Boron neutron capture therapy: Current status and future perspectives

The development of new accelerators has given a new impetus to the development of new drugs and treatment technologies using boron neutron capture therapy (BNCT). We analyzed the current status and future directions of BNCT for cancer treatment, as well as the main issues related to its introduction. This review highlights the principles of BNCT and the key milestones in its development: new boron delivery drugs and different types of charged particle accelerators are described; several important aspects of BNCT implementation are discussed. BCNT could be used alone or in combination with chemotherapy and radiotherapy, and it is evaluated in light of the outlined issues. For the speedy implementation of BCNT in medical practice, it is necessary to develop more selective boron delivery agents and to generate an epithermal neutron beam with definite characteristics. Pharmacological companies and research laboratories should have access to accelerators for large‐scale screening of new, more specific boron delivery agents.

[1]  P. Mi,et al.  Polymeric Micelles with Endosome Escape and Redox-Responsive Functions for Enhanced Intracellular Drug Delivery. , 2019, Journal of biomedical nanotechnology.

[2]  Yi-Wei Chen,et al.  Pulsed-Focused Ultrasound Enhances Boron Drug Accumulation in a Human Head and Neck Cancer Xenograft-Bearing Mouse Model , 2014, Molecular Imaging and Biology.

[3]  Y. Omidi,et al.  Blood-brain barrier transport machineries and targeted therapy of brain diseases , 2016, BioImpacts : BI.

[4]  N. Nonoguchi,et al.  Survival benefit from boron neutron capture therapy for the newly diagnosed glioblastoma patients. , 2009, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[5]  S. Altieri,et al.  Selective uptake of p-boronophenylalanine by osteosarcoma cells for boron neutron capture therapy. , 2009, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[6]  M. Yoshioka.  Review of Accelerator-based Boron Neutron Capture Therapy Machines , 2016 .

[7]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[8]  T. Komori,et al.  The 2016 WHO Classification of Tumours of the Central Nervous System: The Major Points of Revision , 2017, Neurologia medico-chirurgica.

[9]  B. Çalişkan,et al.  Interaction with Matter of Ionizing Radiation and Radiation Damages (Radicals) , 2018 .

[10]  Satoshi Nakamura,et al.  Non‐invasive estimation of 10B‐4‐borono‐L‐phenylalanine‐derived boron concentration in tumors by PET using 4‐borono‐2‐18F‐fluoro‐phenylalanine , 2018, Cancer science.

[11]  M. Narabayashi,et al.  Pilot clinical study of boron neutron capture therapy for recurrent hepatic cancer involving the intra-arterial injection of a (10)BSH-containing WOW emulsion. , 2014, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[12]  L. Policastro,et al.  Reprint of Application of BNCT to the treatment of HER2+ breast cancer recurrences: Research and developments in Argentina. , 2015, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[13]  H. Hatanaka.  Clinical results of boron neutron capture therapy. , 1990, Basic life sciences.

[14]  B. Stockwell,et al.  Lipid peroxidation in cell death. , 2017, Biochemical and biophysical research communications.

[15]  Y. Yura,et al.  Effectiveness of BNCT for recurrent head and neck malignancies. , 2004, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[16]  J. Hendry,et al.  Radiobiology for the Radiologist , 1979, British Journal of Cancer.

[17]  M. Perona,et al.  Experimental Studies of Boronophenylalanine ((10)BPA) Biodistribution for the Individual Application of Boron Neutron Capture Therapy (BNCT) for Malignant Melanoma Treatment. , 2015, International journal of radiation oncology, biology, physics.

[18]  H. Kumada,et al.  Project for the development of the linac based NCT facility in University of Tsukuba. , 2014, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[19]  R. Kanaar,et al.  Characteristics of DNA-binding proteins determine the biological sensitivity to high-linear energy transfer radiation , 2010, Nucleic acids research.

[20]  A. Ito,et al.  DNA Strand Breaks Induced by Fast and Thermal Neutrons from YAYOI Research Reactor in the Presence and Absence of Boric Acid , 2019, Radiation Research.

[21]  Y. Uesugi,et al.  Planned fractionated boron neutron capture therapy using epithermal neutrons for a patient with recurrent squamous cell carcinoma in the temporal bone: A case report , 2009, Head & neck.

[22]  S. Savolainen,et al.  Boron neutron capture therapy in the treatment of locally recurred head-and-neck cancer: final analysis of a phase I/II trial. , 2012, International journal of radiation oncology, biology, physics.

