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PubMed1994

Boron neutron capture therapy: a guide to the understanding of the pathogenesis of late radiation damage to the rat spinal cord.

PURPOSE: Before the commencement of new boron neutron capture therapy (BNCT) clinical trials in Europe and North America, detailed information on normal tissue tolerance is required. In this study, the pathologic effects of BNCT on the central nervous system (CNS) have been investigated using a rat spinal cord model. METHODS AND MATERIALS: The neutron capture agent used was 10B enriched sodium mercaptoundecahydro-closododecaborate (BSH), at a dosage of 100 mg/kg body weight. Rats were irradiated on the thermal beam at the Brookhaven Medical Research Reactor. The large spine of vertebra T2 was used as the lower marker of the irradiation field. Rats were irradiated with thermal neutrons alone to a maximum physical absorbed dose of 11.4 Gy, or with thermal neutrons in combination with BSH, to maximum absorbed physical doses of 5.7 Gy to the CNS parenchyma and 33.7 Gy to the blood in the vasculature of the spinal cord. An additional group of rats was irradiated with 250 kVp X rays to a single dose of 35 Gy. Spinal cord pathology was examined between 5 and 12 months after irradiation. RESULTS: The physical dose of radiation delivered to the CNS parenchyma, using thermal neutron irradiation in the presence of BSH, was a factor of two to three lower than that delivered to the vascular endothelium, and could not account for the level of damage observed in the parenchyma. CONCLUSION: The histopathological observations of the present study support the hypothesis that the blood vessels, and the endothelial cells in particular, are the critical target population responsible for the lesions seen in the spinal cord after BNCT type irradiation and by inference, after more conventional irradiation modalities such as photons or fast neutrons.

Animals↗

PubMed1994

Clinical phase-I study of Na2B12H11SH (BSH) in patients with malignant glioma as precondition for boron neutron capture therapy (BNCT).

PURPOSE: Within the European collaboration on boron neutron capture therapy (BNCT), a clinical Phase I study is being carried out to establish BNCT as an alternative treatment modality for malignant glioma (WHO III/IV). Data about the pharmacokinetics, biodistribution and toxicity of the boron compound Na2B12H11SH (BSH) are of great importance to avoid radiation damage of healthy tissue and to deliver a sufficient radiation dose. METHODS AND MATERIALS: Twenty four patients suffering from a glioblastoma multiforme entered the study to date, infused with a maximum concentration of up to 50 mg BSH/kg. Boron concentration measurements in tissues, urine, and blood were carried out, using inductively coupled plasma-atomic spectroscopy (ICP-AES) and quantitative neutron capture radiography (QNCR). A cross-calibration of these boron determination techniques was carried out. RESULTS: In tumor tissue, confirmed by histopathology of small biopsies, we found a consistently high but heterogeneous boron uptake. Necrotic parts contain much lower amounts of boron; normal brain tissue has shown no significant uptake. In skin, bone, muscle, and dura mater only small amounts of boron were found. In blood samples, we found biphasic kinetics, but with variations of the half-lives from patient to patient. The compound is mainly excreted through the urine, but an additional entero-hepatic pathway can be demonstrated. Systematic investigations revealed no toxic side effect of the intravenously administered BSH. Comparable data were obtained by using ICP-AES and QNCR for boron concentration measurements. CONCLUSION: Taking into account the radiobiological considerations of the neutron beam source, we found promising facts that BNCT could be a useful irradiation method for highly malignant brain tumors. Favorable amounts of the boron compound BSH were found in tumor tissue, whereas healthy brain tissue has shown no significant uptake.

Aged↗

PubMed2004

Neutron capture autoradiographic study of the biodistribution of 10B in tumor-bearing mice.

For the study on boron neutron capture therapy, the whole-body sections of tumor-bearing mice infused with 10B attached to CR-39 plastic track detectors were exposed to thermal and cold neutron beams. Neutron capture autoradiographic images obtained by the cold neutron irradiation were extremely superior in quality to those of the thermal neutron beams. From the autoradiographic images, the 10B reaction dose of the neutron-induced particles was estimated using the differential LET distribution.

Animals↗

PubMed2004

Accumulation of boron compounds to tumor with polyethylene-glycol binding liposome by using neutron capture autoradiography.

