Boron neutron capture therapy in cancer: past, present and future

Pisarev, Mario A.; Dagrosa, María Alejandra; Juvenal, Guillermo

doi:10.1590/s0004-27302007000500024

Cited by 31 publications

(22 citation statements)

References 17 publications

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“…An ideal BNCT agent would have minimal systemic cytotoxicity and most importantly selective tumor accumulation with a T/N ratio of 3:1 or greater (6, 8, 35-40). In vitro cellular uptake studies show that B-381 selectively accumulated in a hypoxic tumor environment.…”

Section: Discussionmentioning

confidence: 99%

A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma

et al. 2016

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Purpose Boron neutron capture therapy (BNCT) has the potential to become a viable cancer treatment modality, but its clinical translation has been limited by the poor tumor selectivity of agents. To address this unmet need, a boronated 2-nitroimidazole derivative (B-381) was synthesized and evaluated for its capability of targeting hypoxic glioma cells. Methods B-381 has been synthesized from a 1-step reaction. Using D54 and U87 glioma cell lines, the in vitro cytotoxicity and cellular accumulation of B-381 has been evaluated under normoxic and hypoxic conditions compared to L-boronophenylalanine (BPA). Furthermore, tumor retention of B-381 was evaluated in vivo. Results B-381 had low cytotoxicity in normal and cancer cells. Unlike BPA, B-381 illustrated preferential retention in hypoxic glioma cells compared to normoxic glioma cells and normal tissues in vitro. In vivo, B-381 illustrated significantly higher long-term tumor retention compared to BPA, with 9.5-fold and 6.5-fold higher boron levels at 24 and 48 h, respectively. Conclusions B-381 represents a new class of BNCT agents in which their selectivity to tumors is based on tumor hypoxic metabolism, and further studies are warranted to evaluate this compound and similar compounds as preclinical candidates for future BNCT clinical trials for the treatment of glioma.

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Section: Discussionmentioning

confidence: 99%

A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma

et al. 2016

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“…The advantages of boron neutron capture therapy (BNCT) have been demonstrated in the treatment of malignant glioblastomas, melanomas and other cancers because of its selective destruction of tumor cells [1–3]. In essence, a non-cytotoxic boron compound is selectively enriched in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Effect of bevacizumab treatment on p-boronophenylalanine distribution in murine tumor

Liu

Suzuki

Masunaga

et al. 2012

Journal of Radiation Research

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Previous studies have demonstrated that angiogenesis inhibitors can enhance tumor inhibitory effects of chemo- and radiotherapy via their action on tumor vessels. Here, we studied the effect of the angiogenesis inhibitor, bevacizumab (Avastin), on boron distribution in a murine tumor model. The human head and neck squamous cell carcinoma cell line was used for inoculation into mice. Boron-10 concentrations in tissues were measured by prompt γ-ray spectrometry (PGA). Hoechst 33342 perfusion and p-boronophenylalanine (BPA) distribution were determined by immunofluorescence staining. Our results revealed enhanced tumor blood perfusion and BPA accumulation in tumors after Avastin treatment, suggesting that combination of angiogenesis inhibition with treatment with boron compound administration may improve the efficacy of boron neutron capture therapy (BNCT) by modifying tumor vessels. In addition, our results also demonstrated the usefulness of immunofluorescence staining for investigating boron compound distribution at the cellular level.

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“…For example, the method is currently used as an adjunct to surgery in the treatment of glioblastoma multiforme (Yamamoto et al, 2008). The effectiveness of BNCT relies on its ability to eradicate micrometastases in the brain that are otherwise undetectable by surgical methods (Pisarev et al, 2007). BNCT uses an isotope of boron to deliver targeted bursts of radiation to malignant cells.…”

Section: Introductionmentioning

confidence: 99%

Permeability of the Blood-Brain Barrier to a Rhenacarborane

Hawkins¹,

Jelliss²,

Nonaka³

et al. 2009

J Pharmacol Exp Ther

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The treatment of brain malignancies with boron neutron capture therapy depends on their ability to cross the blood-brain barrier (BBB). An especially promising class of boron-containing compounds is the rhenacarboranes that, if able to cross the BBB, could act as delivery vehicles as well as a source of boron. Here, we examined the ability of the 3-NO-3,3-2 -(2,2Ј-N 2 C 10 H 6 (Me){(CH 2 ) 7 131 I}-4,4Ј)-closo-3,1,2-ReC 2 B 9 H 11 (rhenacarborane) labeled with iodine-131 to be taken up into the bloodstream after subcutaneous administration and to cross the BBB. The 131 I-rhenacarborane was quickly absorbed from the injection site and reached a steady state in arterial serum of 2.59%/ml of the administered dose. Between 73 and 95% of the radioactivity in serum 6 h after administration represented intact 131 I-rhenacarborane. Its octanol/buffer partition coefficient was 1.74, showing it to be lipophilic. Tissue/serum ratios for brain, lung, and liver showed classic patterns for a lipidsoluble substance with high levels immediately achieved and rapid redistribution. For brain, a steady state of approximately 0.107% of the administered dose/gram-brain was rapidly reached, and 71% of the radioactivity in brain 6 h after subcutaneous administration represented intact 131 I-rhenacarborane. Steady-state values were 1.53 and 0.89% of the injected dose per gram for lung and liver, respectively. 131 I-Rhenacarborane was quickly effluxed from brain by a nonsaturable system after its injection into the lateral ventricle of the brain. In conclusion, these results show that a rhenacarborane was enzymatically resistant and able to cross the BBB by transmembrane diffusion and accumulate in brain in substantial amounts. This supports their use as therapeutic agents for targeting the central nervous system. Boron neutron capture therapy (BNCT) holds promise as a treatment for various malignancies of the central nervous system (CNS). For example, the method is currently used as an adjunct to surgery in the treatment of glioblastoma multiforme (Yamamoto et al., 2008). The effectiveness of BNCT relies on its ability to eradicate micrometastases in the brain that are otherwise undetectable by surgical methods (Pisarev et al., 2007). BNCT uses an isotope of boron to deliver targeted bursts of radiation to malignant cells. Upon uptake into the cells, boron-10 is externally irradiated with neutrons and becomes unstable, decaying to lithium and releasing a high-energy ␣ particle. A further advantage is that boron can form polyhedral clusters that allow for the delivery of multiple boron-10 atoms in a single molecule. The potency of treatment as well as the selectivity of neutron captures by the boron atom makes this option an encouraging alternative to other more toxic therapies.An especially promising class of boron compounds are the closo-3,1,2-ReC 2 B 9 rhenacarboranes, which consist of nidoicosahedral carborane cages 5 -bonded to the d-block transition element rhenium (Hawthorne, 1968;Blandford et al., 1998;Fischer et al., 200...

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Boron neutron capture therapy in cancer: past, present and future

Cited by 31 publications

References 17 publications

A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma

A Hypoxia-Targeted Boron Neutron Capture Therapy Agent for the Treatment of Glioma

Effect of bevacizumab treatment on p-boronophenylalanine distribution in murine tumor

Permeability of the Blood-Brain Barrier to a Rhenacarborane

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