Design and Bio-evaluation of 64Cu-NOTA-Herceptin for Tumor Targeted Micro-PET Imaging†

doi:10.7503/cjcu20160593

Chem. J. Chinese Universities ›› 2016, Vol. 37 ›› Issue (12): 2132.doi: 10.7503/cjcu20160593

• Articles: Inorganic Chemistry • Previous Articles Next Articles

Design and Bio-evaluation of ⁶⁴Cu-NOTA-Herceptin for Tumor Targeted Micro-PET Imaging^†

ZHU Hua¹, LI Yilin², ZHAO Chuanke³, XIE Qinghua^1,⁴, LIU Fei¹, HAN Xuedi¹, GAO Jing², XIA Chuanqin⁴, SHEN Lin^2,^*(), YANG Zhi^1,^*()

1. Department of Nuclear Medicine, 2. Department of Gastrointestinal Oncology,3. Departments of Biochemistry and Molecular Biology, Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education), Peking University Cancer Hospital & Institute,Beijing 100142, China
4. College of Chemistry, Sichuan University, Chengdu 610041, China

Received:2016-08-22 Online:2016-12-10 Published:2016-11-22
Contact: SHEN Lin,YANG Zhi E-mail:linshenpku@163.com;pekyz@163.com
Supported by:
† Supported by the National Natural Science Foundation of China(Nos.81371592, 81401467, 81501519, 81301323, 81571705) and the Natural Science Foundation of Beijing, China(Nos.7154185, 7162041)

Abstract

Abstract:

The precursor compound 2-(p-thiocyanatobenzyl)-1,4,7-triazacyclononane-1,4,7-triacetic acid-Herceptin(NOTA-Herceptin) was synthesized by the nucleophilic addition reaction of Herceptin and bi-functional chelator NCS-Bz-NOTA. The original Herceptin and NOTA-Herceptin conjugate were investigated by UV-Vis and MALDI-TOF mass spectra. The average number of chelators per Herceptin for the conjugated used in this study was 5.4. The enzyme-linked immunosorbent assay(ELISA) was conducted to compare the biological activity of original Herceptin and NOTA-Herceptin. NOTA-Herceptin kept high immunoreactivity towards HER2 antigen. Then, the PET radio-nuclide ⁶⁴Cu(T_1/2=12.7 h) was labeled to got the novel tumor Immuno-Theranostics probe ⁶⁴Cu-NOTA-Herceptin. The labeling efficiency of ⁶⁴Cu-NOTA-Herceptin was tested by Radio-TLC/HPLC. The radiolabeling yield was over 90%, the radio chemical purity was over 98% after PD-10 column purification and the specific activity was 185 MBq/nmol. The immune reactivity and specific activity of radiolabeled Herceptin with HER2 antigen were performed by HER2 positive NCI-N87 cell line and HER2 negative BGC823 cell line. Micro-PET imaging of BGC823 tumor-bearing nude mice revealed that tumor uptake of ⁶⁴Cu-NOTA-Herceptin got a gradual accumulation from 4 h to 60 h after intravenous injection of 7.4 MBq radiolabeled Herceptin. Uptake in the tumor was clearly visualized by emission computed tomography. ⁶⁴Cu-NOTA-Herceptin owns a great potential for molecular imaging of PET for diagnosis and follow-up of HER2 expression.

Key words: Herceptin, 64Cu, Immunoreactivity, Molecular imaging, Tumor targeting therapy

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ZHU Hua, LI Yilin, ZHAO Chuanke, XIE Qinghua, LIU Fei, HAN Xuedi, GAO Jing, XIA Chuanqin, SHEN Lin, YANG Zhi. Design and Bio-evaluation of ⁶⁴Cu-NOTA-Herceptin for Tumor Targeted Micro-PET Imaging^†[J]. Chem. J. Chinese Universities, 2016, 37(12): 2132.

Figures/Tables 6

Fig.1 Modification of Herceptin antibody and radiolabeling methodology of 64Cu radionuclide

Fig.2 TMALDI-TOF mass spectrum analysis of Herceptin(A) and NOTA-Herceptin(B)

Fig.3 Biological activity of Herceptin before(a) and after(b) NOTA modification tested by ELISA

Fig.4 64Cu-NOTA-Herceptin cell uptake in HER2 negative BCG823(A) and HER2 positive NCl-N87(B)(A) Uptake time/min: a. 0; b. 5; c. 30; d. 60; (B) uptake time/min: a. 0; b. 5; c. 30; d. 60; e. 120; f.120(block group).

Fig.5 Micro-PET imaging of BGC823 tumor-bearing nude miceRed arrow indicates tumors. (A) 4 h PET imaging; (B) 60 h PET imaging.

Fig.6 Micro-PET imaging of human gastric BGC823 tumor-bearing nude mice(A) Sagittal, 4 h; (B) coronal, 4 h; (C) transverse, 4 h; (D) sagittal, 60 h; (E) coronal, 60 h; (F) transverse, 60 h.

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Design and Bio-evaluation of ⁶⁴Cu-NOTA-Herceptin for Tumor Targeted Micro-PET Imaging^†

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