The cytotoxic effect of boron neutron capture therapy (BNCT) is due to a nuclear reaction between 10B and thermal neutrons. It is necessary to accumulate the 10B atoms to the tumor cells selectively for effective BNCT. In order to achieve an accurate measurement of 10B concentrations in the biological samples, we employed a technique of neutron capture autoradiography (NCAR) of the sliced whole-body samples of tumor bearing mice using CR-39 plastic track detectors. The CR-39 detectors attached with samples were exposed to thermal neutrons in the thermal column of the TRIGA II reactor at the Institute for Atomic Energy, Rikkyo University and thermal neutron facility of Paul Scherer Institute(PSI). We obtained NCAR images for mice injected intravenously by 10B-PEG liposome, 10B-transferrin-PEG liposome, or 10B-bare liposome. The 10B concentrations in the tumor tissue of mice were estimated by means of alpha-track density measurements. In this study, we can increase the accumulation of 10B atoms in the tumor tissues by binding polyethylene-glycol chains to the surface of liposome, which increase the retention in the blood flow and escape the phagocytosis by reticulo-endothelial systems. Therefore, we will be able to apply NCAR technique for selection of effective 10B carrier in BNCT for cancer.

Animals↗

PubMed2004

Moderated 252Cf neutron energy spectra in brain tissue and calculated boron neutron capture dose.

While there is significant clinical experience using both low- and high-dose (252)Cf brachytherapy, combination therapy using (10)B for neutron capture therapy-enhanced (252)Cf brachytherapy has not been performed. Monte Carlo calculations were performed in a brain phantom (ICRU 44 brain tissue) to evaluate the dose enhancement predicted for a range of (10)B concentrations over a range of distances from a clinical (252)Cf source. These results were compared to experimental measurements and calculations published in the literature. For (10)B concentrations </=50 microg/g, the (10)B neutron capture dose enhancement was small in comparison to the (252)Cf fast neutron dose.

Boron Neutron Capture Therapy↗

PubMed2004

Intra-arterial administration of sodium borocaptate (BSH)/lipiodol emulsion delivers B-10 to liver tumors highly selectively for boron neutron capture therapy: experimental studies in the rat liver model.

PURPOSE: Boron neutron capture therapy (BNCT) is particle radiotherapy with alpha ((4)He) particle and recoiled lithium nucleus ((7)Li) derived from a reaction of boron ((10)B) and thermal neutron. We investigated applying BNCT to malignant liver tumors. The purpose of the present study was to reveal the efficacy for administration of emulsion of a boron compound (sodium borocaptate; BSH) and lipiodol via a hepatic artery using a rat liver tumor model. METHODS AND MATERIALS: Rat liver tumors were developed by direct injection of Walker 256 cells into the liver parenchyma. BSH (75 mg/kg)/lipiodol (0.3 mL/kg) emulsion was administered via the hepatic artery. Boron concentrations in the tumors, liver, and blood were measured at 1, 6, and 12 h after administration. Neutron capture radiography (NCR) was taken to confirm the selective accumulation of (10)B in the liver tumors. RESULTS: Boron concentrations in the liver tumors and the tumor/liver (T/L) boron concentration ratio at 1, 6, and 12 h after administration of BSH/lipiodol emulsion (concentration: T/L ratio) were 479.2 ppm: 4.0, 197.3 ppm: 14.9, and 96.5 ppm: 6.6, respectively. Highly selective irradiation was clearly demonstrated by the NCR images. CONCLUSIONS: Intra-arterial administration of BSH/lipiodol emulsion is effective method for delivering high concentration of (10)B selectively to the liver tumors.

Animals↗

PubMed2006

Boron neutron capture therapy using mixed epithermal and thermal neutron beams in patients with malignant glioma-correlation between radiation dose and radiation injury and clinical outcome.