[23]  K. Ono,et al.  BNCT for advanced or recurrent head and neck cancer. , 2014, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[24]  A. Diaz.  Assessment of the Results from the Phase I/II Boron Neutron Capture Therapy Trials at the Brookhaven National Laboratory from a Clinician's Point of View , 2004, Journal of Neuro-Oncology.

[25]  H. Joensuu,et al.  Boron neutron capture therapy for locally recurrent head and neck squamous cell carcinoma: An analysis of dose response and survival. , 2019, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[26]  L. Recht,et al.  Low-grade gliomas. , 1995, Neurologic clinics.

[27]  L. Mannina,et al.  Tetra-2,3-pyrazinoporphyrazines with Peripherally Appended Pyridine Rings. 19. Pentanuclear Octa(2-pyridyl)tetrapyrazinoporphyrazines Carrying Externally Carboranthiolate Groups: Physicochemical Properties and Potentialities as Anticancer Drugs. , 2018, Inorganic chemistry.

[28]  K. Ono,et al.  The Effect of p53 Status on Radio-Sensitivity of Quiescent Tumor Cell Population Irradiated With γ-Rays at Various Dose Rates , 2018, Journal of clinical medicine research.

[29]  S. Taskaev.  Accelerator based epithermal neutron source , 2015, Physics of Particles and Nuclei.

[30]  O. Desouky,et al.  Targeted and non-targeted effects of ionizing radiation , 2015 .

[31]  R. Musah,et al.  Impact on Glioblastoma U87 Cell Gene Expression of a Carborane Cluster-Bearing Amino Acid: Implications for Carborane Toxicity in Mammalian Cells. , 2018, ACS chemical neuroscience.

[32]  E. Chang,et al.  Effective treatment of glioblastoma requires crossing the blood-brain barrier and targeting tumors including cancer stem cells: The promise of nanomedicine. , 2015, Biochemical and biophysical research communications.

[33]  D. A. Gomes,et al.  An Assessment of the Potential Use of BNNTs for Boron Neutron Capture Therapy , 2017, Nanomaterials.

[34]  Youngjoo Byun,et al.  Evaluation of TK1 targeting carboranyl thymidine analogs as potential delivery agents for neutron capture therapy of brain tumors. , 2015, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[35]  W. Beard,et al.  A review of recent experiments on step-to-step “hand-off” of the DNA intermediates in mammalian base excision repair pathways , 2011, Molecular Biology.

[36]  S. Miyatake,et al.  Survival benefit of boron neutron capture therapy for recurrent malignant gliomas. , 2009, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[37]  P. Fisher,et al.  Autophagy: cancer's friend or foe? , 2013, Advances in cancer research.

[38]  S. Lipton,et al.  Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 , 2018, Cell Death & Differentiation.

[39]  L. Salford,et al.  Boron neutron capture therapy for glioblastoma multiforme: clinical studies in Sweden , 2007, Journal of Neuro-Oncology.

[40]  Y. Fujita,et al.  Effectiveness of boron neutron capture therapy for recurrent head and neck malignancies. , 2009, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[41]  I. Kato,et al.  Boronophenylalanine, a boron delivery agent for boron neutron capture therapy, is transported by ATB0,+, LAT1 and LAT2 , 2015, Cancer science.

[42]  M. S. Muthu,et al.  Transferrin liposomes of docetaxel for brain-targeted cancer applications: formulation and brain theranostics , 2016, Drug delivery.

[43]  S. Boulton,et al.  Playing the end game: DNA double-strand break repair pathway choice. , 2012, Molecular cell.

[44]  N. Nonoguchi,et al.  Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats , 2018, Radiation and environmental biophysics.

[45]  D. R. Smith,et al.  Quantitative imaging and microlocalization of boron-10 in brain tumors and infiltrating tumor cells by SIMS ion microscopy: relevance to neutron capture therapy. , 2001, Cancer research.

[46]  Y. Kajimoto,et al.  Modified boron neutron capture therapy for malignant gliomas performed using epithermal neutron and two boron compounds with different accumulation mechanisms: an efficacy study based on findings on neuroimages. , 2005, Journal of neurosurgery.

[47]  T. Hirayama,et al.  Design, Synthesis, and Evaluation of Lipopeptide Conjugates of Mercaptoundecahydrododecaborate for Boron Neutron Capture Therapy , 2019, ChemMedChem.

[48]  James R. Smith,et al.  Liposome formulations of o-carborane for the boron neutron capture therapy of cancer. , 2019, Biophysical chemistry.

