Low-dose pleiotropic radiosensitive nanoformulations for three-pronged radiochemotherapy of hypoxic brain glioblastoma under BOLD/DWI monitoring

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

An Overview of Nanotherapeutic Drug Delivery Options for the Management of Glioblastoma

“…These nanoparticles contained NaGdF 4 :Eu 3+ nanocrystals and banoxantrone, a selectively hypoxic chemotherapy pro-drug. In orthotopic U87MG glioma-bearing mice, treatment with the nanoparticles along with low-dose radiotherapy reduced tumor burden and prolonged the median survival to 46 days compared to 23 days in mice given low-dose radiotherapy alone [121]. This preclinical trial provides a novel and promising approach in overcoming the hypoxic hurdle that often reduces the radiotherapeutic efficacy seen in gliomas.…”