Author:
Zhao Fangshi,Wang Xiaoyi,Zhu Wei,Zhao Dongju,Ye Caihua,Guo Yanyan,Dou Yan
Abstract
Abstract
Background
Hypoxia-mediated radioresistance is the main obstacle to the successful treatment of glioblastoma (GBM). Enhancing hypoxic radiosensitivity and alleviating tumor hypoxia are both effective means to improve therapeutic efficacy, and the combination of the two is highly desirable and meaningful.
Results
Herein, we construct a low-dose pleiotropic radiosensitive nanoformulation consisting of a high-Z atomic nanocrystal core and mesoporous silica shell, surface-modified with angiopep-2 (ANG) peptide and loaded with nitric oxide (NO) donor and hypoxia-activated prodrug (AQ4N). Benefiting from ANG-mediated transcytosis, this nanoformulation can efficiently cross the BBB and accumulate preferentially in the brain. Low-dose radiation triggers this nanoformulation to exert a three-pronged synergistic therapeutic effect through high-Z-atom-dependent dose deposition enhancement, NO-mediated hypoxia relief, and AQ4N-induced hypoxia-selective killing, thereby significantly inhibiting GBM in situ growth while prolonging survival and maintaining stable body weight in the glioma-bearing mice. Meanwhile, the proposed in vivo 9.4 T BOLD/DWI can realize real-time dynamic assessment of local oxygen supply and radiosensitivity to monitor the therapeutic response of GBM.
Conclusions
This work provides a promising alternative for hypoxia-specific GBM-targeted comprehensive therapy, noninvasive monitoring, and precise prognosis.
Graphical Abstract
Funder
The Second Hospital of Tianjin Medical University Youth Research Fund Project
Natural Science Foundation of Tianjin City
National Natural Science Foundation of China
Publisher
Springer Science and Business Media LLC
Subject
Physical and Theoretical Chemistry,Pharmaceutical Science,Oncology,Biomedical Engineering
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