PURPOSE: To clarify the correlation between the radiation dose and clinical outcome of sodium borocaptate-based intraoperative boron neutron capture therapy in patients with malignant glioma. METHODS AND MATERIALS: The first protocol (P1998, n = 8) prescribed a maximal gross tumor volume (GTV) dose of 15 Gy. In 2001, a dose-escalated protocol was introduced (P2001, n = 11), which prescribed a maximal vascular volume dose of 15 Gy or, alternatively, a clinical target volume (CTV) dose of 18 Gy. RESULTS: The GTV and CTV doses in P2001 were 1.1-1.3 times greater than those in P1998. The maximal vascular volume dose of those with acute radiation injury was 15.8 Gy. The mean GTV and CTV dose in long-term survivors with glioblastoma was 26.4 and 16.5 Gy, respectively. A statistically significant correlation between the GTV dose and median survival time was found. In the 11 glioblastoma patients in P2001, the median survival time was 19.5 months and 1- and 2-year survival rate was 60.6% and 37.9%, respectively. CONCLUSION: Dose escalation contributed to the improvement in clinical outcome. To avoid radiation injury, the maximal vascular volume dose should be <12 Gy. For long-term survival in patients with glioblastoma after boron neutron capture therapy, the optimal mean dose of the GTV and CTV was 26 and 16 Gy, respectively.

Adolescent↗

PubMed2026

Comparison of paralog identification methods and their impact on species tree topologies in target capture phylogenomics within the Sindora clade (Detarioideae: Leguminosae).

Target capture is a common method of generating high throughput DNA sequencing data for phylogenetic reconstruction of species relationships, for which single copy genes are usually most informative. However, a pervasive problem with target capture is that putatively single copy genes may in fact be paralogs resulting from gene duplication, which are problematic for phylogenetic inference because their evolutionary history may differ from the divergence history of species. Here, we use as a case study a target enrichment dataset of 88 species of Detarioideae (Leguminosae) with a focus on the Sindora clade to examine approaches for handling paralogs, including the built-in paralog handling functions in HybPiper and CAPTUS, plus subsequent steps using Putative Paralog Detection and the tree-based Yang & Smith orthology inference approach. We compare the paralogs flagged using these methods and verify their performance with BLAST mapping against a reference genome sequence of Sindora glabra, and then subsequently compare the species tree topologies produced across these methods. Our comparisons of paralogs flagged across the Sindora clade show that the Putative Paralog Detection pipeline was the most accurate in identifying paralogs in terms of its similarity to the BLAST mapping, followed by the built-in paralog identification function of CAPTUS. However, the results we recovered for the Detarioideae subfamily suggest that the largest differences in species tree topology resulted from the use of paralog-filtered alignments (such as with the Putative Paralog Detection pipeline and the Yang & Smith orthology inference approaches) rather than just by removing the sequences of identified paralogous genes. This was the true for HybPiper-assembled datasets but was not seen in CAPTUS-assembled datasets. In all comparisons, the topological differences caused by different paralog handling methods tended to be confined to clades where processes such as hybridisation and introgression are prevalent. Our study provides a roadmap to establish the best approach to identify, eliminate or separate paralogs in the absence of a chromosomally contiguous reference genome for a study group, and highlights the importance of careful data inspection and processing in addition to understanding the extent of paralogy and paralog characteristics (e.g. sequence divergence between copies) for their study group.

Phylogeny↗

PubMed2003

Biodistribution of a carborane-containing porphyrin as a targeting agent for Boron Neutron Capture Therapy of oral cancer in the hamster cheek pouch.

