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그림 A. KB 종양 마우스 모델에서의 Tc-99m-folate-GGCE 정맥 내 주사 micro-SPECT/CT 영상

그림 B. KB 종양 마우스 모델에서의 Re-188-folate-GGCE 복강 내 주사 micro-SPECT/CT 영상

Abstract

OBJECTIVE:

The purpose of the present study was to prepare isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu (folate-GGCE), and to evaluate the feasibility of their use for folate receptor (FR)-targeted molecular imaging and as theranostic agents in a mouse tumor model.

METHODS:

Folate-GGCE was synthesized using solid-phase peptide synthesis and radiolabeled with Tc-99m or Re-188. Radiochemical characterization was performed by radio-high-performance liquid chromatography. The biodistribution of Tc-99m-folate-GGCE was studied, with or without co-injection of excess free folate, in mice bearing both FR-positive (KB cell) and FR-negative (HT1080 cell) tumors. Biodistribution of Re-188-folate-GGCE was studied in mice bearing KB tumors. Serial planar scintigraphy was performed in the dual tumor mouse model after intravenous injection of Tc-99m-folate-GGCE. Serial micro-single photon emission computed tomography/computed tomography (SPECT/CT) studies were performed, with or without co-injection of excess free folate, in the mouse tumor model after injection of Tc-99m-folate-GGCE or Re-188-folate-GGCE.

RESULTS:

The radiolabeling efficiency and radiochemical stability of Tc-99m- and Re-188-folate-GGCE were more than 95 % for up to 4 h after radiolabeling. Uptake of Tc-99m-folate-GGCE at 1, 2, and 4 h after injection in KB tumor was 16.4, 23.2, and 17.6 % injected dose per gram (%ID/g), respectively. This uptake was suppressed by 97.4 % when excess free folate was co-administered. Tumor:normal organ ratios at 4 h for blood, liver, lung, muscle, and kidney were 54.3, 25.2, 38.3, 97.8, and 0.3, respectively. Tumor uptake of Re-188-folate-GGCE at 2, 4, 8, and 16 h after injection was 17.4, 21.7, 24.1, and 15.6 %ID/g, respectively. Tumor:normal organ ratios at 8 h for blood, liver, lung, muscle, and kidney were 126.8, 21.9, 54.8, 80.3, and 0.4, respectively. KB tumors were clearly visualized at a high intensity using serial scintigraphy and micro-SPECT/CT in mice injected with Tc-99m- or Re-188-folate-GGCE. The tumor uptake of these molecules was completely suppressed when excess free folate was co-administered.

CONCLUSION:

Isostructural Tc-99m- and Re-188-folate-GGCE showed high and FR-specific uptake by tumors and generally favorable tumor:normal organ ratios. The tumor targeting capabilities of Tc-99m- and Re-188-folate-GGCE were clearly evident on serial imaging studies. This isostructural pair may have potential diagnostic and theranostic applications for FR-positive tumors.

Author information

Kim WH1,2, Kim CG3, Kim MH2, Kim DW2, Park CR4, Park JY4, Lee YS4,5, Youn H4,6,7,8, Kang KW1,4,6,9, Jeong JM4, Chung JK4,6,7,9.

1Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea.

2Department of Nuclear Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, 895 Moowangro, Iksan, 54538, Republic of Korea.

3Department of Nuclear Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, 895 Moowangro, Iksan, 54538, Republic of Korea. leokim@wonkwang.ac.kr.

4Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.

5Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, and College of Medicine or College of Pharmacy, Seoul National University, Seoul, Republic of Korea.

6Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.

7Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Republic of Korea.

8Cancer Imaging Center, Seoul National University Hospital, Seoul, Republic of Korea.

9Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.