분자영상 및 방사화학

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  • [Mol Pharm .] Preclinical Evaluation of a Companion Diagnostic Radiopharmaceutical, [18F]PSMA-1007, in a Subcutaneous Prostate Cancer Xenograft Mouse Model
    피하 전립선암 이종이식 마우스 모델에서 [18F]PSMA-1007 의 전임상 평가

    연세의대, 서울의대 / 김수빈, 윤미진*, 박현수*, 김상은*

  • 출처
    Mol Pharm .
  • 등재일
    2023 Feb 6
  • 저널이슈번호
    20(2):1050-1060. doi: 10.1021/acs.molpharmaceut.2c00788.
  • 내용

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    Abstract
    Several radiolabeled prostate-specific membrane antigen (PSMA)-targeted agents have been developed for detecting prostate cancer, using positron emission tomography imaging and targeted radionuclide therapy. Among them, [18F]PSMA-1007 has several advantages, including a comparatively long half-life, delayed renal excretion, and compatible structure with α-/β-particle emitter-labeled therapeutics. This study aimed to characterize the preclinical pharmacokinetics and internal radiation dosimetry of [18F]PSMA-1007, as well as its repeatability and specificity for target binding using prostate tumor-bearing mice. In PSMA-positive tumor-bearing mice, the kidney showed the greatest accumulation of [18F]PSMA-1007. The distribution in the tumor attained its peak concentration of 2.8%ID/g at 112 min after intravenous injection. The absorbed doses in the tumor and salivary glands were 0.079 ± 0.010 Gy/MBq and 0.036 ± 0.006 Gy/MBq, respectively. The variance of the net influx (Ki) of [18F]PSMA-1007 to the tumor was minimal between scans performed in the same animals (within-subject coefficient of variation = 7.57%). [18F]PSMA-1007 uptake in the tumor was specifically decreased by 32% in Ki after treatment with a PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (2-PMPA). In the present study, we investigated the in vivo preclinical characteristics of [18F]PSMA-1007. Our data from [18F]PSMA-1007 PET/computed tomography (CT) studies in a subcutaneous prostate cancer xenograft mouse model supports clinical therapeutic strategies that use paired therapeutic radiopharmaceuticals (such as [177Lu]Lu-PSMA-617), especially strategies with a quantitative radiation dose estimate for target lesions while minimizing radiation-induced toxicity to off-target tissues.

     

     

     

    Affiliations

    Su Bin Kim 1 2, In Ho Song 2, Seon Yoo Kim 3, Hae Young Ko 3, Hee Seup Kil 4, Dae Yoon Chi 4, Frederik L Giesel 5, Klaus Kopka 6 7 8 9, Alexander Hoepping 10, Joong-Hyun Chun 3, Hyun Soo Park 2 11, Mijin Yun 3, Sang Eun Kim 2 11 12 13
    1Department of Applied Bioengineering, Graduate School of Convergence Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul08826, Korea.
    2Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam13620, Korea.
    3Department of Nuclear Medicine, Severance Hospital, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul03722, Korea.
    4Research Institute of Radiopharmaceuticals, FutureChem Co. Ltd, Seoul04793, Korea.
    5Department of Nuclear Medicine, Heinreich-Heine-University, University Hospital Duesseldorf, Duesseldorf40225, Germany.
    6Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR) e.v., Bautzner Landstrasse 400, Dresden01328, Germany.
    7Technische Universität Dresden, Faculty of Chemistry and Food Chemistry, School of Science, Dresden01069, Germany.
    8National Center for Tumor Diseases (NCT) Dresden, University Hospital Carl Gustav Carus, Fetscherstraße 74, Dresden01307, Germany.
    9German Cancer Consortium (DKTK), Partner Site Dresden, Dresden01307, Germany.
    10Department of Medicinal Chemistry, ABX Advanced Biochemical Compounds GmbH, Radeberg1454, Germany.
    11Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul08826, Korea.
    12Advanced Institutes of Convergence Technology, 145 Gwanggyo-ro, Yeongtong-gu, Suwon16229, Korea.
    13BIK Therapeutics Inc., 172 Dolma-ro, Bundang-gu, Seongnam13605, Korea.

  • 키워드
    [18F]PSMA-1007; biodistribution; internal radiation dosimetry; positron emission tomography; theranostics.
  • 연구소개
    본 연구에서는, [18F]PSMA-1007의 임상적 유용성을 결정하기 위한 전임상평가의 가치를 입증했습니다. 전립선암 이종 이식 마우스 모델 (xenograft mouse model)을 이용하여 [18F]PSMA-1007 의 전임상 약동학 및 체내 흡수선량을 평가하고, 전립선막특이항원 (PSMA) 결합 특성을 반복성(repeatability)과 특이성(specificitiy)으로 설명한 논문입니다. GATE Monte Carlo 시뮬레이션을 이용하여 평가가 어려웠던 장기인 종양과 침샘에서, 기존의 장기 수준 흡수선량평가 방식에서 나아가 개체별 특성을 고려하여 복셀 수준 (voxel-level) 흡수선량을 평가했습니다. 또한, Irreversible Two tissue Compartment model (2TCM)을 이용하여 종양에서 PSMA 억제제 (2-(phosphonomethyl)-pentanedioic acid) 투여 전과 후에 [18F]PSMA-1007의 net influx (Ki)를 비교해 논의했습니다. 본 연구의 방법과 결과는 알파 또는 베타 입자를 이용한 짝(paired) 치료용 방사성의약품의 치료 전략을 수립하고, 개인별 분자영상 (PET/CT)를 이용한 개인별 투여 용량 (personalized dosimetry)을 설정하기 위한 기초 자료로 확대될 수 있을 거라 기대됩니다.
  • 편집위원

    전립선암 연구에서 prostate-specific membrane antigen (PSMA) 표적을 위한 방사성의약품의 개발은 다양하게 진행되어왔다. 주로 반감기가 68분으로 상대적으로 짧은 Ga-68을 이용한 연구들인데, 본 논문은 이 보다 더 긴 반감기를 갖기에 용이한 F-18을 표지한 PSMA 표적 의약품 [18F]PSMA-1007의 개발 및 종양 동물 모델에서의 PK, dosimetry 등 유효성 평가에 대한 연구를 다루고 있다.

    2023-03-07 09:41:39

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