Introduction

After decades of intensive research, high-grade gliomas, and specifically glioblastoma multiforme (GBM), are still extremely resistant to all current forms of therapy including surgery, chemotherapy, radiotherapy, immunotherapy and gene therapy.1-5 The five-year survival rate of patients diagnosed with GBM in the United States is less than a few percent6,7 despite aggressive treatment using combinations of therapeutic modalities. This is due to the infiltration of malignant cells beyond the margins of resection and their spread into both gray and white matter by the time of surgical resection.8,9 High-grade gliomas are histologically complex and heterogeneous in their cellular composition. Recent molecular genetic studies of gliomas have shown how complex the development of these tumors is.10 Glioma cells and their neoplastic precursors have biologic properties that allow them to evade a tumor associated host immune response,11 and biochemical properties that allow them to invade the unique extracellular environment of the brain.12,13 Consequently, high-grade supratentorial gliomas must be regarded as a whole-brain disease.14 The inability of chemo- and radiotherapy to cure patients with high-grade gliomas is due to their failure to eradicate micro-invasive tumor cells within the brain. To successfully treat these tumors, strategies must be developed that can selectively target malignant cells with little or no effect on normal cells and tissues adjacent to the tumor. Boron neutron capture therapy (BNCT) is based on the nuclear capture and fission reactions that occur when non radioactive boron-10 is irradiated with low-energy thermal neutrons to yield high-linear-energy-transfer (LET) alpha particles (4He) and recoiling lithium-7 (7Li) nuclei. For BNCT to be successful, a sufficient number of 10B atoms (approximately 109 atoms/cell) must be delivered selectively to the tumor and enough thermal neutrons must be absorbed by them to sustain a lethal 10B(n,a) 7Li-capture reaction. The destructive effects of these high-energy particles are limited to boron-containing cells. BNCT primarily has been used to treat high-grade gliomas,15,16 and either cutaneous primaries17 or cerebral metastases of melanoma.18 More recently, it also has been used to treat patients with head-

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and-neck19,20 and metastatic liver cancer.21,22 BNCT is a biologically rather than physically targeted type of radiation treatment. If sufficient amounts of 10B and thermal neutrons can be delivered to the target volume, the potential exists to destroy tumor cells dispersed in the normal tissue parenchyma. Readers interested in more in depth coverage of other topics related to

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BNCT are referred to several recent reviews and monographs. , This review will focus on boron-containing macromolecules and nanovehicles as boron delivery agents.

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