[49]  N. Nonoguchi,et al.  Boron Neutron Capture Therapy Combined with Early Successive Bevacizumab Treatments for Recurrent Malignant Gliomas – A Pilot Study , 2018, Neurologia medico-chirurgica.

[50]  C. Yeh,et al.  Enhancing Boron Uptake in Brain Glioma by a Boron-Polymer/Microbubble Complex with Focused Ultrasound. , 2019, ACS applied materials & interfaces.

[51]  J. Chadwick,et al.  The existence of a neutron , 1932 .

[52]  G. Stella,et al.  Malignant pleural mesothelioma: history, controversy and future of a manmade epidemic , 2015, European Respiratory Review.

[53]  K. Ono,et al.  Boron neutron capture therapy for vulvar melanoma and genital extramammary Paget’s disease with curative responses , 2018, Cancer communications.

[54]  J. V. van Meerbeeck,et al.  Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moonshot? , 2017, Oncotarget.

[55]  A. Paetau,et al.  L-boronophenylalanine-mediated boron neutron capture therapy for malignant glioma progressing after external beam radiation therapy: a Phase I study. , 2011, International journal of radiation oncology, biology, physics.

[56]  G. Kabalka,et al.  Quantitative evaluation of boron neutron capture therapy (BNCT) drugs for boron delivery and retention at subcellular‐scale resolution in human glioblastoma cells with imaging secondary ion mass spectrometry (SIMS) , 2014, Journal of microscopy.

[57]  R. Jalali,et al.  Long-term Survivors of Childhood Brain Tumors: Impact on General Health and Quality of Life , 2017, Current Neurology and Neuroscience Reports.

[58]  Minoru Suzuki,et al.  Evaluation of a Novel Boron-Containing α-d-Mannopyranoside for BNCT , 2020, Cells.

[59]  N. Aswath,et al.  Boron Neutron Capture Therapy - A Literature Review. , 2016, Journal of clinical and diagnostic research : JCDR.

[60]  Jike Wang,et al.  The potential role of borophene as a radiosensitizer in boron neutron capture therapy (BNCT) and particle therapy (PT). , 2020, Biomaterials science.

[61]  Shinji Kawabata,et al.  Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer , 2012, Radiation oncology.

[62]  Haichao Wang,et al.  HMGB1 in health and disease. , 2014, Molecular aspects of medicine.

[63]  S. Savolainen,et al.  Biokinetic analysis of tissue boron (¹⁰B) concentrations of glioma patients treated with BNCT in Finland. , 2015, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[64]  Y. Matsumoto,et al.  Functionalized mesoporous silica nanoparticles for innovative boron-neutron capture therapy of resistant cancers , 2018, bioRxiv.

[65]  D. Winn,et al.  Smoking and drinking in relation to oral and pharyngeal cancer. , 1988, Cancer research.

[66]  H. Joensuu,et al.  Boron Neutron Capture Therapy in the Treatment of Recurrent Laryngeal Cancer. , 2016, International journal of radiation oncology, biology, physics.

[68]  J. Little.  Genomic instability and bystander effects: a historical perspective , 2003, Oncogene.

[69]  B. Ross,et al.  Convection enhanced delivery of boronated EGF as a molecular targeting agent for neutron capture therapy of brain tumors , 2009, Journal of Neuro-Oncology.

[70]  K. Ono,et al.  Reirradiation for locally recurrent lung cancer in the chest wall with boron neutron capture therapy (BNCT) , 2012, International Cancer Conference Journal.

[71]  A. B. Tiku,et al.  Significance and nature of bystander responses induced by various agents. , 2017, Mutation research.

[72]  A. Jemal,et al.  Annual Report to the Nation on the status of cancer, 1975‐2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer , 2014, Cancer.

[73]  H. Inohara,et al.  Boron delivery for boron neutron capture therapy targeting a cancer-upregulated oligopeptide transporter. , 2019, Journal of pharmacological sciences.

[74]  J. V. van Meerbeeck,et al.  Biomarkers for early diagnosis of malignant mesothelioma: Do we need another moonshot? , 2017, Oncotarget.

[75]  M. Ichihashi,et al.  First human clinical trial of melanoma neutron capture. Diagnosis and therapy. , 1989, Strahlentherapie und Onkologie : Organ der Deutschen Rontgengesellschaft ... [et al].

[76]  S. Miyatake,et al.  Boron Neutron Capture Therapy of Malignant Gliomas. , 2018, Progress in neurological surgery.

