Borocaptate sodium: a potential boron delivery compound for boron neutron capture therapy evaluated in dogs with spontaneous intracranial tumors.

Abstract

Borocaptate sodium (Na2B12HjjSH) is a boron-carrying compound under consideration for use in boron neutron capture therapy. The biodistribution of boron from borocaptate sodium adminition will partly determine boron neutron capture therapy efficacy and normal tissue radiation tolerance. The biodistribution of boron was determined in 30 dogs with spontaneous intracranial tumors at 2, 6, or 12 hr after intravenous borocaptate sodium infusion. Blood and tissue boron concentrations were measured using inductively coupled plasma atomic emission spectroscopy. Mean tumor boron concentration (mean ± standard error) was 35.9 ± 4.6 (n = 15), 22.5 ± 6.0 (n = 9), and 7.0 ± 1.1 jpg of boron per g (a = 6) at 2, 6, and 12 hr, respectively, after borocaptate sodium infusion. Peritumor boron concentrations were elevated above that of normal brain in half of the dogs. Normal brain boron concentration (mean ± standard error) was 4.0 1 0.5, 2.0 ± 0.4, and 2.0 ± 0.3 jg of boron per g at 2, 6, and 12 hr after infusion, respectively. Some cranial and systemic tissues, and blood, had high boron concentration relative to tumor tissue. Geometric dose sparing should partly offset these relatively high normal tissue and blood concentrations. Borocaptate sodium biodistribution is favorable because tumor boron concentrations of recommended magnitude for boron neutron capture therapy were obtained and there was a high tumor-to-normal brain boron concentration ratio.Boron neutron capture therapy (BNCT) is an experimental form of radiation therapy for cancer that results in targeted high linear energy transfer (LET) radiation. BNCT has a number oftheoretical advantages over conventional low LET radiation therapy and has recently been reviewed (1, 2). The localization of a boronated compound within tumor tissue is critical to the success of BNCT, and multiple compounds are under development as potential boron carriers. Promising biodistribution results were obtained with the administration of borocaptate sodium (BSH) in rodents with experimental tumors (3). BSH has low relative toxicity, is available in a standardized form, and has produced favorable results during Japanese clinical trials in humans with malignant brain tumors (4). However, few data are available on biodistribution and pharmacokinetics of BSH, and data are needed prior to approval of human pharmacokinetic trials in the United States. Studies using dogs with spontaneous brain tumors were performed to evaluate the relative biodistribution of BSH and potential implications for use of BSH for BNCT are discussed.MATERIALS AND METHODS Dogs with spontaneous intracranial tumors were referred by regional veterinary practitioners. Diagnosis of intracranial tumors was based on results of pre-and post-contrast magnetic resonance imaging and computed tomography of the brain. BSH (natural isotopic ratio: 80% 11B, 20% 10B; Callery Chemical, Pittsburgh) was administered intravenously at 55 mg of boron per kg of body weight dissolved in 11 ml of physiological saline per kg ofbody weight ...

In Vivo Accelerator-Based Boron Neutron Capture Therapy for Spontaneous Tumors in Large Animals: Case Series

“…In 1992, Kraft et al studied biodistribution of boron in 30 dogs with spontaneous intracranial tumors after intravenous BSH (55 mg of natural boron/kg of body weight) infusion. They showed that the highest and feasible BNCT boron concentration in tumor tissue was observed at the first assessable time point of 2 h after infusion (35.9 ± 4.6 µg/g), that a high tumor/normal cell boron concentration ratio was achieved, and a subsequent linear decrease to the insufficient level of 7.0 ± 1.1 µg/g was seen at 12 h (indicating optimal time intervals for neutron irradiation) [ 93 ]. In another publication, the authors reported higher mean boron accumulation in extracranial compared to intracranial spontaneous tumors in dogs with maximum levels at 2 h after BSH infusions of the same dose as their previous report.…”

Clinical Veterinary Boron Neutron Capture Therapy (BNCT) Studies in Dogs with Head and Neck Cancer: Bridging the Gap between Translational and Clinical Studies

“…Dogs have previously been used in BNCT-related studies to evaluate the RBE of an epithermal beam for brain tissue [ 36 ], the tolerance of normal canine brain to epithermal neutron irradiation in the presence of BPA [ 37 ], and normal tissue tolerance with BNCT mediated by sodium borocaptate (BSH) [ 38 , 39 ]. Kraft et al [ 40 , 41 ] used dogs with spontaneous brain tumors to evaluate BSH biodistribution and implications for BSH-mediated BNCT. These authors stressed the relevance of studying spontaneous tumors as opposed to experimental tumors.…”

Canine brain tumours: a model for the human disease?

“…More recently, a study including 51 dogs utilizing frameless SRS indicated a median survival time of 399 days for meningiomas indicating that SRS may provide similar outcomes as traditional radiation therapy with only a single episode of anaesthesia and fewer acute adverse side effects . Boron neutron capture therapy has also been evaluated in dogs in a phase I trial with safety demonstrated; initial clinical results similar to that achieved with conventional radiation have been seen . Dogs have also been used in radiation treatment trials evaluating hyperthermia and photodynamic therapy …”