Boron Neutron Capture Therapy (BNCT) is a bimodal cancer treatment based on the selective accumulation of 10B in tumors and concurrent irradiation with thermalized neutrons. The short-range, high-LET radiation produced by the capture of neutrons by 10B could potentially control tumor while sparing normal tissue if the boron compound targets tumor selectively within the treatment volume. In previous studies, we proposed and validated the hamster cheek pouch model of oral cancer for BNCT studies, proved that absolute and relative uptake of the clinically employed boron compound boronophenylalanine (BPA) would be potentially therapeutic in this model and provided evidence of the efficacy of in vivo BPA-mediated BNCT to control hamster oral mucosa tumors with virtually no damage to normal tissue. We herein present the biodistribution and pharmacokinetics of a lipophilic, carborane-containing tetraphenylporphyrin (CuTCPH) in the hamster oral cancer model. CuTCPH is a novel, non-toxic compound that may be advantageous in terms of selective and absolute delivery of boron to tumor tissues. For potentially effective BNCT, tumor boron concentrations from a new agent should be greater than 30 ppm and tumor/blood and tumor/normal tissue boron concentration ratios should be greater than 5/1 without causing significant toxicity. We administered CuTCPH intraperitoneally (i.p.) as a single dose of 32 microg/g body weight (b.w.) (10 microg B/g b.w.) or as four doses of 32 microg/g b.w. over 2 days. Blood (Bl) and tissues were sampled at 3, 6, 12, 24, 48, and 72 h in the single-dose protocol and at 1-4 days after the last injection in the multidose protocol. The tissues sampled were tumor (T), precancerous tissue surrounding tumor, normal pouch (N), skin, tongue, cheek and palate mucosa, liver, spleen, parotid gland and brain. The maximum mean B ratios for the single-dose protocol were T/N: 9.2/1 (12h) and T/Bl: 18.1/1 (72 h). The B value peaked to 20.7+/-18.5 ppm in tumor at 24h. The multidose protocol maximum mean ratios were T/N: 11.9/1 (3 days) and T/Bl: 235/1 (4 days). Absolute boron concentration in tumor reached a maximum value of 116 ppm and a mean value of 71.5+/-48.3 ppm at 3 days. The fact that absolute and relative B values markedly exceeded the BNCT therapeutic threshold with no apparent toxicity may confer on this compound a therapeutic advantage. CuTCPH-mediated BNCT would be potentially useful for the treatment of oral cancer in an experimental model.

Animals↗

PubMed2001

Optimal timing of neutron irradiation for boron neutron capture therapy after intravenous infusion of sodium borocaptate in patients with glioblastoma.

PURPOSE: A cooperative study in Europe and Japan was conducted to determine the pharmacokinetics and boron uptake of sodium borocaptate (BSH: Na(2)B(12)H(11)SH), which has been introduced clinically as a boron carrier for boron neutron capture therapy in patients with glioblastoma. METHODS AND MATERIALS: Data from 56 patients with glioblastoma who received BSH intravenous infusion were retrospectively reviewed. The pharmacokinetics were evaluated in 50 patients, and boron uptake was investigated in 47 patients. Patients received BSH doses between 12 and 100 mg/kg of body weight. For the evaluation, the infused boron dose was scaled linearly to 100 mg/kg BSH. RESULTS: In BSH pharmacokinetics, the average value for total body clearance, distribution volume of steady state, and mean residence time was 3.6 +/- 1.5 L/h, 223.3 +/- 160.7 L, and 68.0 +/- 52.5 h, respectively. The average values of the boron concentration in tumor adjusted to 100 mg/kg BSH, the boron concentration in blood adjusted to 100 mg/kg BSH, and the tumor/blood boron concentration ratio were 37.1 +/- 35.8 ppm, 35.2 +/- 41.8 ppm, and 1.53 +/- 1.43, respectively. A good correlation was found between the logarithmic value of T(adj) and the interval from BSH infusion to tumor tissue sampling. About 12-19 h after infusion, the actual values for T(adj) and tumor/blood boron concentration ratio were 46.2 +/- 36.0 ppm and 1.70 +/- 1.06, respectively. The dose ratio between tumor and healthy tissue peaked in the same interval. CONCLUSION: For boron neutron capture therapy using BSH administered by intravenous infusion, this work confirms that neutron irradiation is optimal around 12-19 h after the infusion is started.

Adult↗

PubMed2002

Neutron capture therapy of intracerebral melanoma: enhanced survival and cure after blood-brain barrier opening to improve delivery of boronophenylalanine.

