Controlled administration of penicillamine reduces radiation exposure in critical organs during 64Cu-ATSM internal radiotherapy: a novel strategy for liver protection.
OBJECTIVE
(64)Cu-diacetyl-bis (N (4)-methylthiosemicarbazone) ((64)Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with (64)Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during (64)Cu-ATSM IRT.


METHODS
Biodistribution was evaluated in HT-29 tumor-bearing mice injected with (64)Cu-ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between (64)Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg×3 at 1- or 2-h intervals from 1 h after (64)Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic (64)Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses.


RESULTS
Penicillamine reduced (64)Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after (64)Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic (64)Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine.


CONCLUSIONS
We developed a novel strategy to reduce radiation exposure in critical organs during (64)Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other (64)Cu-labeled compounds.
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Yukie
Y
Yoshii
Research Centre, Nihon Medi-Physics Co., Ltd., Chiba, Japan.
Hiroki
H
Matsumoto
Division of Functional Imaging, National Cancer Center Hospital East, Chiba, Japan.
Mitsuyoshi
M
Yoshimoto
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Takako
T
Furukawa
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Yukie
Y
Morokoshi
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Chizuru
C
Sogawa
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Ming-Rong
MR
Zhang
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Hidekatsu
H
Wakizaka
Emergency Radiation Exposure Medical Care Research Center, National Institute of Radiological Sciences, Chiba, Japan.
Hiroshi
H
Yoshii
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Yasuhisa
Y
Fujibayashi
Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Tsuneo
T
Saga
D000818:Animals; D003110:Colonic Neoplasms / Q000532:radiotherapy*; D056831:Coordination Complexes; D003692:Delayed-Action Preparations; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000187:drug effects*; D051379:Mice; D009942:Organometallic Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D010396:Penicillamine / Q000008:administration & dosage / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011832:Radiation Injuries / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000009:adverse effects* / Q000627:therapeutic use
D056831:Coordination Complexes; D003692:Delayed-Action Preparations; D009942:Organometallic Compounds; D011837:Radiation-Protective Agents; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D010396:Penicillamine