title: 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.
authors: Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Daniel Y
authors: DY
authors: Joh
authors: Lova
authors: L
authors: Sun
authors: Melissa
authors: M
authors: Stangl
authors: Ajlan
authors: A
authors: Al Zaki
authors: Surya
authors: S
authors: Murty
authors: Phillip P
authors: PP
authors: Santoiemma
authors: James J
authors: JJ
authors: Davis
authors: Brian C
authors: BC
authors: Baumann
authors: Michelle
authors: M
authors: Alonso-Basanta
authors: Dongha
authors: D
authors: Bhang
authors: Gary D
authors: GD
authors: Kao
authors: Andrew
authors: A
authors: Tsourkas
authors: Jay F
authors: JF
authors: Dorsey
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D006046:Gold / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000627:therapeutic use* / Q000648:ultrastructure
chemical_list: D006046:Gold
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