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PubMed1999

Relaxation properties of a dual-labeled probe for MRI and neutron capture therapy.

Pharmaceutical agents labeled with both boron and gadolinium have potential applications in both boron neutron capture therapy (NCT) and magnetic resonance imaging. Pre- and post-injection T1 maps provide a method for the indirect measurement of the gadolinium and boron concentrations that can then be used in NCT treatment planning. This requires an understanding of the relaxation properties of the agent. In this paper we present an analysis of the relaxation properties of a dual boron and gadolinium agent, Gd (III)-diethylenetriaminepentaacetate-carborane [Gd (III)-DTPA-carborane], in vitro in the presence and absence of serum albumin. The nuclear magnetic relaxation dispersion profile of solutions containing albumin obtained with a field cycling relaxometer exhibit a peak in the frequency range from 8 to 50 MHz. This indicates a long rotational correlation time relative to the solution without serum albumin. Results from other experiments indicate that this peak results from the binding of Gd (III)-DTPA-carborane derivative to serum albumin. Temperature studies indicate that the water proton relaxation efficiency of bound agent is limited by the water residence time as the relaxivity increases from 19 +/- 1 to 32.6 +/-; 0.8 (sec.mM)-1 when the temperature is increased from 5 to 35 degrees C.

Contrast Media↗
PubMed2007

Analysis of boron distribution in vivo for boron neutron capture therapy using two different boron compounds by secondary ion mass spectrometry.

The efficiency of boron neutron capture therapy (BNCT) for malignant gliomas depends on the selective and absolute accumulation of (10)B atoms in tumor tissues. Only two boron compounds, BPA and BSH, currently can be used clinically. However, the detailed distributions of these compounds have not been determined. Here we used secondary ion mass spectrometry (SIMS) to determine the histological distribution of (10)B atoms derived from the boron compounds BSH and BPA. C6 tumor-bearing rats were given 500 mg/kg of BPA or 100 mg/kg of BSH intraperitoneally; 2.5 h later, their brains were sectioned and subjected to SIMS. In the main tumor mass, BPA accumulated heterogeneously, while BSH accumulated homogeneously. In the peritumoral area, both BPA and BSH accumulated measurably. Interestingly, in this area, BSH accumulated distinctively in a diffuse manner even 800 microm distant from the interface between the main tumor and normal brain. In the contralateral brain, BPA accumulated measurably, while BSH did not. In conclusion, both BPA and BSH each have advantages and disadvantages. These compounds are considered to be essential as boron delivery agents independently for clinical BNCT. There is some rationale for the simultaneous use of both compounds in clinical BNCT for malignant gliomas.

Animals↗
PubMedDate not supplied

Preparation and in vitro evaluation of B-lipiodol as a boron delivery agent for neutron capture therapy of hepatoma.

BACKGROUND: We prepared boron containing lipiodol (B-lipiodol), elucidated the retention of B-lipiodol in hepatoma cells and evaluated the in vitro cellular toxicity of B-lipiodol for neutron capture therapy. MATERIALS AND METHODS: Human hepatoma HepG2 cells were used to examine the uptake and retention of B-lipiodol. Light microscopes were used to examine the interaction and retention of B-lipiodol globules in individual hepatoma cells. Boron and lipiodol concentrations were determined by inductively coupled plasma-atomic emission spectroscopy and neutron activation analysis, respectively. RESULTS: The boron concentration in B-lipiodol drug could reach 2500 ppm. B-lipiodol could be stably retained in serum and culture medium. HepG2 cells appeared proficiently at internalization and persistent retention of B-lipiodol. The boron concentration reached 3.5 micrograms/10(6) cells without approaching saturation at 48 h treatment. CONCLUSION: Hepatoma cells could actively uptake B-lipiodol and a sufficient amount of boron was retained inside the HepG2 cells which could be used for neutron capture therapy.

Animals↗
PubMed2001

Boron neutron capture therapy of brain tumors: investigation of urinary metabolites and oxidation products of sodium borocaptate by electrospray ionization mass spectrometry.

