P13.09ADVANCES IN CLINICAL APPLICATION OF BORON NEUTRON CAPTURE THERAPY (BNCT) IN GLIOBLASTOMA

摘要

BNCT is a biologically targeted form of enhanced cellular radiotherapy where preferential accumulation of boron in the cancerous as opposed to adjacent normal cells is able to interact with incident neutrons to cause irreversible alpha particle DNA damage. The key to the implementation of this potentially powerful and selective therapy is the delivery of at least 30ppm ¹⁰B within the tumour tissue while minimising superfluous ¹⁰B in healthy tissue. It is thus an elegant technique for treating infiltrating tumours such as diffuse gliomas. In order to assess its clinical potential we carried out a pharmacokinetic study in glioblastoma patients where we sought to determine the optimal route of delivering a new formulation of the boronated drug (p-boronophenylalanine, BPA), its pharmacokinetic behaviour, toxicity profile, and cellular uptake. Using a number of analytical techniques, including inductively-coupled plasma mass spectrometry, secondary ion mass spectrometry (SIMS) and immunohistochemistry (IHC), boron was measured at various times in blood, urine, cerebrospinal fluid, extracellular fluid (ECF), and tumour-related solid tissue spanning 0.5 h pre- and up to 48 h post-BPA infusion in newly-diagnosed patients (n = 10). Blood was sampled through a central catheter whilst the ECF was sampled by parenchymal microdialysis catheters, placed remotely from the tumour site. Urine was collected over the same time period. Tumour and brain-around tumour (BAT) tissue was sampled stereotactically at 2.5 h and 3.5 h post-infusion. IHC expression levels of the BPA transporter molecule, L-amino acid transporter 1 (LAT-1), were recorded as % LAT-1 positive cells, and cellular boron levels were estimated as spatially resolved pixels in normalised-to-C⁺ isotopic SIMS images of the biopsies. There were no toxicity-related issues with this new formulation of BPA given at 375 mg/kg as a 2 h intravenous or intracarotid infusion with or without pre-infusion mannitol-induced BBB disruption. The pharmacokinetic profile indicates a high plasma-to-brain concentration gradient from intracarotid infusion and BBB manipulation and reliably places boron in high concentrations in the brain compartment. However, tumour and BAT uptake varied, but a continuing uptake in BAT over time to >30 ppm boron suggests a more favourable capacity to concentrate boron for BNCT after debulking surgery. At the cellular level, the ratio of boron uptake as measured by SIMS in tumour vs BAT was 0.96, 1.85 and 2.40 in the intravenous, intravenous plus mannitol BBB-D, and intracarotid cohorts respectively. Thus improved specific and targeted delivery of boron is possible. These observations conform to a three compartment model where tumoural uptake of boron is governed solely by the abundance and two-way kinetics of tumour LAT-1 activity rather than BBB penetration and may explain some of the variation in clinical results of others.