Publications by authors named "Minoru Suzuki"

234 Publications

Quantitative autoradiography in boron neutron capture therapy considering the particle ranges in the samples.

Phys Med 2021 Feb 12;82:306-320. Epub 2021 Mar 12.

Particle Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka, Japan. Electronic address:

Purpose: Boron neutron capture therapy is a cellular-scale particle therapy exploiting boron neutron capture reactions in boron compounds distributed in tumour cells. Its therapeutic effect depends on both the accumulation of boron in tumour cells and the neutron fluence. Autoradiography is used to visualise the micro-distribution of boron compounds.

Methods: Here, we present an equation for the relationship between boron concentration and pit density on the solid-state nuclear track detector, taking into consideration the particle ranges in the samples. This equation is validated using liver-tissue sections and boron standard solutions. Moreover, we present a simple co-localisation system for pit and tissue-section images that requires no special equipment.

Results: The equation reproduces the experimentally observed trends between boron concentration and pit density. This equation provides a theoretical explanation for the widely used calibration curve between pit density and boron concentration; it also provides a method to correct for differences of tissue-section thickness in quantitative autoradiography.

Conclusions: Using the equation together with this co-localisation system could improve micro-scale quantitative estimation in tissue sections.
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http://dx.doi.org/10.1016/j.ejmp.2021.02.012DOI Listing
February 2021

Construction of Boronophenylalanine-Loaded Biodegradable Periodic Mesoporous Organosilica Nanoparticles for BNCT Cancer Therapy.

Int J Mol Sci 2021 Feb 24;22(5). Epub 2021 Feb 24.

Institute for Integrated Cell-Material Sciences, Institute for Advanced Study, Kyoto University, Kyoto 606-8501, Japan.

Biodegradable periodic mesoporous organosilica (BPMO) has recently emerged as a promising type of mesoporous silica-based nanoparticle for biomedical applications. Like mesoporous silica nanoparticles (MSN), BPMO possesses a large surface area where various compounds can be attached. In this work, we attached boronophenylalanine (BPA) to the surface and explored the potential of this nanomaterial for delivering boron-10 for use in boron neutron capture therapy (BNCT). This cancer therapy is based on the principle that the exposure of boron-10 to thermal neutron results in the release of a-particles that kill cancer cells. To attach BPA, the surface of BPMO was modified with diol groups which facilitated the efficient binding of BPA, yielding BPA-loaded BPMO (BPA-BPMO). Surface modification with phosphonate was also carried out to increase the dispersibility of the nanoparticles. To investigate this nanomaterial's potential for BNCT, we first used human cancer cells and found that BPA-BPMO nanoparticles were efficiently taken up into the cancer cells and were localized in perinuclear regions. We then used a chicken egg tumor model, a versatile and convenient tumor model used to characterize nanomaterials. After observing significant tumor accumulation, BPA-BPMO injected chicken eggs were evaluated by irradiating with neutron beams. Dramatic inhibition of the tumor growth was observed. These results suggest the potential of BPA-BPMO as a novel boron agent for BNCT.
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http://dx.doi.org/10.3390/ijms22052251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956258PMC
February 2021

Fructose-functionalized polymers to enhance therapeutic potential of p-boronophenylalanine for neutron capture therapy.

J Control Release 2021 Feb 24;332:184-193. Epub 2021 Feb 24.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsutacho, Midori-ku, Yokohama, Kanagawa 226-8503, Japan; Department of Life Science and Technology, School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsutacho, Midori-ku, Yokohama, Kanagawa 226-8503, Japan; Innovation Center of Nanomedicine (iCONM), Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa 210-0821, Japan. Electronic address:

In boron neutron capture therapy (BNCT), boron drugs should accumulate selectively within a tumor and be quickly cleared from blood and normal organs. However, it is usually challenging to achieve the efficient tumor accumulation and the quick clearance simultaneously. Here we report the complex composed of a fructose-modified poly(ethylene glycol)-poly(l-lysine) block copolymer and p-boronophenylalanine, termed PEG-P[Lys/Lys(fructose)]-BPA, as a boron delivery system permitting selective accumulation within the target tumor with quick clearance from normal organs as well as blood. Our PEG-P[Lys/Lys(fructose)]-BPA could be internalized into tumor cells through LAT1 amino acid transporter-mediated endocytosis and retain in the targeted cells, thereby accomplishing more efficient accumulation and retention in a subcutaneous tumor than clinically used fructose-BPA complexes. Importantly, the moderately cationic property of the polymer facilitated renal clearance and PEG-P[Lys/Lys(fructose)]-BPA exhibited high accumulation contrast between the target tumor and the blood/normal organ. Finally, upon thermal neutron irradiation, PEG-P[Lys/Lys(fructose)]-BPA significantly inhibited the tumor growth in mice. PEG-P[Lys/Lys(fructose)]-BPA may be a promising boron delivery system for BNCT.
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http://dx.doi.org/10.1016/j.jconrel.2021.02.021DOI Listing
February 2021

Tumor vasculature-targeted B delivery by an Annexin A1-binding peptide boosts effects of boron neutron capture therapy.

BMC Cancer 2021 Jan 15;21(1):72. Epub 2021 Jan 15.

Department of Urology, Hirosaki University Graduate School of Medicine, 5-Zaifu-cho, Hirosaki, 036-8562, Japan.

