Albert H. Soloway

Advances in Neutron Capture Therapy

This volume contains the proceedings of the Fifth International Symposium on Neutron Capture Therapy held September 14--17, 1992 in Columbus, Ohio. Individual papers were separately abstracted and indexed for the database.

Boron neutron capture therapy of brain tumors: an emerging therapeutic modality.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10, a stable isotope, is irradiated with low-energy thermal neutrons to yield alpha particles and recoiling lithium-7 nuclei. For BNCT to be successful, a large number of 10B atoms must be localized on or preferably within neoplastic cells, and a sufficient number of thermal neutrons must be absorbed by the 10B atoms to sustain a lethal 10B (n, alpha) lithium-7 reaction. There is a growing interest in using BNCT in combination with surgery to treat patients with high-grade gliomas and possibly metastatic brain tumors. The present review covers the biological and radiobiological considerations on which BNCT is based, boron-containing low- and high-molecular weight delivery agents, neutron sources, clinical studies, and future areas of research. Two boron compounds currently are being used clinically, sodium borocaptate and boronophenylalanine, and a number of new delivery agents are under investigation, including boronated porphyrins, nucleosides, amino acids, polyamines, monoclonal and bispecific antibodies, liposomes, and epidermal growth factor. These are discussed, as is optimization of their delivery. Nuclear reactors currently are the only source of neutrons for BNCT, and the fission reaction within the core produces a mixture of lower energy thermal and epithermal neutrons, fast or high-energy neutrons, and gamma-rays. Although thermal neutron beams have been used clinically in Japan to treat patients with brain tumors and cutaneous melanomas, epithermal neutron beams now are being used in the United States and Europe because of their superior tissue-penetrating properties. Currently, there are clinical trials in progress in the United States, Europe, and Japan using a combination of debulking surgery and then BNCT to treat patients with glioblastomas. The American and European studies are Phase I trials using boronophenylalanine and sodium borocaptate, respectively, as capture agents, and the Japanese trial is a Phase II study. Boron compound and neutron dose escalation studies are planned, and these could lead to Phase II and possibly to randomized Phase III clinical trials that should provide data regarding therapeutic efficacy.

Boron neutron capture therapy of brain tumors: enhanced survival and cure following blood–brain barrier disruption and intracarotid injection of sodium borocaptate and boronophenylalanine

PURPOSE Boronophenylalanine (BPA) and sodium borocaptate (Na(2)B(12)H(11)SH or BSH) have been used clinically for boron neutron capture therapy (BNCT) of high-grade gliomas. These drugs appear to concentrate in tumors by different mechanisms and may target different subpopulations of glioma cells. The purpose of the present study was to determine if the efficacy of BNCT could be further improved in F98-glioma-bearing rats by administering both boron compounds together and by improving their delivery by means of intracarotid (i.c.) injection with or without blood-brain barrier disruption (BBB-D). METHODS AND MATERIALS For biodistribution studies, 10(5) F98 glioma cells were implanted stereotactically into the brains of syngeneic Fischer rats. Eleven to 13 days later animals were injected intravenously (i.v.) with BPA at doses of either 250 or 500 mg/kg body weight (b.w.) in combination with BSH at doses of either 30 or 60 mg/kg b.w. or i.c. with or without BBB-D, which was accomplished by i.c. infusion of a hyperosmotic (25%) solution of mannitol. For BNCT studies, 10(3) F98 glioma cells were implanted intracerebrally, and 14 days later animals were transported to the Brookhaven National Laboratory (BNL). They received BPA (250 mg/kg b.w.) in combination with BSH (30 mg/kg b.w. ) by i.v. or i.c. injection with or without BBB-D, and 2.5 hours later they were irradiated with a collimated beam of thermal neutrons at the BNL Medical Research Reactor. RESULTS The mean tumor boron concentration +/- standard deviation (SD) at 2.5 hours after i. c. injection of BPA (250 mg/kg b.w.) and BSH (30 mg/kg b.w.) was 56. 3 +/- 37.8 microgram/g with BBB-D compared to 20.8 +/- 3.9 microgram/g without BBB-D and 11.2 +/- 1.8 microgram/g after i.v. injection. Doubling the dose of BPA and BSH produced a twofold increase in tumor boron concentrations, but also concomitant increases in normal brain and blood levels, which could have adverse effects. For this reason, the lower boron dose was selected for BNCT studies. The median survival time was 25 days for untreated control rats, 29 days for irradiated controls, 42 days for rats that received BPA and BSH i.v., 53 days following i.c. injection, and 72 days following i.c. injection + BBB-D with subsets of long-term survivors and/or cured animals in the latter two groups. No histopathologic evidence of residual tumor was seen in the brains of cured animals. CONCLUSIONS The combination of BPA and BSH, administered i.c. with BBB-D, yielded a 25% cure rate for the heretofore incurable F98 rat glioma with minimal late radiation-induced brain damage. These results demonstrate that using a combination of boron agents and optimizing their delivery can dramatically improve the efficacy of BNCT in glioma-bearing rats.