Boron neutron capture therapy (BNCT) is based on a nuclear capture reaction that occurs when boron-10, a stable isotope, is irradiated with low energy neutrons to produce high-energy alpha particles and recoiling lithium-7 nuclei. The purpose of the present study was to determine what urinary metabolites, if any, could be detected in patients with brain tumors who were given sodium borocaptate (BSH), a drug that has been used clinically for BNCT. BSH was infused intravenously over a 1-h time period at doses of 26.5, 44.1, or 88.2 mg/kg of body weight to patients with high-grade brain tumors. Electrospray ionization mass spectrometry has been used to investigate possible urinary metabolites of BSH. Chemical and instrument conditions were established to detect BSH and its possible metabolites in both positive and negative electrospray ionization modes. Using this methodology, boronated ions were found in patients' urine samples that appeared to be consistent with the following chemical structures: BSH sulfenic acid (BSOH), BSH sulfinic acid (BSO(2)H), BSH disulfide (BSSB), BSH thiosulfinate (BSOSB), and a BSH-S-cysteine conjugate (BSH-CYS). Although BSH has been used clinically for BNCT since the late 1960s, this is the first report of specific biotransformation products following administration to patients. Further studies will be required to determine both the biological significance of these metabolites and whether any of these accumulate in significant amounts in brain tumors.

Biotransformation↗
PubMed2004

Targeting liposomes to tumor endothelial cells for neutron capture therapy.

The aim of our work is to target (10)B to the tumor vasculature for neutron capture therapy (NCT). Alpha (v)-integrin specific RGD-peptides were coupled to liposomes that encapsulated dodecahydrododecaborate. These RGD-liposomes strongly associated with human umbilical vein endothelial cells (HUVEC) expressing this integrin and were internalized. Proliferating HUVEC proved sensitive to treatment with gamma-irradiation resulting in decreased cell viability and pronounced inhibition of DNA-synthesis with increasing dose. Irradiation of RGD-(10)B-liposome incubated HUVEC with neutrons strongly inhibited endothelial cell viability. These results suggest that efficient NCT can be achieved by targeting (10)B-liposomes to angiogenic endothelium in tumors.

Boron↗
PubMed1991

Dosimetry and fluence measurements with a new irradiation arrangement for neutron capture therapy of tumours in mice.

Incorporation of 10B in human tumours treated with fast neutrons would increase the local dose in the tumour. In tissue the neutrons are thermalized mainly causing the neutron capture reaction 10B (n,a) 7Li. The dose enhancement can be calculated using the thermal neutron fluence measured by activation of gold foils in a phantom. At a phantom depth of 5 cm a dose enhancement of (0.056 +/- 0.0028)% for each microgram of 10B per gram of tissue was determined in the tumour. A therapeutic gain by this dose enhancement in fast neutron therapy should be examined for a solid tumour in a mouse. The feasibility for neutron capture therapy of tumours in mice depends on the distribution of the tumour dose and on the effective shielding of the bodies of the mice. Therefore, a special holding device for simultaneous irradiation of four tumours was developed. The dose distribution in the tumours and in the surrounding bodies of mice was measured with TLD-300 in a special mouse phantom.

Animals↗
PubMed1997

The role of boron MRI in boron neutron capture therapy.

Boron magnetic resonance imaging (MRI) and spectroscopy (MRS) are being developed for use in boron neutron capture therapy (BNCT). With continued development, boron MRI may be used to locate BNCT agents in vivo, evaluate the pharmacokinetics of BNCT agents, and aid in treatment planning.

Animals↗
PubMed1996

An improved neutron collimator for brain tumor irradiations in clinical boron neutron capture therapy.

To improve beam penetration into a head allowing the treatment of deeper seated tumors, two neutron collimators were built sequentially and tested for use in the clinical boron neutron capture therapy (BNCT) program at the epithermal neutron irradiation facility of the Brookhaven Medical Research Reactor. The collimators were constructed from lithium-impregnated polyethylene, which comprises Li2CO3 powder (approximately 93% enriched isotopic 6Li) uniformly dispersed in polyethylene to a total 6Li content of 7.0 wt. %. The first collimator is 7.6 cm thick with a conical cavity 16 cm in diameter on the reactor core side tapering to 8 cm facing the patient's head. The second collimator is 15.2 cm thick with a conical cavity 20 cm in diameter tapering to 12 cm. A clinical trial of BNCT for patients with malignant brain tumors is underway using the first collimator. Results of phantom dosimetry and Monte Carlo computations indicate that the new 15.2 cm thick collimator will improve the neutron beam penetration. Thus, the second collimator was made and will be used in an upcoming clinical trial. In-air and in-phantom mixed-field dosimetric measurements were compared to Monte Carlo computations for both collimators. The deeper penetration is achieved but at a sacrifice in beam intensity. In this report, a performance comparison of both collimators regarding various fluence rate and absorbed dose distributions in a head model is presented and discussed.