Background: p-Boronophenylalanine (BPA) is a powerful B drug used in current clinical trials of BNCT. For BNCT to be successful, a high (500 mg/kg) dose of BPA must be administered over a few hours. Here, we report BNCT efficacy after rapid, ultralow-dose administration of either tumor vasculature-specific annexin A1-targeting IFLLWQR (IF7)-conjugated BPA or borocaptate sodium (BSH).

Methods: (1) IF7 conjugates of either B drugs intravenously injected into MBT2 bladder tumor-bearing mice and biodistribution of B in tumors and normal organs analyzed by prompt gamma-ray analysis. (2) Therapeutic effect of IF7-B drug-mediated BNCT was assessed by either MBT2 bladder tumor bearing C3H/He mice and YTS-1 tumor bearing nude mice.

Results: Intravenous injection of IF7C conjugates of either B drugs into MBT2 bladder tumor-bearing mice promoted rapid B accumulation in tumor and suppressed tumor growth. Moreover, multiple treatments at ultralow (10-20 mg/kg) doses of IF7-B drug-mediated BNCT significantly suppressed tumor growth in a mouse model of human YTS-1 bladder cancer, with increased Anxa1 expression in tumors and infiltration by CD8-positive lymphocytes.

Conclusions: We conclude that IF7 serves as an efficient B delivery vehicle by targeting tumor tissues via the tumor vasculature and could serve as a relevant vehicle for BNCT drugs.
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http://dx.doi.org/10.1186/s12885-020-07760-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7809749PMC
January 2021

BNCT for primary synovial sarcoma.

Appl Radiat Isot 2021 Mar 29;169:109407. Epub 2020 Dec 29.

Department of Pathology, Hyogo Cancer Center, Japan.

Synovial sarcoma is a rare tumor requiring new treatment methods. A 46-year-old woman with primary monophasic synovial sarcoma in the left thigh involving the sciatic nerve, declining surgery because of potential dysfunction of the affected limbs, received two courses of BNCT. The tumor thus reduced was completely resected with no subsequent recurrence. The patient is now able to walk unassisted, and no local recurrence has been observed, demonstrating the applicability of BNCT as adjuvant therapy for synovial sarcoma. Further study and analysis with more experience accumulation are needed to confirm the real impact of BNCT efficacy for its application to synovial sarcoma.
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http://dx.doi.org/10.1016/j.apradiso.2020.109407DOI Listing
March 2021

Non-isotope enriched phenylboronic acid-decorated dual-functional nano-assembles for an actively targeting BNCT drug.

Biomaterials 2021 Jan 24;268:120551. Epub 2020 Nov 24.

Department of Materials Science, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8573, Japan; Master's Program in Medical Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8573, Japan; Center for Research in Isotopes and Environmental Dynamics (CRiED), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan. Electronic address:

The feasibility of boron neutron capture therapy (BNCT) greatly depends on the selective accumulation of B in tumors. The p-boronophenylalanine-fructose (BPA-f) complex has been established as a conventional BNCT agent due to its preferential uptake into tumors, which is driven by amino acid transporters. However, the retention of BPA-f in tumors is highly limited because of an antiport mechanism, which is regulated by a gradient of amino acid concentration across the cancer cell membrane. Thus, to preserve a high B concentration in tumors, patients are inevitably subjected to a constant intravenous infusion. To this end, we employed a phenylboronic acid (PBA)-decorated polymeric nanoparticle (Nano) as a sialic acid-targeting BNCT agent. In this manner, the PBA can exhibit dual functionalities, i.e., exhibiting a neutron capture capacity and hypersialyated cancer cell targeting effect. Our developed Nano possesses a supramolecular structure composed of a core and shell comprised of poly(lactic acid) (PLA) and poly(ethylene glycol) (PEG) segments, respectively. The PBA moiety is installed at the PEG end, providing an unusually strong targeting effect, supposedly via multivalent binding onto the cancer cell membrane. As in BNCT, we verified the feasibility of Nano against a B16 melanoma-bearing mouse model. By virtue of efficient tumor targeting, even at a 100-fold lower dose than BPA-f, the Nano achieved a potent antitumor effect.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120551DOI Listing
January 2021

The Therapeutic Effects of Dodecaborate Containing Boronophenylalanine for Boron Neutron Capture Therapy in a Rat Brain Tumor Model.

Biology (Basel) 2020 Dec 1;9(12). Epub 2020 Dec 1.

Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-shi, Osaka 569-8686, Japan.

Background: The development of effective boron compounds is a major area of research in the study of boron neutron capture therapy (BNCT). We created a novel boron compound, boronophenylalanine-amide alkyl dodecaborate (BADB), for application in BNCT and focused on elucidating how it affected a rat brain tumor model.

Methods: The boron concentration of F98 rat glioma cells following exposure to boronophenylalanine (BPA) (which is currently being utilized clinically) and BADB was evaluated, and the biodistributions in F98 glioma-bearing rats were assessed. In neutron irradiation studies, the in vitro cytotoxicity of each boron compound and the in vivo corresponding therapeutic effect were evaluated in terms of survival time.

Results: The survival fractions of the groups irradiated with BPA and BADB were not significantly different. BADB administered for 6 h after the termination of convection-enhanced delivery ensured the highest boron concentration in the tumor (45.8 μg B/g). The median survival time in the BADB in combination with BPA group showed a more significant prolongation of survival than that of the BPA group.