PURPOSE: Multicentric cerebral metastases of melanoma represent an important clinical problem for which there currently is no satisfactory treatment. We previously developed a model for melanoma metastatic to the brain employing nude rats bearing intracerebral implants of the human MRA27 melanoma. The purpose of the present study was to determine if the efficacy of boron neutron capture therapy (BNCT) could be improved by either Cereport (RMP-7) mediated modulation of blood-brain barrier (BBB) permeability or hyperosmotic mannitol-induced BBB disruption using boronophenylalanine (BPA) as the capture agent. METHODS AND MATERIALS: Biodistribution studies were carried out at 0.5, 2.5, and 4 h after intracarotid administration of Cereport (1.5 microg/kg) and intracarotid or i.v. administration of BPA (500 mg/kg). Peak tumor boron concentrations (65.4 microg/g) and the best composite tumor:brain (6.1:1) and tumor:blood (6.3:1) ratios were observed at 2.5 h after intracarotid administration. BNCT was initiated at the Brookhaven Medical Research Reactor 13-14 days after intracerebral implantation of 10(6) MRA27 cells. RESULTS: Untreated control rats had a median survival time (MeST) of 22 days and for irradiated controls, it was 30 days. Rats that received i.v. or intracarotid BPA without Cereport followed by BNCT 2.5 h later had MeSTs of 41 days and 57 days, respectively, with 20% long-term survivors (>180 days) in the latter group. Rats that received intracarotid BPA with Cereport had an MeST of 86 days with 36% long-term survivors, which was very close to that of rats that had hyperosmotic mannitol-induced disruption of the BBB (85 days with 25% long-term survivors). When these two groups were combined, and survival times were compared, using the Wilcoxon rank sum test, to those of rats that received intracarotid BPA without blood-brain barrier disruption, these differences were significant at the level p = 0.01. CONCLUSIONS: Our data show that optimizing the delivery of BPA by means of intracarotid injection combined with opening the BBB by infusing Cereport or a hyperosmotic solution of mannitol significantly enhanced survival times and produced long-term cures of MRA27 melanoma-bearing rats. These observations are relevant to future clinical studies using BNCT for the treatment of intracerebral melanoma.

Animals↗

PubMed2002

Treatment planning and dosimetry for the Harvard-MIT Phase I clinical trial of cranial neutron capture therapy.

PURPOSE: A Phase I trial of cranial neutron capture therapy (NCT) was conducted at Harvard-MIT. The trial was designed to determine maximum tolerated NCT radiation dose to normal brain. METHODS AND MATERIALS: Twenty-two patients with brain tumors were treated by infusion of boronophenylalanine-fructose (BPA-f) followed by exposure to epithermal neutrons. The study began with a prescribed biologically weighted dose of 8.8 RBE (relative biologic effectiveness) Gy, escalated in compounding 10% increments, and ended at 14.2 RBE Gy. BPA-f was infused at a dose 250-350 mg/kg body weight. Treatments were planned using MacNCTPlan and MCNP 4B. Irradiations were delivered as one, two, or three fields in one or two fractions. RESULTS: Peak biologically weighted normal tissue dose ranged from 8.7 to 16.4 RBE Gy. The average dose to brain ranged from 2.7 to 7.4 RBE Gy. Average tumor dose was estimated to range from 14.5 to 43.9 RBE Gy, with a mean of 25.7 RBE Gy. CONCLUSIONS: We have demonstrated that BPA-f-mediated NCT can be precisely planned and delivered in a carefully controlled manner. Subsequent clinical trials of boron neutron capture therapy at Harvard and MIT will be initiated with a new high-intensity, high-quality epithermal neutron beam.

Adult↗

PubMed2003

Boron concentrations in brain during boron neutron capture therapy: in vivo measurements from the phase I trial EORTC 11961 using a gamma-ray telescope.

PURPOSE: Gamma-ray spectroscopic scans to measure boron concentrations in the irradiated volume were performed during treatment of 5 patients suffering from brain tumors with boron neutron capture therapy (BNCT). In BNCT, the dose that is meant to be targeted primarily to the tumor is the dose coming from the reaction 10B(n,alpha)7Li, which is determined by the boron concentration in tissue and the thermal neutron fluence rate. The boron distribution throughout the head of the patient during the treatment is therefore of major interest. The detection of the boron distribution during the irradiation was until now not possible. METHODS AND MATERIALS: Five patients suffering from glioblastoma multiforme and treated with BNCT in a dose escalation study were administered the boron compound, boron sulfhydryl (BSH; Na(2)B(12)H(11)SH). Boron concentrations were reconstructed from measurements performed with the gamma-ray telescope which detects locally the specific gamma rays produced by neutron capture in 10B and 1H. RESULTS: For all patients, at a 10B concentration in blood of 30 ppm, the boron concentration in nonoperated areas of the brain was very low, between 1 and 2.5 ppm. In the target volume, which included the area where the tumor had been removed and where remaining tumor cells have to be assumed, much higher boron concentrations were measured with large variations from one patient to another. Superficial tissue contained a higher concentration of 10B than the nonoperated areas of the brain, ranging between 8 and 15 ppm. CONCLUSIONS: The measured results correspond with previous tissue uptake studies, confirming that normal brain tissue hardly absorbs the boron compound BSH. Gamma-ray telescope measurements seem to be a promising method to provide information on the biodistribution of boron during therapy. Furthermore, it also opens the possibility of in vivo dosimetry.

