Jiajia Liang1,2,3, Qi Luo1,2,3, Dongjian Zhang1,3, Qiaomei Jin1,3, Lichao Liu1,2,3, Wei Liu4, Meng Gao1,3, Jian Zhang5,6, Zhiqi Yin7. 1. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu Province, People's Republic of China. 2. Department of TCMs Pharmaceuticals & State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No.24, Tongjiaxiang, Gulou District, Nanjing, 210009, Jiangsu Province, People's Republic of China. 3. Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No.100, Shizi Street, Hongshan Road, Qixia District, Nanjing, 210028, Jiangsu Province, People's Republic of China. 4. Department of Nuclear Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu Province, People's Republic of China. 5. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu Province, People's Republic of China. zjwonderful@hotmail.com. 6. Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, No.100, Shizi Street, Hongshan Road, Qixia District, Nanjing, 210028, Jiangsu Province, People's Republic of China. zjwonderful@hotmail.com. 7. Department of TCMs Pharmaceuticals & State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No.24, Tongjiaxiang, Gulou District, Nanjing, 210009, Jiangsu Province, People's Republic of China. cpu-yzq@cpu.edu.cn.
Abstract
PURPOSE: Noninvasive imaging of treatment-induced necrosis is important to distinguish early responders from patients resistant to the treatment plan, enabling the tailored-made therapeutic intervention. The purpose of this study was to explore the feasibility of [99mTc]EDDA-HYNIC-2C-rhein for early assessment of tumor response to treatment. PROCEDURES: In vitro necrosis avidity of [99mTc]EDDA-HYNIC-2C-rhein was evaluated in human lung cancer A549 cells treated with hyperthermia. Single photon emission-computed tomography/X-ray-computed tomography (SPECT/CT) imaging was performed in rats bearing subcutaneous W256 tumor treated with combretastatin A-4 disodium phosphate (CA4P) and rats bearing orthotopic liver W256 tumor treated with a single microwave ablation. All rats were euthanized immediately after the imaging session for biodistribution and histology studies. The mechanism of necrosis avidity for the tracer was further explored by in vivo blocking experiment and in vitro histochemistry and fluorescence staining. RESULTS: The uptake of [99mTc]EDDA-HYNIC-2C-rhein in necrotic cells was significantly higher than that in viable cells (p < 0.05). SPECT/CT imaging showed that an obvious "hot spot" was observed in the CA4P-treated tumor while not in the control tumor at 5 h after tracer injection. Ex vivo γ-counting revealed that the uptake of [99mTc]EDDA-HYNIC-2C-rhein in tumor was increased 3.5-fold in rats treated with CA4P compared with rats treated with vehicle. Autoradiography and corresponding H&E staining suggested that the higher overall radiotracer uptake in the treated tumors was attributed to the increased necrosis. Blocking with unlabeled HYNIC-2C-rhein demonstrated the specific binding of the radiotracer to necrotic tissues. The perfect match of autoradiograph and histochemistry staining and PI fluorescence staining revealed that necrosis avidity of the tracer may be attributable to intercalation with exposed DNA in necrotic tissues. CONCLUSION: [99mTc]EDDA-HYNIC-2C-rhein can image necrosis induced by anticancer therapy and holds potential for early assessment of treatment response.
PURPOSE: Noninvasive imaging of treatment-induced necrosis is important to distinguish early responders from patients resistant to the treatment plan, enabling the tailored-made therapeutic intervention. The purpose of this study was to explore the feasibility of [99mTc]EDDA-HYNIC-2C-rhein for early assessment of tumor response to treatment. PROCEDURES: In vitro necrosis avidity of [99mTc]EDDA-HYNIC-2C-rhein was evaluated in humanlung cancerA549 cells treated with hyperthermia. Single photon emission-computed tomography/X-ray-computed tomography (SPECT/CT) imaging was performed in rats bearing subcutaneous W256tumor treated with combretastatin A-4 disodium phosphate (CA4P) and rats bearing orthotopic liver W256 tumor treated with a single microwave ablation. All rats were euthanized immediately after the imaging session for biodistribution and histology studies. The mechanism of necrosis avidity for the tracer was further explored by in vivo blocking experiment and in vitro histochemistry and fluorescence staining. RESULTS: The uptake of [99mTc]EDDA-HYNIC-2C-rhein in necrotic cells was significantly higher than that in viable cells (p < 0.05). SPECT/CT imaging showed that an obvious "hot spot" was observed in the CA4P-treated tumor while not in the control tumor at 5 h after tracer injection. Ex vivo γ-counting revealed that the uptake of [99mTc]EDDA-HYNIC-2C-rhein in tumor was increased 3.5-fold in rats treated with CA4P compared with rats treated with vehicle. Autoradiography and corresponding H&E staining suggested that the higher overall radiotracer uptake in the treated tumors was attributed to the increased necrosis. Blocking with unlabeled HYNIC-2C-rhein demonstrated the specific binding of the radiotracer to necrotic tissues. The perfect match of autoradiograph and histochemistry staining and PI fluorescence staining revealed that necrosis avidity of the tracer may be attributable to intercalation with exposed DNA in necrotic tissues. CONCLUSION: [99mTc]EDDA-HYNIC-2C-rhein can image necrosis induced by anticancer therapy and holds potential for early assessment of treatment response.
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