Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.jddst.2023.105176

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Language：English   Publishing type：Research paper (scientific journal)  

In this study, we developed a water-soluble complex-hydrogel viscosity-controlled formulation of amphotericin B (AmB). AmB is insoluble in water, but borax makes it soluble by forming a complex with AmB. Borax also forms complexes with poly(vinyl alcohol) (PVA) to produce viscous hydrogels. Furthermore, boric acid interacts with mucin expressed in corneal epithelial cells. Accordingly, by utilizing these properties of borax simultaneously, we prepared a water-soluble AmB complex-hydrogel with poly(vinyl alcohol)/borate (PVA-B-AmB), which is suitable for eye drops. PVA-B-AmB was easily prepared by simply mixing aqueous AmB solution dissolved in borax, PVA solution, and water. The 11B-NMR results suggested that PVA-B-AmB existed by bonding PVA and AmB via boronic acid. PVA-B-AmB (gel ratio = 0.55) has a viscosity of 18.3 ± 0.5 mPa·s and is suitable for ophthalmic formulations. This formulation exhibited sustained release of AmB of approximately 45% at 24 h. It was also shown that this formulation interacts with mucin. These results suggest that PVA-B-AmB can be used as a water-soluble AmB preparation suitable for ophthalmic use.

DOI： 10.1248/cpb.c22-00534

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Akademiai Kiado Zrt.  

<title>Abstract</title>
Several studies on the pharmacokinetic parameters of antidementia drugs have reported that plasma concentration is linked to the drugs’ efficacy and adverse effects. At present, there is no quantitation method that is highly sensitive and can be applied to simultaneous monitoring of the pharmacokinetics of rivastigmine and its metabolites (NAP 226-90) in rat plasma. No methods fulfilling the assay validation requirements of the US Food and Drug Administration and the European Medicines Agency was also established. Therefore, this study developed a quantitative method for measuring rivastigmine and NAP 226-90 concentrations using high-performance liquid chromatography and tandem mass spectrometry, examining plasma samples after rivastigmine administration. Rat plasma samples were prepared via the protein precipitation method. The methods for measuring rivastigmine and NAP 226-90 concentrations showed good fit over wide ranges of 1–100 ng mL⁻¹ and 0.5–50 ng mL⁻¹, with lower limits of quantification at 1 ng mL⁻¹ and 0.5 ng mL⁻¹, respectively. The plasma concentrations of rivastigmine and NAP 226-90 in six healthy rats were successfully determined, demonstrating the feasibility of applying the developed method. Thus, this research has successfully developed a sensitive, selective method, to simultaneously quantify rivastigmine and NAP 226-90 concentrations in rat plasma and be applicable to a pharmacokinetic study.

DOI： 10.1556/1326.2021.00989

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Other Link： https://akjournals.com/downloadpdf/journals/1326/aop/article-10.1556-1326.2021.00989/article-10.1556-1326.2021.00989.xml

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (bulletin of university, research institution)  

CiNii Books

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Tumor sphere-forming (TS) glioma stem cells and cancerous TS cells were analyzed in vivo and in vitro. The boron concentration in murine TS tumors was higher than normal tissue. The boron concentration at 24 h was 0.80 ± 0.09 μg/107 in the TS cells, and 1.08 ± 0.08 μg/107 in the cancerous cells. The LAT-1 amino-acid transporter positive rate was 35.4% in the TS cells and 100% in the cancerous cells. These results suggested the relation between LAT-1 expression and boronophenylalanine concentration in vitro.

DOI： 10.1016/j.apradiso.2020.109234

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Language：English   Publishing type：Research paper (scientific journal)  

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 10B delivery agents. However, continuous drug administration at high concentrations is needed to maintain sufficient 10B concentration within tumors. To address the issue of 10B 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 10B-MMT1242 is a candidate for further clinical BNCT studies.

DOI： 10.3390/cells9051277

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier B.V.  

Objective: We aimed to clarify the optimal timing for the fluorescence imaging of brain tumor tissue differentiated from brain edema after the administration of photosensitizers. Methods: We have performed an in vivo study of the kinetics of 5-aminolevulinic acid (5-ALA) in comparison with talaporfin sodium using the rat brain tumor model and rat vasogenic edema model produced by cold injury. The in vivo kinetics of 5-ALA and talaporfin sodium in brain tumor model and the vasogenic edema model was determined by a fluorescence macroscope and a microplate reader. Results: The in vivo kinetic study of 5-ALA showed mild fluorescence intensity of protoporphyrin IX (PpIX) in brain tumor differentiated from vasogenic edema. The mean lesion-to-normal-brain ratio (L/N ratio) in the group of brain tumor model 2 h after the administration of 5-ALA was 7.78 ± 4.61, which was significantly higher (P &lt
0.01) than that of the vasogenic edema 2 h after the administration of 5-ALA (2.75 ± 1.12). In vivo kinetic study of talaporfin sodium showed high fluorescence intensity and retention in brain tumor differentiated from vasogenic edema. The mean L/N ratio of the fluorescence intensity in the group of brain tumor model 12 h after the administration of talaporfin sodium was 23.1 ± 11.9, which was significantly higher (P &lt
0.01) than that of the vasogenic edema 12 h after the administration (8.93 ± 8.03). Conclusions: The optimization of fluorescence imaging of brain tumors differentiated from brain edema is possible in the case of 5-ALA within 6 h, and also possible in the case of talaporfin sodium beyond 12 h. © 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.pdpdt.2009.03.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

