Selective Targeting of Brain Tumors with Gold Nanoparticle-Induced Radiosensitization

Abstract

Successful treatment of brain tumors such as glioblastoma multiforme (GBM) is limited in large part by the cumulative dose of Radiation Therapy (RT) that can be safely given and the blood-brain barrier (BBB), which limits the delivery of systemic anticancer agents into tumor tissue. Consequently, the overall prognosis remains grim. Herein, we report our pilot studies in cell culture experiments and in an animal model of GBM in which RT is complemented by PEGylated-gold nanoparticles (GNPs). GNPs significantly increased cellular DNA damage inflicted by ionizing radiation in human GBM-derived cell lines and resulted in reduced clonogenic survival (with dose-enhancement ratio of ∼1.3). Intriguingly, combined GNP and RT also resulted in markedly increased DNA damage to brain blood vessels. Follow-up in vitro experiments confirmed that the combination of GNP and RT resulted in considerably increased DNA damage in brain-derived endothelial cells. Finally, the combination of GNP and RT increased survival of mice with orthotopic GBM tumors. Prior treatment of mice with brain tumors resulted in increased extravasation and in-tumor deposition of GNP, suggesting that RT-induced BBB disruption can be leveraged to improve the tumor-tissue targeting of GNP and thus further optimize the radiosensitization of brain tumors by GNP. These exciting results together suggest that GNP may be usefully integrated into the RT treatment of brain tumors, with potential benefits resulting from increased tumor cell radiosensitization to preferential targeting of tumor-associated vasculature.

Enhancement of Tumor Regression by Coulomb Nanoradiator Effect in Proton Treatment of Iron-Oxide Nanoparticle-Loaded Orthotopic Rat Glioma Model: Implication of Novel Particle Induced Radiation Therapy

“…Thus intravenous injection of 300 mg/kg would be too much for clinical practice in human. In this regard, targeted NP with BBB-crossing and radiation-enhanced BBB disruption [14] may further increase tumoral uptake of NP even in the tumor infiltration of malignant glioma where it often occurs at intact-BBB normal tissue. This advance in nanotechnology combined with energy-delivery by high-energy ion beam may enable tumor control of malignant glioma without side effects.…”

Targeting integrins with RGD-conjugated gold nanoparticles in radiotherapy decreases the invasive activity of breast cancer cells

“…The percentage of cells with high γ-H2AX foci (.8 per nucleus) increased in the TiONts and IR group compared to IR alone in SNB-19 human glioma cell line. Joh et al 51 used PEGylated AuNPs to treat the human U251 glioblastoma cell line with 4 Gy IR. A custom macro in ImageJ software was used to quantify γ-H2AX density.…”

Low-cost, rapidly-developed, 3D printed in vitro corpus callosum model for mucopolysaccharidosis type I

“…This 3D modeling platform can potentially offer a more realistic and more standard geometry for monitoring drug release. Additionally, many therapeutic approaches to treat brain cancer and other diseases rely on injecting or implanting material that maintains a high interfacial concentration to improve drug bioavailability and efficacy, such as gold nanoparticle radiosensitizers for radiotherapy 14,15 . The drug depot material can be tested in vitro on this platform to determine the proper interfacial concentration given to-scale surface area of the tissue, and monitor the duration to which this concentration can be maintained.…”