Boron neutron capture therapy of brain tumors: past history, current status, and future potential.

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield alpha particles and recoiling lithium-7 nuclei. High-grade astrocytomas, glioblastoma multiforme, and metastatic brain tumors constitute a major group of neoplasms for which there is no effective treatment. There is growing interest in using BNCT in combination with surgery to treat patients with primary, and possibly metastatic brain tumors. For BNCT to be successful, a large number of 10B atoms must be localized on or preferably within neoplastic cells, and a sufficient number of thermal neutrons must reach and be absorbed by the 10B atoms to sustain a lethal 10B(n, alpha)7 Li reaction. Two major questions will be addressed in this review. First, how can a large number of 10B atoms be delivered selectively to cancer cells? Second, how can a high fluence of neutrons be delivered to the tumor? Two boron compounds currently are being used clinically, sodium borocaptate (BSH) and boronophenylalanine (BPA), and a number of new delivery agents are under investigation, including boronated porphyrins, nucleosides, amino acids, polyamines, monoclonal and bispecific antibodies, liposomes, and epidermal growth factor. These will be discussed, and potential problems associated with their use as boron delivery agents will be considered. Nuclear reactors, currently, are the only source of neutrons for BNCT, and the fission process within the core produces a mixture of lower-energy thermal and epithermal neutrons, fast or high (> 10,000 eV) energy neutrons, and gamma rays. Although thermal neutron beams have been used clinically in Japan to treat patients with brain tumors and cutaneous melanomas, epithermal neutron beams should be more useful because of their superior tissue-penetrating properties. Beam sources and characteristics will be discussed in the context of current and future BNCT trials. Finally, the past and present clinical trials on BNCT for brain tumors will be reviewed and the future potential of BNCT will be assessed.

Boron neutron capture therapy of brain tumors: Enhanced survival following intracarotid injection of sodium borocaptate with or without blood-brain barrier disruption

PURPOSE Sodium borocaptate (Na2B12H11SH or BSH) has been used clinically for boron neutron capture therapy (BNCT) of patients with primary brain tumors. The purpose of the present study was to determine if tumor uptake of BSH and efficacy of BNCT could be enhanced in F98 glioma-bearing rats by intracarotid (i.c.) injection of the compound with or without blood-brain barrier disruption (BBB-D). METHODS AND MATERIALS For biodistribution studies 100,000 F98 glioma cells were implanted stereotactically into the brains of Fischer rats, and 12 days later BBB-D was carried out by i.c. infusion of 25% mannitol, followed immediately thereafter by i.c. injection of BSH (30 mg B/kg body weight). Animals were killed 1, 2.5, and 5 h later, and their brains were removed for boron determination. For BNCT experiments, which were initiated 14 days after intracerebral implantation of 1000 F98 cells, BSH (30 mg B/kg b.wt. was administered intravenously (i.v.) without BBB-D, or i.c. with or without BBB-D. The animals were irradiated 2.5 h later with a collimated beam of thermal neutrons at the Brookhaven National Laboratory Medical Research Reactor. RESULTS The mean tumor boron concentration after i.c. injection with BBB-D was 48.6 +/- 17.2 microg/g at 2.5 h compared with 30.8 +/- 12.2 microg/g after i.c. injection without BBB-D and 12.9 +/- 4.2 microg/g after i.v. injection. The best composite tumor to normal tissue ratios were observed at 2.5 h after BBB-D, at which time the tumor:blood (T:B1) ratio was 5.0, and the tumor: brain (T:Br) ratio was 12.3, compared to 1.1 and 4.6, respectively, in i.v. injected rats. The mean survival time for untreated control rats was 24 +/- 3 days, 29 +/- 4 days for irradiated controls, 33 +/- 6 days for those receiving i.v. injection of BSH, 40 +/- 8 days for rats receiving i.c. BSH without BBB-D, and 52 +/- 13 days for BBB-D followed by BNCT (p = 0.003 vs. i.v. injected BSH). CONCLUSIONS Intracarotid administration of BSH with or without BBB-D significantly increased tumor uptake of BSH and enhanced survival of F98 glioma-bearing rats following BNCT. BBB-D may be a useful way to enhance the delivery of both low and high molecular weight boron compounds to brain tumors. Further studies are in progress to assess this approach with other boron delivery agents.

