, 2013, 6(3): 146-151.
20. Karimi Ghodoosi E, D’Alessandria C, Li Y, et al. The effect of attenuation map, scatter energy window width, and volume of interest on the calibration factor calculation in quantitative ¹⁷⁷Lu SPECT imaging: Simulation and phantom study. Phys Med, 2018, 56: 74-80.
21. Hippeläinen E, Tenhunen M, Mäenpää H, et al. Quantitative accuracy of ¹⁷⁷Lu SPECT reconstruction using different compensation methods: phantom and patient studies. EJNMMI Res, 2016, 6(1): 16.

Chinese Journal of Reparative and Reconstructive Surgery

Theranostics of osteosarcoma and lung metastasis with new integrin α_vβ₃ receptor targeted radiotracers

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content

Chinese Journal of Reparative and Reconstructive Surgery

Theranostics of osteosarcoma and lung metastasis with new integrin αvβ3 receptor targeted radiotracers

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content

Theranostics of osteosarcoma and lung metastasis with new integrin α_vβ₃ receptor targeted radiotracers