title: Preclinical evaluation of isostructural Tc-99m- and Re-188-folate-Gly-Gly-Cys-Glu for folate receptor-positive tumor targeting.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Nuclear Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, 895 Moowangro, Iksan, 54538, Republic of Korea.
authors.forename: Woo Hyoung
authors.initials: WH
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, 895 Moowangro, Iksan, 54538, Republic of Korea. leokim@wonkwang.ac.kr.
authors.forename: Chang Guhn
authors.initials: CG
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, 895 Moowangro, Iksan, 54538, Republic of Korea.
authors.forename: Myoung Hyoun
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, 895 Moowangro, Iksan, 54538, Republic of Korea.
authors.forename: Dae-Weung
authors.initials: DW
authors.lastname: Kim
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Cho Rong
authors.initials: CR
authors.lastname: Park
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Ji Yong
authors.initials: JY
authors.lastname: Park
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department 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.
authors.forename: Yun-Sang
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Republic of Korea.|Cancer Imaging Center, Seoul National University Hospital, Seoul, Republic of Korea.
authors.forename: Hyewon
authors.initials: H
authors.lastname: Youn
authors.affiliation: Department of Nuclear Medicine, Seoul National University Hospital, Seoul, Republic of Korea.|Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: Jae Min
authors.initials: JM
authors.lastname: Jeong
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.|Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.|Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Republic of Korea.|Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
authors.forename: June-Key
authors.initials: JK
authors.lastname: Chung
mesh_terms: D000818:Animals; D005240:Feasibility Studies; D005260:Female; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D005492:Folic Acid / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007624:KB Cells; D051379:Mice; D057054:Molecular Imaging / Q000379:methods*; D009842:Oligopeptides / Q000737:chemistry*; D009942:Organometallic Compounds / Q000737:chemistry*; D011854:Radiochemistry; D011868:Radioisotopes; D012211:Rhenium / Q000737:chemistry*; D013667:Technetium / Q000737:chemistry*; D014018:Tissue Distribution; D009927:Tissue and Organ Procurement
chemical_list: C000613575:188Re-folate-glycyl-glycyl-cysteinyl-glutamic acid; D058973:Folate Receptors, GPI-Anchored; D009842:Oligopeptides; D009942:Organometallic Compounds; D011868:Radioisotopes; D012211:Rhenium; D013667:Technetium; D005492:Folic Acid
keywords: Folate receptor; Re-188; SPECT/CT; Tc-99m; Tumor