A general, convenient way to carborane-containing amino acids for boron neutron capture therapy

Abstract A general convenient procedure for the synthesis of caborane-containing amino acids in good yield has been developed. The synthesis of o-carboranylalanine 1, O-(o-carboran-1-ylmethyl)-tyrosine 2 and p-(o-carboran-1-yl)-phenylalanine 3 is reported.

Boron Neutron Capture Therapy of Brain Tumors: Biodistribution, Pharmacokinetics, and Radiation Dosimetry of Sodium Borocaptate in Patients with Gliomas

OBJECTIVEThe purpose of this study was to obtain tumor and normal brain tissue biodistribution data and pharmacokinetic profiles for sodium borocaptate (Na2B12H11SH) (BSH), a drug that has been used clinically in Europe and Japan for boron neutron capture therapy of brain tumors. The study was performed with a group of 25 patients who had preoperative diagnoses of either glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) and were candidates for debulking surgery. Nineteen of these patients were subsequently shown to have histopathologically confirmed diagnoses of GBM or AA, and they constituted the study population. METHODSBSH (non-10 B-enriched) was infused intravenously, in a 1-hour period, at doses of 15, 25, and 50 mg boron/kg body weight (corresponding to 26.5, 44.1, and 88.2 mg BSH/kg body weight, respectively) to groups of 3, 3, and 13 patients, respectively. Multiple samples of tumor tissue, brain tissue around the tumors, and normal brain tissue were obtained at either 3 to 7 or 13 to 15 hours after infusion. Blood samples for pharmacokinetic studies were obtained at times up to 120 hours after termination of the infusion. Sixteen of the patients underwent surgery at the Beijing Neurosurgical Institute and three at The Ohio State University, where all tissue samples were subsequently analyzed for boron content by direct current plasma-atomic emission spectroscopy. RESULTSBlood boron values peaked at the end of the infusion and then decreased triexponentially during the 120-hour sampling period. At 6 hours after termination of the infusion, these values had decreased to 20.8, 29.1, and 62.6 &mgr;g/ml for boron doses of 15, 25, and 50 mg/kg body weight, respectively. For a boron dose of 50 mg/kg body weight, the maximum (mean ± standard deviation) solid tumor boron values at 3 to 7 hours after infusion were 17.1 ± 5.8 and 17.3 ± 10.1 &mgr;g/g for GBMs and AAs, respectively, and the mean tumor value averaged across all samples was 11.9 &mgr;g/g for both GBMs and AAs. In contrast, the mean normal brain tissue values, averaged across all samples, were 4.6 ± 5.1 and 5.5 ± 3.9 &mgr;g/g and the tumor/normal brain tissue ratios were 3.8 and 3.2 for patients with GBMs and AAs, respectively. The large standard deviations indicated significant heterogeneity in uptake in both tumor and normal brain tissue. Regions histopathologically classified either as a mixture of tumor and normal brain tissue or as infiltrating tumor exhibited slightly lower boron concentrations than those designated as solid tumor. After a dose of 50 mg/kg body weight, boron concentrations in blood decreased from 104 &mgr;g/ml at 2 hours to 63 &mgr;g/ml at 6 hours and concentrations in skin and muscle were 43.1 and 39.2 &mgr;g/g, respectively, during the 3- to 7-hour sampling period. CONCLUSIONWhen tumor, blood, and normal tissue boron concentrations were taken into account, the most favorable tumor uptake data were obtained with a boron dose of 25 mg/kg body weight, 3 to 7 hours after termination of the infusion. Although blood boron levels were high, normal brain tissue boron levels were almost always lower than tumor levels. However, tumor boron concentrations were less than those necessary for boron neutron capture therapy, and there was significant intratumoral and interpatient variability in the uptake of BSH, which would make estimation of the radiation dose delivered to the tumor very difficult. It is unlikely that intravenous administration of a single dose of BSH would result in therapeutically useful levels of boron. However, combining BSH with boronophenylalanine, the other compound that has been used clinically, and optimizing their delivery could increase tumor boron uptake and potentially improve the efficacy of boron neutron capture therapy.

