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.
Highlights
Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain malignancy and carries a dismal prognosis
UV-vis spectroscopy showed that the nanoparticles exhibited strong absorption peaks at,522 nm resulting from their characteristic surface plasmon resonance
gold nanoparticles (GNPs)-incubated cells treated with radiation therapy (RT) displayed an increased density of ch2ax foci compared to cells receiving irradiation alone (p,0.01)
Summary
Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain malignancy and carries a dismal prognosis. Large and advanced brain tumors exhibit especially disrupted BBB integrity This is due to loss of occludin [4] and extensive abnormal angiogenesis, which induces structural and functional alterations including increased endothelial permeability [6]. Tumor blood vessel walls often exhibit loss of integrity due to endothelial cell irregularity [7]; while this disruption may enable metastasis via tumor cell migration into vasculature, it may allow for increased extravasation of blood-borne agents into tumor tissue Such behavior is known as the enhanced permeability and retention (EPR) effect, attributed to the abnormal anatomy and physiology of tumors (i.e leaky vasculature, endothelial fenestrations, poor lymphatic drainage) [8]. Patchy variations in BBB permeability throughout a tumor can result in inconsistent and unpredictable dissemination of circulating drugs or radiosensitizers [11]
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