DOI： 10.1016/j.pdpdt.2016.12.008

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

clarify the intra tumor distribution of gadlinium containing fullerene (Gd@C-82), micro particle induced X-ray emission (Micro-PIXE) analysis were performed. The tumor bearing BALB/c mice were injected Gd@C-82 and subcutaneous tumors were taken from 48 h after the intravenous injection. Using the Micro-PIXE method, we could visualize Gd intra tumor distribution. Therefore our results indicate the possibility that Micro-PIXE is useful technique for imaging the bioditribution of Gd, and Gd@C-82 is potentially useful Gd carrier for NCT. (C) 2014 Published by Elsevier Ltd.

DOI： 10.1016/j.apradiso.2013.12.037

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

To determine the influence of buthionine sulfoximine (BSO) on boron biodistribution after sulfhydryl borane (BSH) administration for boron neutron capture therapy, the effectiveness of the combination of BSO with sulfhydril- (BSH) and non-sulfhydril (B12H12 and BNH3) boron compounds, and the interval between BSO and BSH administration, the retention of boron in tissues have been evaluated using a 9L rat tumor model. Simultaneous administration of BSH and BSO showed significantly higher boron accumulation compared to that without BSO, however there was no difference in tissue boron level between B12H12 and BNH3 administration with BSO or without BSO. The longer interval (6 h) between BSH and BSO administration related to the highest boron concentration in the brain and subcutaneous tumors compared to shorter intervals (0.5, 3 h). Boron concentration in subcutaneous and brain tumors was maintained for 6 and 12 h after the administration of BSH following BSO pretreatment. (C) 2014 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.apradiso.2014.02.025

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Since 1998, we are performing clinical studies on treatment of GBM using conventional fractionated photon radiation therapy (CRT), proton beam therapy (PBT) or boron neutron capture therapy (BNCT). We investigated whether these radiation modalities improves the survival of patients with GBM.
Sixty-eight cases of newly diagnosed GBM have been treated in our institution. After surgery, radiation therapy was performed using CRT with a dose of 60.0-61.2 Gy (n = 36), hyperfractionated PBT concomitant with fractionated photon irradiation with a total dose of 96.6 Gy (n = 17), or a single fraction of BNCT (n = 15). In PBT, the surrounding volume of 2 cm from main tumor mass and the volume of perifocal edema were irradiated at dose of 75.6 and 60 Gy, respectively.
The median OS time of the case series of BNCT for GBM has been reported as 13-20.7 M. In this study, the median OS and median time to MR change (TTM) for all patients were 25.7 and 11.9 M, respectively. The 1- and 2-year survival rates were 85.7% and 45.5%, respectively. On the other hand, in the patients who underwent CRT and ACNU-based chemotherapy, OS and 2-year survival rate were 14.2 M and 17.9%, respectively. In the patients who underwent high-dose PBT, OS and 2-year survival rate were 21.3 M and 38.5%, respectively.
The present small case series of selected patients showed survival benefit after BNCT. The comparison using previously reported prognostic factor-based classifications suggest that outcome of BNCT in terms of survival appeared to have non-inferiority compared to the standard therapy. With respect to the case series as a high-dose radiation trial, the outcome (OS: 9.5-25 M) of previously reported may still be comparable to that of BNCT. Randomized trials of comparably selected patients are required to demonstrate conclusively that prolonged survival is a result of this tumor-selective radiotherapy. (C) 2009 Published by Elsevier Ltd.

DOI： 10.1016/j.apradiso.2009.03.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

