Measurements of neutron distribution in neutrons–γ-rays mixed field using imaging plate for neutron capture therapy

The imaging plate (IP) technique is tried to be used as a handy method to measure the spatial neutron distribution via the ¹⁵⁷Gd(n,γ)¹⁵⁸Gd reaction for neutron capture therapy (NCT). For this purpose, IP is set in a water phantom and irradiated in a mixed field of neutrons and γ-rays. The Hiroshima University Radiobiological Research Accelerator is utilized for this experiment. The neutrons are moderated with 20-cm-thick D₂O to obtain suitable neutron field for NCT. The signal for IP doped with Gd as a neutron-response enhancer is subtracted with its contribution by γ-rays, which was estimated using IP without Gd. The γ-ray response of Gd-doped IP to non-Gd IP is set at 1.34, the value measured for ⁶⁰Co γ-rays, in estimating the γ-ray contribution to Gd-doped IP signal. Then measured distribution of the ¹⁵⁷Gd(n,γ)¹⁵⁸Gd reaction rate agrees within 10% with the calculated value based on the method that has already been validated for its reproducibility of Au activation. However, the evaluated distribution of the ¹⁵⁷Gd(n,γ)¹⁵⁸Gd reaction rate is so sensitive to γ-ray energy, e.g. the discrepancy of the ¹⁵⁷Gd(n,γ)¹⁵⁸Gd reaction rate between measurement and calculation becomes 30% for the photon energy change from 33 keV to 1.253 MeV.     

The usefulness of 2-nitroimidazole-sodium borocaptate-10B conjugates as 10B-carriers in boron neutron capture therapy.

We evaluated the usefulness of five new (10)B-compounds (TX-2016, TX-2017, TX-2018, TX-2041, and TX-2042) as (10)B-carriers in boron neutron capture therapy (BNCT). They are 2-nitroimidazole-sodium borocaptate-(10)B (BSH) conjugates, that is, hybrid compounds that have both hypoxic tumor cell sensitizing unit under gamma-ray irradiation, 2-nitroimidazoles, and thermal neutron-sensitizing unit, BSH. (10)B distribution analyses in tumors and blood indicated that TX-2041 has the most favorable characteristics for localizing a sufficient amount of (10)B into tumors and keeping the (10)B concentration high during neutron beam irradiation. In addition, TX-2041 showed a significantly higher radio-sensitization effect with reactor thermal neutron beams than BSH on both total (=proliferating (P) + quiescent (Q)) and hypoxia-rich Q cell populations in solid tumors. Further, TX-2041 clearly demonstrated a radio-sensitization effect with gamma-rays on both cell populations, which could never be achieved by BSH. (10)B-carriers with a hypoxic tumor cell-sensitizing effect on tumors with gamma-rays as well as the potential to selectively localize and keep (10)B in tumors, such as TX-2041, are promising for use in actual BNCT.     

Evaluation of hypoxia-specific cytotoxic bioreductive agent-sodium borocaptate-10B conjugates as10B-carriers in boron neutron capture therapy

Purpose

To evaluate the usefulness of 5 new¹⁰B-compounds (TX-2091, TX-2095, TX-2097, TX-2100, and TX-2110) as¹⁰B-carriers in boron neutron capture therpy (BNCT). They were conjugates that had been synthesized from a hypoxia-specific cytotoxic bioreductive agent, quinoxaline oxide TX-402 and a clinically used¹⁰B-carrier, sodium borocaptate-¹⁰B (BSH).

Materials and Methods

The 5 new compounds were hybrid compounds that have both a hypoxic cytotoxin unit and a thermal neutron-sensitizing unit, BSH. These new compounds and BSH were administered intraperitoneally to SCC VII tumor-bearing mice. Then, the¹⁰B concentrations in the tumors and normal tissues were measured by γ-ray spectrometry. Subsequently, SCC VII tumor-bearing mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2100, which was chosen based on the results of the above-mentioned biodistribution analyses, or BSH in the same manner as in the biodistribution studies. Right after irradiation, during which intratumor¹⁰B concentrations were kept at levels similar to each other, the tumors were excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling [=quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in the total (P+Q) tumor cell population was determined from the tumors that were not pretreated with BrdU. Clonogenic cell survival was also determined in mice given no BrdU.

Results

¹⁰B biodistribution analyses in tumors, brain, skin, muscles, blood, and liver indicated that TX-2100 has the most favorable characteristics for concentrating a sufficient amount of¹⁰B in tumors and maintaining a high enough¹⁰B concentration during irradiation. In addition, TX-2100 had a significantly stronger radio-sensitizing effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2100 clearly exhibited a radio-sensitizing effect with γ-rays not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH.

