Purpose: Radiation therapy (RT) is a critical component of glioblastoma multiforme (GBM) treatment.1 However, hypoxic tumor microenvironment (TME)-mediated radiation resistance has contributed to poor treatment responses and outcome, as well as frequent recurrence of GBM.1,2 Currently, ineffective delivery radiation sensitizers into GBM tumor masses for hypoxic TME modulation is a major challenge because of their poor blood-brain barrier (BBB) penetration capabilities. To overcome such obstacle, we have developed a novel BBB-penetrating MnO2 nanoparticle (MDNP) with multifunctional MRI/RT enhancement capabilities via reaction with tumoral ROS (H2O2) and localized O2/Mn2+ generation.3–8This work focuses on studying the effects of terpolymer-functionalized MDNP (T-MDNP) on GBM targeting, TME modulation, and radiation enhancement. Methods: T-MDNP was prepared by loading MnO2 in a polymer-lipid matrix. Physicochemical properties of NPs were determined by transmission electron microscopy, dynamic laser light scattering, and ζ-potential measurements. In vitro cellular uptake of the nanoparticles was examined via confocal microscopy, and biocompatibility was evaluated both in vitro and in vivo. Tissue clearance of Mn content was evaluated using MRI and inductively-coupled plasma-atomic emission spectroscopy (ICP-AES). The radiation sensitization effect of T-MDNP was determined in vitro in human U87MG GBM cells under hypoxia and normoxia conditions via clonogenic assay. The in vivo RT enhancement by intravenously injected T-MDNP was assessed in an orthotopic GBM model. Results: T-MDNP was 130±10 nm in diameter and exhibited excellent long-term storage stability at 4°C, and high biocompatibility in vitro and in vivo. Combined T-MDNP+RT treatment significantly increased in vitro radiation sensitivity of U87MG cells under hypoxia and inhibited in vivo tumor progression by 2-folds and prolonged median survival by 2.3-folds when comparison to RT-only group in U87MG GBM-bearing mice. Conclusion: Our work demonstrated the pharmaceutically safe T-MDNP formulation improved RT efficacy in GBM via active BBB penetration and O2 generation. The data suggest that T-MDNP is a promising radiation sensitizer for enhancing radiation therapy of GBM. References: 1. Gzell, C., Back, M., Wheeler, H., Bailey, D. & Foote, M. Radiotherapy in Glioblastoma: the Past, the Present and the Future. Clin. Oncol. 29, 15–25 (2017). 2. Bar, E. E. Glioblastoma, cancer stem cells and hypoxia. Brain Pathology (2011) doi:10.1111/j.1750-3639.2010.00460.x. 3. Zhang, T. et al. Multitargeted Nanoparticles Deliver Synergistic Drugs across the Blood-Brain Barrier to Brain Metastases of Triple Negative Breast Cancer Cells and Tumor-Associated Macrophages. Adv. Healthc. Mater. (2019) doi:10.1002/adhm.201900543. 4. Prasad, P. et al. Multifunctional albumin-MnO2 nanoparticles modulate solid tumor microenvironment by attenuating hypoxia, acidosis, vascular endothelial growth factor and enhance radiation response. ACS Nano (2014) doi:10.1021/nn405773r. 5. He, C. et al. Multifunctional bioreactive-nanoconstructs for sensitive and accurate MRI of cerebrospinal fluid pathology and intervention of Alzheimer’s disease. Nano Today (2020) doi:10.1016/j.nantod.2020.100965. 6. Yen, C. et al. Abstract PO-100: Theragnostic tumor-targeted manganese dioxide-loaded polymer-lipid nanoparticles for magnetic resonance image-guided radiation therapy. Clin. Cancer Res. 27, PO-100 (2021). 7. Lip, H. et al. Redox-responsive nanoparticles enhance radiation therapy by altering multifaceted radio-resistance mechanisms in human castration-resistant prostate cancer cells and xenografts. Radiother. Oncol. 0, (2022). 8. He, C. et al. Two-Step Targeted Hybrid Nanoconstructs Increase Brain Penetration and Efficacy of the Therapeutic Antibody Trastuzumab against Brain Metastasis of HER2-Positive Breast Cancer. Adv. Funct. Mater. (2018) doi:10.1002/adfm.201705668.
Acknowledgments: CIHR Project Grant (PJT-162301), NSERC Equipment grant (EQPEQ 440689-13) and Killam Research Fellowship (702 -18-0051) to XYW, OGS and Departmental Scholarship to TYY.