Boron↗

PubMed1998

Electroporation increases the effect of borocaptate (10B-BSH) in neutron capture therapy.

PURPOSE: The cell membrane permeability of borocaptate (10B-BSH) and its extent of accumulation in cells are controversial. This study was performed to elucidate these points. METHODS AND MATERIALS: Two different treatments were applied to SCCVII tumor cells. The first group of tumor cells was incubated in culture medium with 10B-BSH or 10B-enriched boric acid, and was exposed to neutrons from the heavy water facility of the Kyoto University Reactor (KUR). More than 99% of neutrons were thermal neutrons at flux base. The second group was pretreated by electroporation in combination with 10B-BSH, and thereafter the cells were irradiated with neutrons. The cell killing effects of boron neutron capture therapy (BNCT) using BSH were investigated by colony formation assay. RESULTS: Surviving cell fraction decreased exponentially with neutron fluence, and addition of BSH significantly enhanced the cell killing effect of neutron capture therapy (NCT) depending on 10B concentration. The effect of BSH-BNCT also increased with preincubation time of cells in the medium containing BSH. The electroporation of cells with BSH at 10 ppm 10B markedly enhanced BSH-BNCT effects in comparison with that of preincubation alone. The effect of BSH-BNCT with electroporation was equal to that of BNCT using 10B-boric acid at a same 10B concentration (10 ppm). CONCLUSIONS: BSH is suggested to penetrate the cells slowly and remained after washing. Electroporation can introduce BSH into the cells very efficiently, and BSH stays in the cells and is not lost by washing. Therefore, if electroporation is applied to tumors after BSH injection, 10B remains in tumors but is cleared from normal tissues, and selective accumulation of 10B in tumors will be achieved after an adequate waiting time.

Borohydrides↗

PubMed1998

New horizons for therapy based on the boron neutron capture reaction.

Boron neutron capture therapy (BNCT) is currently undergoing clinical trials in the USA, Japan and The Netherlands with patients afflicted with deadly brain cancer (glioblastoma multiforme) or melanoma. This therapy relies on a binary process in which the capture of a slow neutron by a 10B nucleus leads to an energetic nuclear fission reaction, with the formation of 7Li3+ and 4He2+ and accompanied by about 2.4 MeV of energy. The fleeting 7Li3+ and 4He2+ travel a distance of only about the diameter of one cell, and they are deadly to any cell in which they have been produced. Research in progress is concerned with the development of advanced boron agents and neutron sources, other than nuclear reactors, for the treatment of a variety of cancer types using novel 10B delivery methods. Non-malignant diseases such as rheumatoid arthritis offer additional opportunities for BNCT. The entire BNCT area awaits commercialization.

Animals↗

PubMed1997

Imaging of boron in tissue at the cellular level for boron neutron capture therapy.

Glioblastoma multiforme, and other tumors involving the brain, are undergoing experimental treatment with a promising new technique: boron neutron capture therapy (BNCT). BNCT relies on the capture of thermal neutrons by boron deposited biochemically in the tumor and the subsequent fission of the boron into energetic lithium ions and alpha particles. An important requirement for improved BNCT is the development of more selective boron delivery mechanisms. The ability to image the boron concentration in tissue sections and even inside individual cells would be an important aid in the development of these delivery mechanisms. We have compared both sputter-initiated resonance ionization microprobe (SIRIMP), which combines resonance ionization with a high-energy pulsed focused sputter ion beam and mass spectrometric detection of ions, with laser atomization resonance ionization microprobe (LARIMP), which uses a laser pulse instead of an ion pulse for the atomization process, to determine their characteristics in locating and quantifying boron concentrations as a function of position in tissues obtained from a rat which had been infused with a BNCT drug. The data show that the SIRIMP/LARIMP techniques are well suited for quantitative and ultrasensitive imaging of boron trace element concentrations in biological tissue sections. The LARIMP mode could be used to quickly determine the spatial boron concentration with intercellular resolution over large areas down to the low nanograms-per-gram level, while the SIRIMP mode could be used to determine the spatial boron concentration and its variability in intracellular areas.