Conclusion: BADB is a novel boron compound for BNCT that triggers a prolonged survival effect in patients receiving BNCT.
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http://dx.doi.org/10.3390/biology9120437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759915PMC
December 2020

Glioma Stem-Like Cells Can Be Targeted in Boron Neutron Capture Therapy with Boronophenylalanine.

Cancers (Basel) 2020 Oct 19;12(10). Epub 2020 Oct 19.

Institute for Integrated Radiation and Nuclear Science, Kyoto University, Osaka 590-0494, Japan.

As glioma stem cells are chemo- and radio-resistant, they could be the origins of recurrent malignant glioma. Boron neutron capture therapy (BNCT) is a tumor-selective particle radiation therapy. B(n,α)Li capture reaction produces alpha particles whose short paths (5-9 µm) lead to selective killing of tumor cells. P-boronophenylalanine (BPA) is a chemical compound used in clinical trials for BNCT. Here, we used mass cytometry (Cytof) to investigate whether glioma stem-like cells (GSLCs) take up BPA or not. We used GSLCs, and cells differentiated from GSLCs (DCs) by fetal bovine serum. After exposure to BPA for 24 h at 25 ppm in 5% CO incubator, we immune-stained them with twenty stem cell markers, anti-Ki-67, anti-BPA and anti-CD98 (heterodimer that forms the large BPA transporter) antibodies and analyzed them with Cytof. The percentage of BPA or CD98 cells with stem cell markers (Oct3/4, Nestin, SOX2, Musashi-1, PDGFRα, Notch2, Nanog, STAT3 and C-myc, among others) was 2-4 times larger among GSLCs than among DCs. Analyses of in vivo orthotopic tumor also indicated that 100% of SOX2 or Nestin GSLCs were BPA, whereas only 36.9% of glial fibrillary acidic protein (GFAP) DCs were BPA. Therefore, GSLCs may take up BPA and could be targeted by BNCT.
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http://dx.doi.org/10.3390/cancers12103040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603373PMC
October 2020

Sphingomyelin synthase 2 loss suppresses steatosis but exacerbates fibrosis in the liver of mice fed with choline-deficient, L-amino acid-defined, high-fat diet.

Biochem Biophys Res Commun 2020 12 12;533(4):1269-1275. Epub 2020 Oct 12.

Research Planning Department, Shionogi & Co., Ltd., Toyonaka, Japan.

Sphingomyelin synthase 2 (SMS2) regulates sphingomyelin synthesis and contributes to obesity and hepatic steatosis. Here, we investigated the effect of SMS2 deficiency on liver fibrosis in mice fed with choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) or injected with carbon tetrachloride (CCl), respectively. SMS2 deficiency suppressed hepatic steatosis, but exacerbated fibrosis induced by CDAHFD feeding. Sphingosine 1-phosphate (S1P), which is a key lipid mediator induces fibrosis in various organs, was increased in the liver of mice fed with CDAHFD. The increase of S1P became prominent by SMS2 deficiency. Meanwhile, SMS2 deficiency had no impact on CCl-induced liver injury, fibrosis and S1P levels. Our findings demonstrated that SMS2 deficiency suppresses steatosis but worsens fibrosis in the liver in a specific condition with CDAHFD feeding.
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http://dx.doi.org/10.1016/j.bbrc.2020.09.142DOI Listing
December 2020

Long-term outcome of cutaneous melanoma patients treated with boron neutron capture therapy (BNCT).

J Radiat Res 2020 Nov;61(6):945-951

Department of Particle Radiation Oncology, Integrated Radiation and Nuclear Science, Kyoto University, Kumatori, Osaka 590-0494, Japan.

Our aim was to assess the long-term clinical outcome of boron neutron capture therapy (BNCT) using 10B-para-boronophenylalanine (BPA) as the boron delivery agent for cutaneous melanoma. Eight patients (eight lesions) were treated between October 2003 and April 2014. Their ages ranged from 48 to 86 years at the time of treatment. All of the targets were primary lesions and they were located on the sole or face. No patient had evidence of regional lymph node involvement, distant metastases or an active secondary cancer. The clinical stage was cT1-2N0M0 and performance scores were <2. BNCT was carried out at the Kyoto University Research Reactor (KUR). The patients were irradiated with an epithermal neutron beam between the curative tumor dose and the tolerable skin dose. Eight patients were evaluated and six showed a complete response (CR), while two patients had a partial response (PR). Of the two patients with a PR, one has remained a PR with brown spots persisting for 7.5 years following BNCT. The tumor in the other patient recurred after 6 years at the site of persisting brown macula. The overall control rate (CR + PR without recurrence) for the cohort was 88% (7/8). There have never been any adverse events >Grade 2 for the long follow-up period. Our results suggest that BNCT may be a promising treatment modality in the management of early stage cutaneous melanoma when wide local excision is not feasible.
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http://dx.doi.org/10.1093/jrr/rraa068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674695PMC
November 2020

Boron neutron capture therapy for clear cell sarcoma.

Appl Radiat Isot 2020 Dec 3;166:109324. Epub 2020 Aug 3.

Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan; Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, 7-10- 2 Tomogaoka, Suma-ku, Kobe, 654-0142, Japan.

