Boron neutron capture therapy for the treatment of prostate cancer using a boron-containing cholesteryl ester compound

Abstract

Boron neutron capture therapy (BNCT) for the treatment of prostate cancer using a boron-containing cholesteryl ester compound (BCH) was investigated. BNCT is a binary radiation therapy that relies on targeted delivery of 10B to cancer cells followed by irradiation with thermal neutrons. High-linear energy transfer (LET) α particles and 7Li nuclei released from the 10B neutron capture event result in lethal double-strand DNA breaks within a 9 μm range. Given the high density energy deposition and short range, neighboring cells without 10B remain unharmed. To evaluate the efficacy of BCH as a BNCT compound, a sample chamber within the thermal column experimental facility of the Maryland University Training Reactor (MUTR) was designed to provide a means of irradiating samples in vitro in a thermal neutron field. The thermal neutron fluence rate at 250 kW within the sample chamber is 8.7 x108 n/cm2/s with the < 3 eV neutron energy region representing 94.6% of the total neutron field. The hydrophobic BCH compound was embedded in the lipid bilayer of DPPC:cholesterol liposomes for delivery to PC-3 prostate cancer cells. Liposomes were synthesized by the thin film layer technique with high-pressure homogenization size reduction. Dynamic light scattering analysis of the liposomes yielded a mean diameter of 111.5 nm and 0.113 relative variance. Cytotoxicity of the BCH-containing liposomes was evaluated by neutral red, MTS, LDH, and colony formation assays. Boron uptake by PC-3 cells was analyzed with high-performance liquid chromatography (HPLC) and inductively coupled plasma-mass spectrometry (ICP-MS). Drug delivery conditions that minimized cytotoxic effects yielded a boron uptake of 35.2 + 4.3 μg/g cell. PC-3 cells were irradiated in the MUTR thermal column sample chamber to quantify the enhanced cell killing of the high-LET thermal neutron capture 10B reactions. PC-3 cells treated with BCH and exposed to a 9.4 x 1011 n/cm2/s thermal neutron fluence yielded a 20-25% increase in cell death compared to the untreated control.