Tumor necrosis targeted radiotherapy of non-small cell lung cancer using radioiodinated protohypericin in a mouse model
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Xuejiao Liu1,2, Cuihua Jiang1,5, Dongjian Zhang1,5, Meng Gao1, Fei Peng1, Dejian Huang1, Ziping Sun3, Yicheng Ni1,4, Jian Zhang1, Zhiqi Yin5
1Laboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, Jiangsu Province, P.R.China
2College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, P.R.China
3Shandong Academy of Medical Sciences, Jinan 250062, Shandong, P.R.China
4Theragnostic Laboratory, Campus Gasthuisberg, KU Leuven, 3000 Leuven, Belgium
5Department of Natural Medicinal Chemistry & State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, Jiangsu Province, P.R.China
Zhiqi Yin, e-mail: [email protected]
Jian Zhang, e-mail: [email protected]
Keywords: tumor necrosis targeted radiotherapy, necrosis-avid agent, radiopharmaceutical, protohypericin, drug combination
Received: April 14, 2015 Accepted: July 10, 2015 Published: July 21, 2015
Lung cancer is the leading cause of cancer-related death. About 80% of lung cancers are non–small cell lung cancers (NSCLC). Radiotherapy is widely used in treatment of NSCLC. However, the outcome of NSCLC remains unsatisfactory. In this study, a vascular disrupting agent (VDA) combretastatin-A4-phosphate (CA4P) was used to provide massive necrosis targets. 131I labeled necrosis-avid agent protohypericin (131I-prohy) was explored for therapy of NSCLC using tumor necrosis targeted radiotherapy (TNTR). Gamma counting, autoradiography, fluorescence microscopy and histopathology were used for biodistribution analysis. Magnetic resonance imaging (MRI) was used to monitor tumor volume, ratios of necrosis and tumor doubling time (DT). The biodistribution data revealed 131I-prohy was delivered efficiently to tumors. Tracer uptake peaked at 24 h in necrotic tumor of 131I-prohy with and without combined CA4P (3.87 ± 0.38 and 2.96 ± 0.34%ID/g). 131I-prohy + CA4P enhanced the uptake of 131I-prohy in necrotic tumor compared to 131I-prohy alone. The TNTR combined with CA4P prolonged survival of tumor bearing mice relative to vehicle control group, CA4P control group and 131I-prohy control group with median survival of 35, 20, 22 and 27 days respectively. In conclusion, TNTR appeared to be effective for the treatment of NSCLC.
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