Biophysical Phenomena↗
PubMed1998

Effects of boron neutron capture therapy using borocaptate sodium in combination with a tumor-selective vasoactive agent in mice.

Boron neutron capture therapy (BNCT) destroys tumor cells by means of alpha particles and recoil protons emitted by 10B(n, alpha)7Li reaction. For BNCT to be effective, the tumor/normal tissue concentration ratio of 10B must be larger than 1.0, because neutron distribution is not selective. We examined the combination of 10B-enriched borocaptate sodium (BSH) with flavone acetic acid (FAA) as a model compound which causes vascular collapse in squamous cell carcinoma in mice (SCCVII tumors) and would increase the tumor/normal tissue concentration ratio of 10B. FAA (200 mg/kg, i.p.) was injected, and 5 min later BSH (75 mg/kg, i.v.) was administered, followed 15 to 180 min later by irradiation with thermal neutrons. The 10B concentrations were measured by prompt gamma ray spectrometry. Without FAA, tumor 10B concentrations were less than or equal to normal tissue concentrations at all time intervals, except that the concentrations were 1.7- to 2.7-fold greater in tumor than muscle at 15 and 180 min after injection of BSH. With FAA, 10B concentrations 2.1- to 6.9-fold greater in tumor than in muscle were achieved at all intervals tested. For blood and skin, significant differential accumulations were found in tumors at 120 and 180 min. Tumor/liver ratios were less than 1 at all times. Cell survival was determined by in vivo/in vitro colony assay, and increasing radiosensitization correlated with increasing tumor 10B concentrations, whether or not they were achieved with FAA. Tumor control rates, determined at 180 days after BNCT, similarly appeared to depend only on 10B levels at the time of irradiation. Because 10B levels correlate with the radiation response of tissues, a therapeutic gain would be expected whenever the tumor levels exceed normal tissue levels, such as in tumors located in muscle irradiated at 15-180 min after FAA + BSH, or in those in skin irradiated at 120 and 180 min.

Animals↗
PubMed2000

The effects of boron neutron capture therapy on liver tumors and normal hepatocytes in mice.

To explore the feasibility of employing boron neutron capture therapy (BNCT) to treat liver tumors, the effects of BNCT were investigated by using liver tumor models and normal hepatocytes in mice. Liver tumor models in C3H mice were developed by intrasplenic injection of SCCVII tumor cells. After borocaptate sodium (BSH) and boronophenylalanine (BPA) administration, (10)B concentrations were measured in tumors and liver and the liver was irradiated with thermal neutrons. The effects of BNCT on the tumor and normal hepatocytes were studied by using colony formation assay and micronucleus assay, respectively. To compare the effects of BSH-BNCT and BPA-BNCT, the compound biological effectiveness (CBE) factor was determined. The CBE factors for BSH on the tumor were 4.22 and 2.29 using D(10) and D(0) as endpoints, respectively. Those for BPA were 9.94 and 5.64. In the case of hepatocytes, the CBE factors for BSH and BPA were 0.94 and 4.25, respectively. Tumor-to-liver ratios of boron concentration following BSH and BPA administration were 0.3 and 2.8, respectively. Considering the accumulation ratios of (10)B, the therapeutic gain factors for BSH and BPA were 0.7 - 1.3 and 3.8 - 6.6, respectively. Therefore, it may be feasible to treat liver tumors with BPA-BNCT.

Animals↗
PubMed1995

Monte Carlo calculations of epithermal boron neutron capture therapy with heavy water.

Much work over the past decade has centred upon the development of epithermal neutron beams for boron neutron capture therapy (BNCT) in an effort to increase thermal-neutron flux penetration and dose homogeneity throughout the brain. While heavy water has been used extensively to improve neutron penetration associated with thermal neutron beams, the effects of heavy water with epithermal neutron beams remain largely unexplored. Applying the Monte Carlo code MCNP to a heterogenous ellipsoidal skull/brain model, the effects of heavy-water replacement are studied for the JRC/ECN Petten HFR epithermal neutron beam. Thermal neutron flux and induced gamma depth dose distributions are calculated for 20% D2O replacement in comparison to standard brain and skull materials. Results are presented for both unilateral and bilateral irradiation. With bilateral irradiation, thermal-neutron flux homogeneity is substantially increased with 20% D2O replacement, thus improving the potential to give lethal doses to boron-10-loaded, disseminated cancer cells whilst avoiding local 'hot spots' to healthy tissue. Additionally, the induced gamma dose is reduced by up to 30%, substantially lowering the background dose to healthy tissue. With bilateral irradiation, 20% D2O replacement increases the therapeutic ratio from 2.25 to 2.75 for over 4 cm depth centred at the midline of the brain. These calculations use documented tumour and blood 10B concentrations for boronophenylalanine (BPA) in humans and recently documented neutron relative biological effectiveness (RBE) values.