[77]  S. Thorp,et al.  Abscopal effect of boron neutron capture therapy (BNCT): proof of principle in an experimental model of colon cancer , 2017, Radiation and environmental biophysics.

[78]  Qiang Zhang,et al.  The Endocytic Mechanism and Cytotoxicity of Boron-containing Vesicles. , 2020, Chemical and pharmaceutical bulletin.

[79]  Jeffrey N Myers,et al.  TP53 Mutations in Head and Neck Squamous Cell Carcinoma and Their Impact on Disease Progression and Treatment Response , 2016, Journal of cellular biochemistry.

[80]  T. Watabe,et al.  FBPA PET in boron neutron capture therapy for cancer: prediction of 10B concentration in the tumor and normal tissue in a rat xenograft model , 2014, EJNMMI Research.

[81]  R. Barth,et al.  A realistic appraisal of boron neutron capture therapy as a cancer treatment modality , 2018, Cancer communications.

[82]  Minoru Suzuki.  Boron neutron capture therapy (BNCT): a unique role in radiotherapy with a view to entering the accelerator-based BNCT era , 2019, International Journal of Clinical Oncology.

[83]  V. Dbalý,et al.  Report on the first patient group of the phase I BNCT trial at the LVR-15 reactor , 2004 .

[84]  A. Azab,et al.  Thermal Sensitive Liposomes Improve Delivery of Boronated Agents for Boron Neutron Capture Therapy , 2019, Pharmaceutical Research.

[85]  T. Watabe,et al.  Practical calculation method to estimate the absolute boron concentration in tissues using 18F-FBPA PET , 2017, Annals of Nuclear Medicine.

[86]  F. Chou,et al.  Clinical trials for treating recurrent head and neck cancer with boron neutron capture therapy using the Tsing-Hua Open Pool Reactor , 2018, Cancer communications.

[87]  F. Wenz,et al.  Cellular Pathways in Response to Ionizing Radiation and Their Targetability for Tumor Radiosensitization , 2016, International journal of molecular sciences.

[88]  A. Jemal,et al.  Cancer statistics, 2019 , 2019, CA: a cancer journal for clinicians.

[89]  Recinda L. Sherman,et al.  Annual Report to the Nation on the Status of Cancer, 1975–2014, Featuring Survival , 2017, Journal of the National Cancer Institute.

[90]  Paul Baas,et al.  Malignant pleural mesothelioma: the standard of care and challenges for future management. , 2011, Critical reviews in oncology/hematology.

[91]  S. Jiang,et al.  Renovation of epithermal neutron beam for BNCT at THOR. , 2004, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[92]  Minoru Suzuki,et al.  Maleimide-functionalized closo-dodecaborate albumin conjugates (MID-AC): Unique ligation at cysteine and lysine residues enables efficient boron delivery to tumor for neutron capture therapy. , 2016, Journal of controlled release : official journal of the Controlled Release Society.

[93]  A. Matsumura,et al.  Boron neutron capture therapy for newly diagnosed glioblastoma. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[94]  D. Svirskis,et al.  Cyclic-RGDyC functionalized liposomes for dual-targeting of tumor vasculature and cancer cells in glioblastoma: An in vitro boron neutron capture therapy study , 2017, Oncotarget.

[95]  Tong Liu,et al.  Tracing Boron with Fluorescence and Positron Emission Tomography Imaging of Boronated Porphyrin Nanocomplex for Imaging-Guided Boron Neutron Capture Therapy. , 2018, ACS applied materials & interfaces.

[96]  J. T. Goorley,et al.  Treatment planning and dosimetry for the Harvard-MIT Phase I clinical trial of cranial neutron capture therapy. , 2002, International journal of radiation oncology, biology, physics.

[97]  P. Campbell,et al.  Somatic mutation in cancer and normal cells , 2015, Science.

[98]  J. Hess,et al.  Epidemiology and Molecular Biology of Head and Neck Cancer , 2017, Oncology Research and Treatment.

[99]  I. Kaplan,et al.  Preliminary treatment planning and dosimetry for a clinical trial of neutron capture therapy using a fission converter epithermal neutron beam. , 2004, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[100]  H. Joensuu,et al.  Boron neutron capture therapy (BNCT) followed by intensity modulated chemoradiotherapy as primary treatment of large head and neck cancer with intracranial involvement. , 2011, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[101]  R. Amaravadi,et al.  Targeting autophagy in cancer , 2018, Cancer.

[102]  J. Itami,et al.  Histological and biochemical analysis of DNA damage after BNCT in rat model. , 2014, Applied radiation and isotopes : including data, instrumentation and methods for use in agriculture, industry and medicine.