Clear cell sarcoma of tendons and aponeuroses (CCS) is a rare, malignant tumor arising in lower extremities with no effective treatment other than wide surgical resection. Here described is a case of primary CCS in the peroneal tendon of the right foot of a 54-year-old woman enrolled to undergo BNCT. The tumor mass post-BNCT disappeared totally without damage to other normal tissue, demonstrating, for the first time, the potential efficacy of BNCT in complete local control of CCS.
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http://dx.doi.org/10.1016/j.apradiso.2020.109324DOI Listing
December 2020

Cyclic RGD-Functionalized -Dodecaborate Albumin Conjugates as Integrin Targeting Boron Carriers for Neutron Capture Therapy.

Mol Pharm 2020 10 9;17(10):3740-3747. Epub 2020 Sep 9.

School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8503, Japan.

Cyclic RGD (cRGD) peptide-conjugated boronated albumin was developed to direct toward integrin αβ which overexpresses on many cancer cells. A stepwise conjugation of c[RGDfK(Mal)] and maleimide-conjugated -dodecaborate (MID) to bovine serum albumin (BSA) afforded cRGD-MID-BSA, which was noncytotoxic toward both U87MG and A549 cells. As compared with l-BPA, selective antitumor activity of cRGD-MID-BSA toward U87MG cells overexpressing integrin αβ was identified after thermal neutron irradiation. In vivo fluorescence live imaging of Cy5-conjugated cRGD-MID-BSA and MID-BSA revealed that both cRGD-MID-BSA and MID-BSA similarly reached the maximum accumulation during 8-12 h after injection. The selective accumulation and retention of Cy5-cRGD-MID-BSA was more pronounced than Cy5-MID-BSA after 24 h. An in vivo boron neutron capture therapy (BNCT) study revealed that the cRGD peptide ligand combination enhanced accumulation of MID-BSA into tumor cells in U87MG xenograft models. The significant tumor growth suppression was observed in U87MG xenograft models at a dose of 7.5 mg [B]/kg after neutron irradiation.
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http://dx.doi.org/10.1021/acs.molpharmaceut.0c00478DOI Listing
October 2020

Influence of the particle size of gadolinium-loaded chitosan nanoparticles on their tumor-killing effect in neutron capture therapy in vitro.

Appl Radiat Isot 2020 Oct 5;164:109270. Epub 2020 Jul 5.

Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, 650-8586, Japan. Electronic address:

Neutron capture therapy using Gd (Gd-NCT) is currently under development as a cancer radiotherapy. Melanoma cells were treated with gadolinium-loaded chitosan nanoparticles (Gd-nanoCPs) for Gd-NCT. Smaller Gd-nanoCPs had higher Gd content and better cellular association of Gd and thereby made the tumor-killing effect more efficient in comparison to larger Gd-nanoCPs. This indicates that Gd-nanoCP size reduction is an efficient method for improving the cellular affinity of Gd-nanoCPs and for enhancing the tumor-killing effect of Gd-NCT.
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http://dx.doi.org/10.1016/j.apradiso.2020.109270DOI Listing
October 2020

Preclinical study of boron neutron capture therapy for bone metastasis using human breast cancer cell lines.

Appl Radiat Isot 2020 Nov 6;165:109257. Epub 2020 Jul 6.

Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, 650-8586, Japan.

Bone metastasis has a major impact on the quality of life that general therapy cannot control. We established a bone metastasis model with a human breast cancer cell line and investigated the therapeutic effect of boron neutron capture therapy (BNCT). BNCT suppressed tumor growth in cases of intramedullary small tumors without damaging normal tissues, providing preliminary evidence that it is a potentially new therapeutic option for controlling tumor growth from bone metastasis. Further research is warranted for its clinical application.
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http://dx.doi.org/10.1016/j.apradiso.2020.109257DOI Listing
November 2020

An attempt to improve the therapeutic effect of boron neutron capture therapy using commonly employed 10B-carriers based on analytical studies on the correlation among quiescent tumor cell characteristics, tumor heterogeneity and cancer stemness.

J Radiat Res 2020 Nov;61(6):876-885

Kansai BNCT Medical Center, Osaka Medical College, Japan.

Based on our previously published reports concerning the response of quiescent (Q) tumor cell populations to boron neutron capture therapy (BNCT), the heterogeneous microdistribution of 10B in tumors, which is influenced by the tumor microenvironment and the characteristics of the 10B delivery carriers, has been shown to limit the therapeutic effect of BNCT on local tumors. It was also clarified that the characteristics of 10B-carriers for BNCT and the type of combined treatment in BNCT can also affect the potential for distant lung metastases from treated local tumors. We reviewed the findings concerning the response of Q tumor cell populations to BNCT, mainly focusing on reports we have published so far, and we identified the mode of BNCT that currently offers the best therapeutic gain from the viewpoint of both controlling local tumor and suppressing the potential for distant lung metastasis. In addition, based on the finding that oxygenated Q tumor cells showed a large capacity to recover from DNA damage after cancer therapy, the interrelationship among the characteristics in Q tumor cell populations, tumor heterogeneity and cancer stemness was also discussed.
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http://dx.doi.org/10.1093/jrr/rraa048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674684PMC
November 2020

Single-dose toxicity study by intra-arterial injection of BSH entrapped water-in-oil-in-water emulsion for boron neutron capture therapy to hepatocellular carcinoma.

Appl Radiat Isot 2020 Sep 13;163:109202. Epub 2020 May 13.

Institute of Engineering Innovation, School of Engineering, The University of Tokyo, Tokyo, 113-8656, Japan; Cooperative Unit of Medicine & Engineering, The University of Tokyo Hospital, Tokyo, 113-8655, Japan.