Animals↗

PubMedDate not supplied

Boronated starburst dendrimer-monoclonal antibody immunoconjugates: evaluation as a potential delivery system for neutron capture therapy.

Boron neutron capture therapy (BNCT) is based on the nuclear capture reaction that occurs when boron-10, a stable isotope, is irradiated with low-energy or thermal neutrons (< or = 0.025 eV) to yield high LET alpha particles and recoiling 7Li nuclei [10B + nth-->[11B]-->4He(alpha) + 7Li + 2.39 MeV]. Approximately 10(9) boron-10 atoms must be delivered to each target cell in order to sustain a lethal 10B(n,alpha)7Li reaction. If MoAbs are to be used for targeting boron-10, then it is essential that they recognize a surface membrane epitope that is highly expressed on tumor cells and that a large number of boron-10 atoms be attached to each antibody molecule. In order to heavily boronate MoAbs, we have utilized starburst dendrimers (SD), which are precise, spherical macromolecules composed of repetitive poly(amidoamino) groups. Second- and fourth-generation dendrimers, having 12 and 48 reactive terminal amino groups and molecular weights of 2414 and 10,632 Da, respectively, were boronated using an isocyanato polyhedral borane, Na(CH3)3NB10H8NCO. The boronated starburst dendrimers (BSD), in turn, were derivatized with m-maleimidobenzoyl N-hydroxysulfosuccinimide ester (sulfo-MBS). The MoAbIB16-6, which is directed against the murine B16 melanoma, was derivatized with N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP). The MBS-derivatized BSD and SPDP-derivatized MoAb were reacted to yield stable immunoconjugates.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMedDate not supplied

Boron-containing folate receptor-targeted liposomes as potential delivery agents for neutron capture therapy.

Boron neutron capture therapy (BNCT) depends on the selective delivery of a sufficient number of (10)B atoms to tumor cells to sustain a lethal (10)B(n,alpha)(7)Li reaction. Expression of FR frequently is amplified among human tumors. The goal of the present study was to investigate folate receptor (FR)-targeted liposomes as potential carriers for a series of boron-containing agents. Two highly ionized boron compounds, Na(2)[B(12)H(11)SH] and Na(3) (B(20)H(17)NH(3)), were incorporated into liposomes by passive loading with encapsulation efficiencies of 6% and 15%, respectively. In addition, five weakly basic boronated polyamines were investigated. Two were the spermidine derivatives: N(5)-(4-carboranylbutyl)spermidine.3HCl (SPD-5), N(5)-[4-(2-aminoethyl-o-carboranyl)butyl]spermidine.4HCl (ASPD-5). Three were the spermine derivatives: N(5)-(4-carboranylbutyl)spermine.4HCl (SPM-5), N(5)-[4-(2-aminoethyl-o-carboranyl)butyl]spermine.5HCl (ASPM-5), and N(5),N(10)-bis(4-carboranylbutyl)spermine.4 HCl (SPM-5,10). These were incorporated into liposomes by a pH-gradient-driven remote-loading method with varying loading efficiencies, which were influenced by the specific trapping agent and the structure of the boron compound. Greater loading efficiencies were obtained with lower molecular weight boron derivatives, using ammonium sulfate as the trapping agent, compared to those obtained with sodium citrate. The in vitro uptake of folate-derivatized, boronated liposomes was investigated using human KB squamous epithelial cancer cells, which have amplified FR expression. Higher cellular boron uptake (up to 1584 microg per 10(9) cells) was observed with FR-targeted liposomes than with nontargeted control liposomes (up to 154 microg per 10(9) cells), irrespective of the chemical form of the boron and the method used for liposomal preparation. KB cell binding of the FR-targeted liposomes was saturable and could be blocked by 1 mM free folic acid. Our findings suggest that further evaluation of FR-targeted liposomes is warranted to assess their potential as boron carriers for neutron capture therapy.

Boron Compounds↗