Boron Neutron Capture Therapy↗
PubMed1997

Boron neutron capture therapy. Clinical brain tumor studies.

Since 1968, we have treated 149 patients and performed boron-neutron capture therapy (BNCT) on 164 occasions using 5 reactors in Japan. There were 64 patients with glioblastoma, 39 patients with anaplastic astrocytoma and 17 patients with low grade astrocytoma (grade 1 or 2). There were 30 patients with other types of tumor. The overall response rate in the glioma patients was 64%. Seven patients (12%) of glioblastoma, 22 patients (56%) of anaplastic astrocytoma and 8 patients (62%) of low grade astrocytoma lived more than 2 years. Median survival time of glioblastoma was 640 days. Median survival times of patients with anaplastic astrocytoma was 1811 days, and 1669 days in low grade astrocytoma. Six patients (5 glioblastoma and one anaplastic astrocytoma) died within 90 days after BNCT. Six patients (two glioblastoma and four anaplastic astrocytomas) lived more than 10 years. Histological grading, age of the patients, neutron fluence at the target point and target depth or size of the tumor were proved to be important factors. BNCT is an effective treatment for malignant brain tumors. We are now able to radiate the tumor more correctly with a high enough dose of neutron beam, even if we use thermal neutron beam.

Adult↗
PubMed1995

Neutron capture therapy with gadopentetate dimeglumine: experiments on tumor-bearing rats.

RATIONALE AND OBJECTIVES: The therapeutic effect of neutron capture therapy with the gadolinium (Gd) complex gadopentetate dimeglumine was studied in vivo in rats using a beam of thermal neutrons. METHODS: Rats with Jensen sarcomas 10-15 mm in diameter in their right thigh were irradiated with a thermal neutron beam that had fluences of 3.6 x 10(11) (20 min) or 5.4 x 10(11) n/cm2 (30 min) in the absence and presence of 5,500 or 13,750 ppm gadopentetate dimeglumine. Gadopentetate dimeglumine was administered directly into the tumor prior to neutron irradiation. Four groups of rats were studied: two groups of nonirradiated controls (Gd-n- and Gd+n-) and two irradiated groups (Gd-n+ and Gd+n+). In the follow-up period, we measured the subjects' clinical status and tumor size as a function of time postirradiation. RESULTS: In both control groups (Gd-n- and Gd+n-), the tumor progressively grew. Pure irradiation by thermal neutrons in the Gd-n+ group resulted in a transient inhibition of tumor growth with total regressions of 15%. Intratumoral administration of 13,750 ppm gadolinium per gram of tumor and subsequent neutron irradiation (the Gd+n+ group; fluence = 3.6.10(11) n/cm2) significantly increased the tumoricidal effects (i.e., decrease of tumor growth up to a complete regression of the tumors in about 80%). Treatment-specific differences between the groups were confirmed by histologic observations. CONCLUSION: The intratumoral administration of the hydrophilic magnetic resonance imaging contrast medium gadopentetate dimeglumine prior to irradiation with thermal neutrons leads to a therapeutic gain (i.e., reduction) on experimental Jensen sarcomas.

Animals↗
PubMedDate not supplied

A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease.

A phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase I trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24-78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15 cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The 10B carrier, L-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250 mg kg(-1) over 1 h (10 subjects), 300 mg kg(-1) over 1.5 h (two subjects), or 350 mg kg(-1) over 1.5-2 h (10 subjects). The pharmacokinetic profile of 10B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.

Adult↗
PubMed1995

Biodistribution of boron sulfhydryl for boron neutron capture therapy in patients with intracranial tumors.