We developed a mixing medical device by attaching Shirasu porous glass Millipore membrane to prepare water-in-oil-in-water (WOW) emulsion in a shorter time to be applied as B-entrapped WOW emulsion for hepatocellular carcinoma (HCC) treatment. Single-dose toxicity studies by intra-arterial injection of BSH-entrapped WOW were performed in rabbits and pig, and no side effects were observed. We hope to proceed to the preclinical and clinical studies for further evaluation of B compound as multidisciplinary treatments for HCC.
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http://dx.doi.org/10.1016/j.apradiso.2020.109202DOI Listing
September 2020

Evaluation of a Novel Boron-Containing α-D-Mannopyranoside for BNCT.

Cells 2020 05 21;9(5). Epub 2020 May 21.

Department of Neurosurgery, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Ibaraki, Japan.

Boron neutron capture therapy (BNCT) is a unique anticancer technology that has demonstrated its efficacy in numerous phase I/II clinical trials with boronophenylalanine (BPA) and sodium borocaptate (BSH) used as B delivery agents. However, continuous drug administration at high concentrations is needed to maintain sufficient B concentration within tumors. To address the issue of B accumulation and retention in tumor tissue, we developed MMT1242, a novel boron-containing α-d-mannopyranoside. We evaluated the uptake, intracellular distribution, and retention of MMT1242 in cultured cells and analyzed biodistribution, tumor-to-normal tissue ratio and toxicity in vivo. Fluorescence imaging using nitrobenzoxadiazole (NBD)-labeled MMT1242 and inductively coupled mass spectrometry (ICP-MS) were performed. The effectiveness of BNCT using MMT1242 was assessed in animal irradiation studies at the Kyoto University Research Reactor. MMT1242 showed a high uptake and broad intracellular distribution in vitro, longer tumor retention compared to BSH and BPA, and adequate tumor-to-normal tissue accumulation ratio and low toxicity in vivo. A neutron irradiation study with MMT1242 in a subcutaneous murine tumor model revealed a significant tumor inhibiting effect if injected 24 h before irradiation. We therefore report that B-MMT1242 is a candidate for further clinical BNCT studies.
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http://dx.doi.org/10.3390/cells9051277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290312PMC
May 2020

Potential role of transforming growth factor-beta 1/Smad signaling in secondary lymphedema after cancer surgery.

Cancer Sci 2020 Jul 9;111(7):2620-2634. Epub 2020 Jun 9.

Division of Vascular Surgery, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and skin fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor-beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting fibrosis. Suppression of myofibroblast-dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting skin fibrosis in human secondary lymphedema after cancer surgery.
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http://dx.doi.org/10.1111/cas.14457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385355PMC
July 2020

Reevaluation of CBE value of BPA for hepatocytes.

Appl Radiat Isot 2020 Jul 2;161:109159. Epub 2020 Apr 2.

Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science Kyoto University (KURNS), 2 Asashiro-Nishi, Kumatori-cho, Osaka, 590-0494, Japan. Electronic address:

The compound biological effectiveness (CBE) value of boronophenylalanine (BPA) for hepatocytes was experimentally determined for the purpose of boron neutron capture therapy (BNCT) for liver tumors. In this study, the critical reevaluation of previous value was performed. In previous experimental studies, the contribution of β component of dose was ignored in the response curve to X-ray. X-ray dose cell survival curves were estimated by combining the α/β values obtained in the ordinary micronucleus (MN) assay with the curve of MN-negative cell fraction (MN(-)F) to dose. This curve was compared to the boron neutron capture reaction (BNCR) dose curve. As a result, the CBE value was 4 at doses close to 0 Gy, decreasing to about 1.0 at doses close to 4.5 Gy. The new value is smaller than the previous value 4.2. This indicates that the bioequivalent dose to normal liver is lower than previously expected. Therefore, higher doses can be given to the tumor.
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http://dx.doi.org/10.1016/j.apradiso.2020.109159DOI Listing
July 2020

Poly(vinyl alcohol) boosting therapeutic potential of -boronophenylalanine in neutron capture therapy by modulating metabolism.

Sci Adv 2020 01 22;6(4):eaaz1722. Epub 2020 Jan 22.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsutacho, Midori-ku, Yokohama, Kanagawa 226-8503, Japan.

In the current clinical boron neutron capture therapy (BNCT), -boronophenylalanine (BPA) has been the most powerful drug owing to its ability to accumulate selectively within cancers through cancer-related amino acid transporters including LAT1. However, the therapeutic success of BPA has been sometimes compromised by its unfavorable efflux from cytosol due to their antiport mechanism. Here, we report that poly(vinyl alcohol) (PVA) can form complexes with BPA through reversible boronate esters in aqueous solution, and the complex termed PVA-BPA can be internalized into cancer cells through LAT1-mediated endocytosis, thereby enhancing cellular uptake and slowing the untoward efflux. In in vivo study, compared with clinically used fructose-BPA complexes, PVA-BPA exhibited efficient tumor accumulation and prolonged tumor retention with quick clearance from bloodstream and normal organs. Ultimately, PVA-BPA showed critically enhanced antitumor activity in BNCT. The facile technique proposed in this study offers an approach for drug delivery focusing on drug metabolism.
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http://dx.doi.org/10.1126/sciadv.aaz1722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976296PMC
January 2020

Usefulness of combination with both continuous administration of hypoxic cytotoxin and mild temperature hyperthermia in boron neutron capture therapy in terms of local tumor response and lung metastatic potential.

