Local therapy with hypoxia-targeting radiopharmaceutical [⁶⁴Cu]Cu-ATSM in high-grade glioma patient-derived xenograft models.

Abstract

World Health Organization (WHO)-defined central nervous system (CNS) grade 4 high-grade gliomas (HGGs) are aggressive brain tumors marked by hypoxia and diffuse infiltration, which leaves residual tumor cells after surgery and drives inevitable local recurrence. Here, we propose a novel local therapeutic approach with ⁶⁴Cu-diacetyl-bis(N4-methylthiosemicarbazone) ([⁶⁴Cu]Cu-ATSM), a hypoxia-targeting radiopharmaceutical, using HGG-patient-derived xenograft (PDX) models. The maximum tolerated dose (MTD) of local injection of [⁶⁴Cu]Cu-ATSM into the tumor was determined in mice via biodistribution, dosimetry, and toxicity analyses. Intratumoral distribution was evaluated using PET/CT and MRI in multiple HGG-PDX models recapitulating human tumor characteristics.Therapeutic efficacy was assessed by survival analysis, along with evaluation of DNA damage and apoptosis. The MTD of [⁶⁴Cu]Cu-ATSM local injection was established at 3.7 MBq. PET/CT demonstrated rapid intratumoral penetration, widespread distribution, and prolonged retention of [⁶⁴Cu]Cu-ATSM in HGG-PDX tumors. Local treatment significantly extended survival and induced pronounced DNA double-strand breaks and apoptosis within tumors. Local injection of [⁶⁴Cu]Cu-ATSM into the tumor is a novel therapeutic strategy for HGG-PDX models, which combines hypoxia-targeted radiotherapy with PET-based treatment monitoring to address residual tumor cells and improve therapeutic outcomes.