The biodistribution of boron sulfhydryl (BSH) was evaluated for boron neutron capture therapy of brain tumors. A selective boron delivery to the neoplasm is a prerequisite for successful therapy. The uptake of BSH after intravenous administration was analyzed in neoplastic and normal tissues in 61 patients undergoing craniotomies for intracranial tumors. The patients received 10 to 100 mg of BSH/kg (5-50 mg of 10B/kg) body weight, 2 to 72 hours before surgery. The tumor boron concentrations ranged from 0.2 ppm (micrograms/g) in a low-grade glioma to 19.5 ppm in a high-grade glioma. The tumor to blood boron ratio rose above 1 in 15 of 24 high-grade intracerebral tumors, 18 h or more after BSH infusion. The boron concentration in high-grade tumors was heterogeneous. Low-grade intracerebral tumors showed a low boron concentration with a tumor to blood ratio below 1. Extracerebral tumors, mainly meningiomas, showed boron concentrations comparable with high-grade tumors, with a tumor to blood ratio above 1 in 10 of 17 patients. The boron concentrations in skin and muscle compared roughly with the blood values. Boron did not enter normal brain in any significant amount. In high-grade tumors, tumor to brain ratios were above 2. Low boron concentrations in normal brain make BSH safe for a Phase I normal tissue tolerance study. Computed tomographic contrast enhancement was evaluated to tumor boron uptake for 30 patients. Tumor enhancement on computed tomography does not permit the prediction of individual tumor boron concentrations; however, the absence of a contrast enhancement was always associated with low boron uptake.

Adult↗
PubMed1997

Binding and distribution of Na2B12H11SH on cellular and subcellular level in tumor tissue of glioma patients in boron neutron capture therapy.

To determine binding and distribution of Na2B12H11SH (BSH) in glioma tissue in case of boron neutron capture therapy, an antibody to this compound was produced and used in immunohistochemical investigations. It is possible to trace BSH in immunohistochemistry, because BSH is firmly bound to the glioma tissue. The antibody against BSH is specific for that antigen, as tumor tissue from patients without BSH administration did not stain. In areas of healthy brain from BSH infused patients, no staining of tissue was detectable. In tumor tissues, BSH is presenting as a strong staining in cytoplasm and nucleus areas.

Antibodies↗
PubMed2003

Computational study of the required dimensions for standard sized phantoms in boron neutron capture therapy dosimetry.

The minimum size of a water phantom used for calibration of an epithermal neutron beam of the boron neutron capture therapy (BNCT) facility at the VTT FiR 1 research reactor is studied by Monte Carlo simulations. The criteria for the size of the phantom were established relative to the neutron and photon radiation fields present at the thermal neutron fluence maximum in the central beam axis (considered as the reference point). At the reference point, for the most commonly used beam aperture size at FiR 1 (14 cm diameter), less than 1% disturbance of the neutron and gamma radiation fields in a phantom were achieved with a minimum a 30 cm x 30 cm cross section of the phantom. For the largest 20 cm diameter beam aperture size, a minimum 40 cm x 40 cm cross-section of the phantom and depth of 20 cm was required to achieve undisturbed radiation field. This size can be considered as the minimum requirement for a reference phantom for dosimetry at FiR 1. The secondary objective was to determine the phantom dimensions for full characterization of the FiR 1 beam in a rectangular water phantom. In the water scanning phantom, isodoses down to the 5% level are measured for the verifications of the beam model in the dosimetric and treatment planning calculations. The dose distribution results without effects caused by the limited phantom size were achieved for the maximum aperture diameter (20 cm) with a 56 cm x 56 cm x 28 cm rectangular phantom. A similar approach to study the required minimum dimensions of the reference and water scanning phantoms can be used for epithermal neutron beams at the other BNCT facilities.

Boron Neutron Capture Therapy↗
PubMed2005

Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy.

Novel 3-carboranyl thymidine analogues (3CTAs) were synthesized as potential boron delivery agents for boron neutron capture therapy (BNCT). This library includes six zwitterionic NH(3)(+)-nido-m-carborane-substituted thymidine analogues (Thds) and the corresponding neutral NH(2)-closo-m-carborane-substituted counterparts. All compounds of this library were good substrates for recombinant human thymidine kinase 1 (TK1) with phosphorylation rates up to 89% relative to that of Thd. One compound out of this library, 3-[3-(7-NH(3)(+)-nido-m-carboran-1-yl)propan-1-yl]thymidine (19b), showed selective retention in TK1-expressing murine L929 wild-type tumors versus L929 TK1 (-) tumors in biodistribution studies. The biological evaluation of the zwitterionic NH(3)(+)-nido-m-carborane-substituted Thds indicated improved aqueous solubility and similar or even superior potential as BNCT agents compared with different classes of 3CTAs (Cancer Res. 2004, 64, 6280-6286 and 6287-6295). To complete previous structure-activity relationship (SAR) studies, 3-[(closo-o-carboranyl)methyl]thymidine (4) was also synthesized and evaluated.

Animals↗