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 <super>10</super>B to cancer cells followed by irradiation with thermal neutrons. High-linear energy transfer (LET) &alpha; particles and <super>7</super>Li nuclei released from the <super>10</super>B neutron capture event result in lethal double-strand DNA breaks within a 9 &mu;m range. Given the high density energy deposition and short range, neighboring cells without <super>10</super>B 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 <italic>in vitro</italic> in a thermal neutron field. The thermal neutron fluence rate at 250 kW within the sample chamber is 8.7 x10<super>8</super> n/cm<super>2</super>/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 &mu;g/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 <super>10</super>B reactions. PC-3 cells treated with BCH and exposed to a 9.4 x 10<super>11</super> n/cm<super>2</super>/s thermal neutron fluence yielded a 20-25% increase in cell death compared to the untreated control.