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内容記述 |
Introduction: High-grade gliomas (HGGs) are highly malignant brain tumors with a very poor prognosis. Due to their diffuse infiltrative features, small residual tumors remain around the resection cavity even after extensive resection, leading to local recurrence and indicating the need of a novel therapeutic approach. Our clinical PET study has demonstrated that Cu-diacetyl-bis (N4-methylthiosemicarbazone) (Cu-ATSM) highly accumulated in the HGGs generally expressing hypoxia marker HIF-1α. Herein, we investigated the feasibility and efficacy of local treatment and coupled PET monitoring with 64Cu-diacetyl-bis (N4-methylthiosemicarbazone) (64Cu-ATSM), a hypoxia-targeting radiopharmaceutical, to develop theranostic approaches for the local control of HGGs.Methods: The maximum tolerated dose (MTD) of 64Cu-ATSM after localadministration was determined in mice using biodistribution, dosimetry, and toxicity studies. Multiple HGG patient-derived xenograft (PDX) models recapitulating patient tumor characteristics were used for imaging and treatment studies. Imaging with PET/CT and MRI and autoradiography analyses were conducted to examine the distribution of 64Cu-ATSM after local administration. The efficacy and cytotoxic effect of 64Cu-ATSM local treatment were then investigated.Results: The MTD of 64Cu-ATSM local treatment in mice was 3.7 MBq. After the local treatment with MTD,Imaging and autoradiography analyses demonstrated high tumor penetration, distribution, and retention of64Cu-ATSM within HGG PDX tumors, with highly expressed hypoxic markers of HIF-1α and BNIP3. A single 64Cu-ATSM local treatment significantly prolonged overall survival as well as potently induced DNA double-strand breaks and apoptosis in tumors.Conclusions: Local treatment and PET monitoring with 64Cu-ATSM may be a novel theranostic approach for treating HGGs. |