Boron neutron capture therapy of primary and metastatic brain tumors

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10, is irradiated with low energy (0.025 eV) thermal neutrons (nth) to yield alpha (4He) particles and,7Li nuclei (10B+nth→[11B]→4He+7Li+2.79 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of10B andnth to individual cancer cells to sustain a lethal10B(n, α)7Li reaction. Boron delivery agents include a variety of compounds, such as the sulfhydryl containing polyhedral borane sodium borocaptate (Na2B12H11SH, [BSH]), boronoporphyrins, boronophenylalanine, carboranyl uridines (CBU), and boronated monoclonal antibodies (MAb). The present review will focus on three delivery systems that currently are under investigation in our laboratories, boronated monoclonal antibodies, carboranyl uridines, and boronophenylalanine. Methodology has been developed to heavily boronate MAb using a precision macromolecule, a “starburst” dendrimer, which can be linked to MAb by means of heterobifunctional reagents. Although the resulting immunoconjugates retain their in vitro immunoreactivity, they lose their in vivo tumor localizing properties and accumulate in the liver. In order to obviate this problem, work is now in progress to produce bispecific MAb, which can simultaneously recognize a tumor-associated antigen and a boronated macromolecule. Boron containing, nucleosides are potential vehicles for incorporating boron compounds into nucleic acids of neoplastic cells. For this purpose, carboranyl uridines have been synthesized with the boron moiety on either the pyrimidine base or on the carbohydrate component. Although such structures appear to be avidly taken up and retained by tumor cells in vitro, only the 5-carboranyl-nucleosides are converted biologically to the nucleotide. There is no evidence, however, that the latter are incorporated into nucleic acids. Other carboranyl nucleosides currently are being synthesized that may have better tumor localizing properties. The potential use of boronophenylalanine as a capture agent for the treatment of melanoma metastatic to the brain also is under investigation. A nude rat model has been developed using human melanoma cells that are stereotactically implanted into the brain. BNCT-treated animals have either had prolonged survival times or continue to live compared to control rats that invariably died of their tumors, thereby suggesting therapeutic efficacy.

A nude rat model for neutron capture therapy of human intracerebral melanoma

PURPOSE The present study was carried out to determine the efficacy of Boron Neutron Capture Therapy (BNCT) for intracerebral melanoma using nude rats, the human melanoma cell line MRA 27, and boronophenylalanine as the capture agent. METHODS AND MATERIALS Pharmacokinetic and tissue distribution studies: MRA 27 cells (2 x 10(5)) were implanted intracerebrally, and 30 days later, 120 mg of 10B-L-BPA were injected intraperitoneally into nude rats. Therapy experiments: Thirty days following implantation, tumor bearing rats were irradiated at the Brookhaven Medical Research Reactor. RESULTS Pharmacokinetic experiments: Six hours following administration of BPA, tumor, blood, and normal brain boron-10 levels were 23.7, 9.4, and 8.4 micrograms/g respectively. Therapy experiments: Median survival time of untreated rats was 44 days compared to 76 days and 93 days for those receiving physical doses of 2.73 Gy and 3.64 Gy, respectively. Rats that had received both 10B-BPA and physical doses of 1.82, 2.73, or 3.64 Gy had median survival times of 170, 182, and 262 days, respectively. Forty percent of rats that had received the highest tumor dose (10.1 Gy) survived for > 300 days and in a replicate experiment 21% of the rats were longterm survivors (> 220 days). Animals that received 12 Gy in a single dose or 18 Gy fractionated (2 Gy x 9) of gamma photons from a 137Cs source had median survival times of 86 and 79 days, respectively, compared to 47 days for untreated animals. Histopathologic examination of the brains of longterm surviving rats, euthanized at 8 or 16 months following BNCT, showed no residual tumor, but dense accumulations of melanin laden macrophages and minimal gliosis were observed. CONCLUSION Significant prolongations in median survival time were noted in nude rats with intracerebral human melanoma that had received BNCT thereby suggesting therapeutic efficacy. Large animal studies should be carried out to further assess BNCT of intracerebral melanoma before any human trials are contemplated.

Strategies for the design and synthesis of boronated nucleic acid and protein components as potential delivery agents for neutron capture therapy

PURPOSE Strategies for the design and synthesis of boronated nucleosides, amino acids, and peptides as potential delivery agents for boron neutron capture therapy (BNCT) are described. METHODS AND MATERIALS For BNCT to be a useful treatment modality, there is a need to design and synthesize nontoxic boron compounds that selectively target tumor cells, accumulate in sufficient amounts (20-30 micrograms 10B/g of tumor) and persist at therapeutic levels for a sufficient time prior to neutron irradiation. Boronated nucleosides, amino acids and peptides are such promising target compounds. Such structures may be selectively used by proliferating neoplastic cells compared with mitotically less active normal cells and therefore achieve the tissue differentials necessary for BNCT. RESULTS The rationale for synthesis of boronated nucleic acid and protein components is discussed. Results of biological and clinical studies of some boronated nucleosides, nucleotides, amino acids and peptides are presented. CONCLUSION Boronated nucleosides, amino acids and peptides can be considered as potential targeting agents for BNCT.