Int J Radiat Biol 2019 12 23;95(12):1708-1717. Epub 2019 Sep 23.

Kansai BNCT Medical Center, Osaka Medical College, Osaka, Japan.

To evaluate the usefulness of combined treatment with both continuous administration of a hypoxic cytotoxin, tirapazamine (TPZ) and mild temperature hyperthermia (MTH) in boron neutron capture therapy (BNCT) in terms of local tumor response and lung metastatic potential, referring to the response of intratumor quiescent (Q) cells. B16-BL6 melanoma tumor-bearing C57BL/6 mice were continuously given 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) cells. The tumors received reactor thermal neutron beam irradiation following the administration of a B-carrier (-boronophenylalanine-B (BPA) or sodium mercaptoundecahydrododecaborate-B (BSH)) after single intraperitoneal injection of an acute hypoxia-releasing agent (nicotinamide), MTH (40 °C for 60 min), and 24-h continuous subcutaneous infusion of TPZ or combined treatment with both TPZ and MTH. Immediately after irradiation, cells from some tumors were isolated and incubated with a cytokinesis blocker. The responses of the Q and total (=P + Q) tumor cell populations were assessed based on the frequency of micronuclei using immunofluorescence staining for BrdU. In other tumor-bearing mice, 17 days after irradiation, macroscopic lung metastases were enumerated. BPA-BNCT increased the sensitivity of the total tumor cell population more than BSH-BNCT. However, the sensitivity of Q cells treated with BPA was lower than that of BSH-treated Q cells. With or without a B-carrier, combination with continuously administered TPZ with or without MTH enhanced the sensitivity of the both total and Q cells, especially Q cells. Even without irradiation, nicotinamide treatment decreased the number of lung metastases. With irradiation, BPA-BNCT, especially in combination with combined treatment with both TPZ and MTH as well as nicotinamide treatment, showed the potential to reduce the number more than BSH-BNCT. BSH-BNCT combined with TPZ with or without MTH improved local tumor control, while BPA-BNCT in combination with both TPZ and MTH as well as nicotinamide is thought to reduce the number of lung metastases. It was elucidated that control of the chronic hypoxia-rich Q cell population in the primary solid tumor has the potential to impact the control of local tumors as a whole and that control of the acute hypoxia-rich total tumor cell population in the primary solid tumor has the potential to impact the control of lung metastases.
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http://dx.doi.org/10.1080/09553002.2019.1666214DOI Listing
December 2019

Effects of Status of Tumor Cells and Combined Treatment With Mild Hyperthermia, Wortmannin or Caffeine on Recovery From Radiation-Induced Damage.

World J Oncol 2019 Jun 29;10(3):132-141. Epub 2019 Jun 29.

Kansai BNCT Medical Center, Osaka Medical College, 2-7 Daigaku-machi Takatsuki, Osaka 569-8686, Japan.

Background: The aim of the study was to examine the dependency of status and the usefulness of mild hyperthermia (MHT) as an inhibitor of recovery from radiation-induced damage, referring to the response of quiescent (Q) tumor cell population.

Methods: Human head and neck squamous cell carcinoma cells transfected with mutant (SAS/) or with neo vector (SAS/) were injected subcutaneously into left hind legs of nude mice. Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) continuously to label all intratumor proliferating (P) cells. They received high dose-rate γ-ray irradiation (HDR) immediately followed by localized MHT (40 °C for 2 h), or caffeine or wortmannin administration, or low dose-rate γ-ray irradiation simultaneously with localized MHT or caffeine or wortmannin administration. Nine hours after the start of irradiation, the tumor cells were isolated and incubated with a cytokinesis blocker, and the micronucleus (MN) frequency in cells without BrdU labeling (= Q cells) was determined using immunofluorescence staining for BrdU.

Results: SAS/ tumor cells, especially intratumor Q cell populations, showed a marked reduction in sensitivity due to the recovery from radiation-induced damage, compared with the total or Q tumor cells within SAS/ tumors that showed little recovery capacity. The recovery from radiation-induced damage was thought to be a dependent event. In both total and Q tumor cells within SAS/ tumors, especially the latter, MHT efficiently suppressed the reduction in sensitivity caused by leaving an interval between HDR irradiation and the assay and decreasing the irradiation dose-rate, as well as the combination with wortmannin administration.

Conclusions: From the viewpoint of solid tumor control as a whole, including intratumor Q-cell control, non-toxic MHT is useful for suppressing the recovery from radiation-induced damage, as well as wortmannin treatment combined with γ-ray irradiation.
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http://dx.doi.org/10.14740/wjon1203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615912PMC
June 2019

Boron neutron capture therapy (BNCT): a unique role in radiotherapy with a view to entering the accelerator-based BNCT era.

Authors:
Minoru Suzuki

Int J Clin Oncol 2020 Jan 5;25(1):43-50. Epub 2019 Jun 5.

Particle Radiation Oncology Research Center, Institute for Integrated Radiation and Nuclear Science, Kyoto University, 2-1010, Asashiro-nishi, Kumatori-cho, Sennan-gun, Osaka, 590-0494, Japan.