Conclusion

A¹⁰B-carrier that acts as a hypoxic cytotoxin on tumor cells as well as having the potential to keep¹⁰B in tumors and sensitize tumor cells more markedly than conventional¹⁰B-carriers, such as TX-2100, is a promising candidate for use in BNCT.     

Evaluation of hypoxia-specific cytotoxic bioreductive agent-sodium borocaptate-10B conjugates as 10B-carriers in boron neutron capture therapy

Purpose To evaluate the usefulness of 5 new¹⁰B-compounds (TX-2091, TX-2095, TX-2097, TX-2100, and TX-2110) as¹⁰B-carriers in boron neutron capture therpy (BNCT). They were conjugates that had been synthesized from a hypoxia-specific cytotoxic bioreductive agent, quinoxaline oxide TX-402 and a clinically used¹⁰B-carrier, sodium borocaptate-¹⁰B (BSH). Materials and Methods The 5 new compounds were hybrid compounds that have both a hypoxic cytotoxin unit and a thermal neutron-sensitizing unit, BSH. These new compounds and BSH were administered intraperitoneally to SCC VII tumor-bearing mice. Then, the¹⁰B concentrations in the tumors and normal tissues were measured by γ-ray spectrometry. Subsequently, SCC VII tumor-bearing mice were continuously given 5-bromo-2′-deoxyuridine (BrdU) to label all proliferating (P) cells in the tumors, then treated with TX-2100, which was chosen based on the results of the above-mentioned biodistribution analyses, or BSH in the same manner as in the biodistribution studies. Right after irradiation, during which intratumor¹⁰B concentrations were kept at levels similar to each other, the tumors were excised, minced, and trypsinized. The tumor cell suspensions thus obtained were incubated with cytochalasin-B (a cytokinesis blocker), and the micronucleus (MN) frequency in cells without BrdU labeling [=quiescent (Q) cells] was determined using immunofluorescence staining for BrdU. Meanwhile, the MN frequency in the total (P+Q) tumor cell population was determined from the tumors that were not pretreated with BrdU. Clonogenic cell survival was also determined in mice given no BrdU. Results ¹⁰B biodistribution analyses in tumors, brain, skin, muscles, blood, and liver indicated that TX-2100 has the most favorable characteristics for concentrating a sufficient amount of¹⁰B in tumors and maintaining a high enough¹⁰B concentration during irradiation. In addition, TX-2100 had a significantly stronger radio-sensitizing effect with reactor thermal neutron beams than BSH on both total and Q cells in solid tumors. Further, TX-2100 clearly exhibited a radio-sensitizing effect with γ-rays not only on total cells but also on Q and hypoxic tumor cells, which was not achieved by BSH. Conclusion A¹⁰B-carrier that acts as a hypoxic cytotoxin on tumor cells as well as having the potential to keep¹⁰B in tumors and sensitize tumor cells more markedly than conventional¹⁰B-carriers, such as TX-2100, is a promising candidate for use in BNCT. A part of this paper was presented at the 64th JRS annual meeting in Yokohama on April 8, 2005.     

The interpretation of dose calculations and cell-survival measurements for the boron neutron capture therapy of brain tumours with 24 keV neurons

Monte-Carlo computer codes have been used to estimate the distribution of doses to borated and unborated tissues in head-sized phantoms when exposed to beams of 2 keV and 24 keV neutrons. For the application of such beams to boron neutron capture therapy (BNCT) these calculations show the superiority of 2 keV neutrons over 24 keV neutrons and the importance of using large-area beams. A 24 keV neutron beam has been used to irradiate HeLa cell cultures in vitro, with and without the addition of 10B, at various depths within a narrow polyethylene phantom. Survival data obtained from these experiments have been used to estimate depth-damage profiles for normal (unboronated) and tumour (boronated) brain tissues when exposed to 24 keV neutrons. A good differential between damage to normal and tumorous tissue is obtained under suitable irradiation conditions. Although lower-energy neutrons are probably preferable, these results demonstrate the possibility of using beams of 24 keV neutrons for the BNCT of brain tumours.     

用于硼中子俘获治疗的超热中子束理论设计

目的 设计用于硼中子俘获治疗(BNCT)的超热中子束理论方案。方法 基于清华大学试验核反应堆,以其1号孔道为材料布放孔道,设计了由慢化材料、热中子吸收材料、γ屏蔽材料组成,但材料布放位置具有差异的5种理论方案;利用蒙特卡罗(MC)模拟方法,分别计算5种方案束出口处的中子注量率、剂量率及γ剂量率值,通过与BNCT技术指标对比,从5种方案中选择一种合适的方案。结果 得到了一个符合BNCT各项技术指标的超热中子束理论方案,其慢化材料厚度为53.5 cm、热中子吸收材料厚度为2 mm、γ屏蔽材料厚度为9 cm。结论 本研究给出的超热中子束理论方案为基于反应堆实现BNCT提供一定的理论参考。