[103]  M. Moeschberger,et al.  Boron Neutron Capture Therapy of Brain Tumors: Biodistribution, Pharmacokinetics, and Radiation Dosimetry of Sodium Borocaptate in Patients with Gliomas , 2000, Neurosurgery.

[104]  Xavier Franceries,et al.  Plate-based transfection and culturing technique for genetic manipulation of Plasmodium falciparum , 2012, Malaria Journal.

[105]  P. Mi,et al.  Boron delivery agents for neutron capture therapy of cancer , 2018, Cancer communications.

[106]  Miroslava Cuperlovic-Culf,et al.  1H NMR Metabolomics Analysis of Glioblastoma Subtypes , 2012, The Journal of Biological Chemistry.

[107]  D. Riley,et al.  Boosting the Efficiency of Photoelectrolysis by the Addition of Non-Noble Plasmonic Metals: Al & Cu , 2018, Nanomaterials.

[108]  Hilla Peretz,et al.  The , 1966 .

[109]  J. Grandis,et al.  BET Inhibition Overcomes Receptor Tyrosine Kinase-Mediated Cetuximab Resistance in HNSCC. , 2018, Cancer research.

[110]  D. Tosi,et al.  Fe3O4 Nanoparticles for Complex Targeted Delivery and Boron Neutron Capture Therapy , 2019, Nanomaterials.

[111]  J. C. Yanch,et al.  Current status of Neutron Capture Therapy in the United States , 1995 .

[112]  Asmita Das,et al.  Radiation-induced autophagy: mechanisms and consequences , 2016, Free radical research.

[113]  W. Sweet,et al.  Neutron capture therapy of gliomas using boron. , 1954, Transactions of the American Neurological Association.

[114]  T. Ohnishi,et al.  Role of p53 mutation in the effect of boron neutron capture therapy on oral squamous cell carcinoma , 2009, Radiation oncology.

[115]  H. Matsubara,et al.  Effects of carbon ion irradiation and X-ray irradiation on the ubiquitylated protein accumulation , 2016, International journal of oncology.

[116]  A. Portu,et al.  Electroporation optimizes the uptake of boron-10 by tumor for boron neutron capture therapy (BNCT) mediated by GB-10: a boron biodistribution study in the hamster cheek pouch oral cancer model , 2019, Radiation and Environmental Biophysics.

[117]  S. Miyatake,et al.  DNA damage induced by boron neutron capture therapy is partially repaired by DNA ligase IV , 2016, Radiation and environmental biophysics.

[118]  Jie Wu,et al.  Boron neutron capture therapy induces cell cycle arrest and cell apoptosis of glioma stem/progenitor cells in vitro , 2013, Radiation oncology.

[119]  H. Samadian,et al.  Physical, dosimetric and clinical aspects and delivery systems in neutron capture therapy. , 2018, Reports of practical oncology and radiotherapy : journal of Greatpoland Cancer Center in Poznan and Polish Society of Radiation Oncology.

[120]  J. Itami,et al.  Predominant contribution of L-type amino acid transporter to 4-borono-2-(18)F-fluoro-phenylalanine uptake in human glioblastoma cells. , 2013, Nuclear medicine and biology.

[121]  M. Pita,et al.  Metallacarboranes on the Road to Anticancer Therapies: Cellular Uptake, DNA Interaction, and Biological Evaluation of Cobaltabisdicarbollide [COSAN]. , 2018, Chemistry.

[122]  David Firmin,et al.  Radiation in medicine: Origins, risks and aspirations , 2014, Global cardiology science & practice.

[123]  K. Ono,et al.  Boron neutron capture therapy outcomes for advanced or recurrent head and neck cancer , 2013, Journal of radiation research.

[124]  S. Miyatake,et al.  Boron neutron capture therapy for recurrent high-grade meningiomas. , 2013, Journal of neurosurgery.

[125]  J. Savage.  Radiation-Induced Chromosome Damage in Man , 1984 .

[126]  C. Harris,et al.  Radical causes of cancer , 2003, Nature Reviews Cancer.

[127]  Sabine S. Lange,et al.  HMGB1: The jack‐of‐all‐trades protein is a master DNA repair mechanic , 2009, Molecular carcinogenesis.

[128]  H. B. Liu,et al.  Derivations of relative biological effectiveness for the high-let radiations produced during boron neutron capture irradiations of the 9L rat gliosarcoma in vitro and in vivo. , 1993, International journal of radiation oncology, biology, physics.