Boron neutron capture therapy (BNCT) has a unique property of tumor-cell-selective heavy-particle irradiation. BNCT can form large dose gradients between cancer cells and normal cells, even if the two types of cells are mingled at the tumor margin. This property makes it possible for BNCT to be used for pre-irradiated locally recurrent tumors. Shallow-seated, locally recurrent lesions have been treated with BNCT because of the poor penetration of neutrons in the human body. BNCT has been used in clinical studies for recurrent malignant gliomas and head and neck cancers using neutron beams derived from research reactors, although further investigation is warranted because of the small number of patients. In the latter part of this review, the development of accelerator-based neutron sources is described. BNCT for common cancers will become available at medical institutes that are equipped with an accelerator-based BNCT system. Multiple metastatic lung tumors have been investigated as one of the new treatment candidates because BNCT can deliver curative doses of radiation to the tumors while sparing normal lung tissue. Further basic and clinical studies are needed to move toward an era of accelerator-based BNCT when more patients suffering from refractory cancers will be treated.
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http://dx.doi.org/10.1007/s10147-019-01480-4DOI Listing
January 2020

Two new brominated C-acetogenins from the red alga .

Nat Prod Res 2020 Oct 31;34(19):2787-2793. Epub 2019 Mar 31.

Coastal Branch of Natural History Museum and Institute , Katsuura , Chiba , Japan.

We report on the chemical characteristics of the red alga , collected off the coast of Yoshio, Katsuura, Boso Peninsula, Japan. We isolated two new brominated C-acetogenins in this species, which we name katsuurenyne A () and katsuurenyne B (), along with two already known halogenated terpenes [2,10-dibromo-3-chloro-α-chamigrene () and aplysiadiol ()]. We extensively analysed spectral data (from IR, ESI-MS, 1D-NMR and 2D-NMR) to confirm the structure of these compounds.
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http://dx.doi.org/10.1080/14786419.2019.1590712DOI Listing
October 2020

Confocal and multiphoton calcium imaging of the enteric nervous system in anesthetized mice.

Neurosci Res 2020 Feb 18;151:53-60. Epub 2019 Feb 18.

Graduate School of Science and Engineering, Saitama University, Saitama, 338-8570, Japan; Brain and Body System Science Institute, Saitama University, Saitama, 338-8570, Japan; RIKEN Center for Brain Science, Wako, Saitama, 351-0198, Japan; RIKEN Center for Advanced Intelligence Project, Tokyo, 103-0072, Japan. Electronic address:

Most imaging studies of the enteric nervous system (ENS) that regulates the function of the gastrointestinal tract are so far performed using preparations isolated from animals, thus hindering the understanding of the ENS function in vivo. Here we report a method for imaging the ENS cellular network activity in living mice using a new transgenic mouse line that co-expresses G-CaMP6 and mCherry in the ENS combined with the suction-mediated stabilization of intestinal movements. With confocal or two-photon imaging, our method can visualize spontaneous and pharmacologically-evoked ENS network activity in living animals at cellular and subcellular resolutions, demonstrating the potential usefulness for studies of the ENS function in health and disease.
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http://dx.doi.org/10.1016/j.neures.2019.02.004DOI Listing
February 2020

Effect of a change in reactor power on response of murine solid tumors in vivo, referring to impact on quiescent tumor cell population.

Int J Radiat Biol 2019 05 8;95(5):635-645. Epub 2019 Jan 8.

c Particle Radiation Oncology Center , Institute for Integrated Radiation and Nuclear Science, Kyoto University , Sennan-gun , Osaka , Japan.

Purpose: To examine the effect of a change in reactor power on the response of solid tumors, referring to impact on quiescent (Q) tumor cell population.

Materials And Methods: Tumor-bearing mice received 5-bromo-2'-deoxyuridine (BrdU) to label all proliferating (P) tumor cells, and were treated with boronophenylalanine-B (BPA) or sodium mercaptododecaborate-B (BSH). After reactor neutron beam irradiation at a power of 1 or 5 MW with an identical beam spectrum, cells from tumors were isolated and incubated with a cytokinesis blocker. The responses of BrdU-unlabeled Q and total (P + Q) tumor cells were assessed based on the frequencies of micronucleation using immunofluorescence staining for BrdU.

Results: After neutron irradiation with or without B-carrier, radio-sensitivity was reduced by decreasing reactor power in both cells, especially in Q cells and after irradiation with BPA. The values of relative and compound biological effectiveness were larger at a power of 5 MW and in Q cells than at a power of 1 MW and in total cells, respectively. The sensitivity difference between total and Q cells was widened when combined with B-carrier, especially with BPA, and through decreasing reactor power.

Conclusion: 5 MW is more advantageous than 1 MW for boron neutron capture therapy.
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http://dx.doi.org/10.1080/09553002.2019.1558300DOI Listing
May 2019

Folate receptor-targeted novel boron compound for boron neutron capture therapy on F98 glioma-bearing rats.

Radiat Environ Biophys 2019 03 24;58(1):59-67. Epub 2018 Nov 24.

Department of Neurosurgery, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki City, Osaka, 569-8686, Japan.

Folic acid (FA) has high affinity for the folate receptor (FR), which is limited expressed in normal human tissues, but over-expressed in several tumor cells, including glioblastoma cells. In the present work, a novel pteroyl-closo-dodecaborate conjugate (PBC) was developed, in which the pteroyl group interacts with FR, and the efficacy of boron neutron capture therapy (BNCT) using PBC was investigated. Thus, in vitro and in vivo studies were performed using F98 rat glioma cells and F98 glioma-bearing rats. For the in vivo study, boronophenylalanine (BPA) was intravenously administered, while PBC was administered by convection-enhanced delivery (CED)-a method for direct local drug infusion into the brain of rats. Furthermore, a combination of PBC administered by CED and BPA administered by intravenous (i.v.) injection was also investigated. In the biodistribution experiment, PBC administration at 6 h after CED termination showed the highest cellular boron concentrations (64.6 ± 29.6 µg B/g). Median survival time (MST) of untreated controls was 23.0 days (range 21-24 days). MST of rats administered PBC (CED) followed by neutron irradiation was 31 days (range 26-36 days), which was similar to that of rats administered i.v. BPA (30 days; range 25-37 days). Moreover, the combination group [PBC (CED) and i.v. BPA] showed the longest MST (38 days; range 28-40 days). It is concluded that a significant MST increase was noted in the survival time of the combination group of PBC (CED) and i.v. BPA compared to that in the single-boron agent groups. These findings suggest that the combination use of PBC (CED) has additional effects.
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http://dx.doi.org/10.1007/s00411-018-0765-2DOI Listing
March 2019

Boron Neutron Capture Therapy Combined with Early Successive Bevacizumab Treatments for Recurrent Malignant Gliomas - A Pilot Study.

Neurol Med Chir (Tokyo) 2018 Dec 21;58(12):487-494. Epub 2018 Nov 21.

Section for Advanced Medical Development, Cancer Center, Osaka Medical College.

Recurrent malignant gliomas (RMGs) are difficult to control, and no standard protocol has been established for their treatment. At our institute, we have often treated RMGs by tumor-selective particle radiation called boron neutron capture therapy (BNCT). However, despite the cell-selectivity of BNCT, brain radiation necrosis (BRN) may develop and cause severe neurological complications and sometimes death. This is partly due to the full-dose X-ray treatments usually given earlier in the treatment course. To overcome BRN following BNCT, recent studies have used bevacizumab (BV). We herein used extended BV treatment beginning just after BNCT to confer protection against or ameliorate BRN, and evaluated; the feasibility, efficacy, and BRN control of this combination treatment. Seven patients with RMGs (grade 3 and 4 cases) were treated with BNCT between June 2013 and May 2014, followed by successive BV treatments. They were followed-up to December 2017. Median overall survival (OS) and progression-free survival (PFS) after combination treatment were 15.1 and 5.4 months, respectively. In one case, uncontrollable brain edema occurred and ultimately led to death after BV was interrupted due to meningitis. In two other cases, symptomatic aggravation of BRN occurred after interruption of BV treatment. No BRN was observed during the observation period in the other cases. Common terminology criteria for adverse events grade 2 and 3 proteinuria occurred in two cases and necessitated the interruption of BV treatments. Boron neutron capture therapy followed by BV treatments well-prevented or well-controlled BRN with prolonged OS and acceptable incidence of adverse events in our patients with RMG.
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http://dx.doi.org/10.2176/nmc.oa.2018-0111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300692PMC
December 2018

Proposal for determining absolute biological effectiveness of boron neutron capture therapy-the effect of 10B(n,α)7Li dose can be predicted from the nucleocytoplasmic ratio or the cell size.

J Radiat Res 2019 Jan;60(1):29-36

Division of Radiation Life Science, Kyoto University, 2-Asashiro-Nishi, Kumatori-cho, Sennan-gun, Osaka, Japan.

The relationship between the radiation dose delivered to a tumor and its effect is not completely predictable. Uncertainty in the estimation of the boron concentration in a tumor, variation in the radiation sensitivity of the tumor cells, and the complexity of the interactions between the four types of radiation comprising the boron neutron capture therapy (BNCT) dose contribute to this uncertainty. We reanalyzed the data of our previous papers to investigate the variation in radiosensitivity of tumor cells to the 10B(n,α)7Li dose: the dose generated by the reaction of thermal neutrons and 10B, hereafter the 'boron-neutron dose'. The radiosensitivities of five tumors (EL4, SAS/neo, SAS/mp53, SCCVII and B16-BL6 melanoma) were examined. For the combination of p-boron-L-phenylalanine (BPA: C9H12BNO4) with neutron irradiation, D0, the cell survival curve for the boron-neutron dose was the smallest for the SAS/neo, followed by the EL4, SAS/mp53, SCCVII and B16-BL6 melanoma, in that order. For the combination of mercaptoundecahydrododecaborate (BSH: Na2B12H11SH) with neutron irradiation, D0 was the smallest for the EL4, followed by the SAS/neo, B16-BL6melanoma, SAS/mp53 and SCCVII, in that order. The relationships between these D0 values and the nucleocytoplasmic ratios (Xncs) or cell size indices (Xcs) obtained by histopathological microslide image were as follows: (D0 = 0.1341Xnc-1.586, R2 = 0.9721) for all tumor types with BPA-BNCT, and D0 = 0.0122Xcs-0.1319 (R2 = 0.9795) for four tumor types (all except the B16-BL6 melanoma) with BSH-BNCT. Based on these results, we proposed a new biologically equivalent effectiveness factor: the absolute biological effectiveness (ABE) factor. The ABE factor is Gy/D0. Thus, the ABE dose is the physical dose multiplied by the ABE factor, and refers to the dose needed to decrease the cell survival rate to e-ABE dose/Gy.
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http://dx.doi.org/10.1093/jrr/rry080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373679PMC
January 2019