The dose distribution and failure pattern after treatment with the external beam boron neutron capture therapy (BNCT) protocol were retrospectively analyzed. BSH (5 g/body) and BPA (250 mg/kg) based BNCT was performed in eight patients with newly diagnosed glioblastoma. The gross tumor volume (GTV) and clinical target volume (CTV)-1 were defined as the residual gadolinium-enhancing volume. CTV-2 and CTV-3 were defined as GTV plus a margin of 2 and 3 cm, respectively. As additional photon irradiation, a total X-ray dose of 30 Gy was given to the T2 high intensity area on MRI. Five of the eight patients were alive at analysis for a mean follow-up time of 20.3 months. The post-operative median survival time of the eight patients was 27.9 months (95% CI = 21.0-34.8). The minimum tumor dose of GTV, CTV-2, and CTV-3 averaged 29.8 +/- 9.9, 15.1 +/- 5.4, and 12.4 +/- 2.9 Gy, respectively. The minimum tumor non-boron dose of GTV, CTV-2, and CTV-3 averaged 2.0 +/- 0.5, 1.3 +/- 0.3, and 1.1 +/- 0.2 Gy, respectively. The maximum normal brain dose, skin dose, and average brain dose were 11.4 +/- 1.5, 9.6 +/- 1.4, and 3.1 +/- 0.4 Gy, respectively. The mean minimum dose at the failure site in cases of in-field recurrence (IR) and out-field recurrence (OR) was 26.3 +/- 16.7 and 14.9 GyEq, respectively. The calculated doses at the failure site were at least equal to the tumor control doses which were previously reported. We speculate that the failure pattern was related to an inadequate distribution of boron-10. Further improvement of the microdistribution of boron compounds is expected, and may improve the tumor control by BNCT. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.apradiso.2009.03.054

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

We measured the toxicity and intracellular uptake of a newly developed boronated porphyrin EC032, and verified the fluorescence-based boron concentration measuring methods. Toxicity study showed that concentration required to produce a 50% reduction in viability (IC(50)) of EC032 was more than 0.25 mM. Fluorescence study showed the intracellular uptake of EC032 increased up until 24 h after its exposure to C6, 9L. U87, and U251 cells. There was also a linear correlation between ICP-AES and fluorescence intensity as an arbitrary unit about measurement of boron concentration.
Fluorescence-based boron concentration measuring methods are very simple and useful methods, especially for screening of slight test dose of porphyrin compounds. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.apradiso.2009.03.098

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Neutron capture therapy (NCT) theoretically allows an unique tumor-cell-selective high-LET particle radiotherapy. The survival benefits and safety of NCT were evaluated in 15 patients with newly diagnosed glioblastoma multiforme (GBM). Seven patients received intra-operative (IO-) NCT and eight patients received external beam (EB-) NCT. Sulfhydryl borane (BSH, 5 g/body) was administered intravenously 12 h before neutron irradiation. Additionally, p-dihydroxyboryl-phenylalanine (BPA, 250 mg/kg) was given I h before irradiation to the eight patients who underwent EB-NCT. EB-NCT was combined with fractionated photon irradiation. Five of 15 patients were alive at analysis for a mean follow-up time of 203 M. In 11 of 15 patients followed up for more than 1-year, eight (72.7%) maintained their Karnofsky performance status (KPS; 90 in 6 and 100 in 2). The median overall survival (OS) and time to magnetic resonance (MR) change (TTM) for all patients were 25.7 and 11.9 M, respectively. There was no difference in TTM between the IO-NCT (12.0 M) and EB-NCT (11.9 M) groups. The 1- and 2-year survival rates were 85.7% and 45.5%, respectively. This NCT pilot study in 15 patients with newly diagnosed GBM showed survival benefits, suggesting that the neutron capture reaction may function sufficiently to control tumors locally, and that further optimized studies in large series of patients are warranted. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.apradiso.2009.03.011

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

In the present study, we aimed to evaluate a T2 corrected quantification method Of L-p-boronophenylalanine (BPA) concentration using proton magnetic resonance spectroscopy (MRS). We used five phantoms containing BPA (1.5, 3.0, 5.0. 7.5, and 10 mmol/kg = 15, 30, 50, 75, and 100 mu g(10)B/g), N-acetyl-aspartic acid (NAA: 3.0 mmol/kg), creatine (Cr: 5.0 mmol/kg), and choline (Cho: 3.0 mmol/kg). The signal intensities of BPA and internal water were corrected by T2 relaxation time. The absolute concentrations of BPA were calculated by proton MRS using an internal water signal as a standard. The major BPA peaks were detected between 7.1 and 7.6 ppm. Mean T2 relaxation time was 314.3 +/- 10.8 ms in BPA, 885.1 +/- 39.7 ms in internal water. The calculated BPA concentrations were almost same as the actual concentration of BPA and the correlation coefficient was 0.99. Our BPA quantification method was very simple and non-invasive, also it had high accuracy. Therefore, our results indicate that proton MRS can be potentially useful technique for in vivo BPA quantification in boron neutron capture therapy (BNCT). (c) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.apradiso.2009.03.060

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier  

The authors regret that the surname of the second author has a misprint in it. The correct surname is Zaboronok. There is only one affiliation for all the authors and the upper register letters a and b is a single institution, as b is indicating the address of the affiliation. The authors would like to apologise for any inconvenience caused.

DOI： 10.1016/j.pdpdt.2016.12.008

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Objective: We aimed to clarify the optimal timing for the fluorescence imaging of brain tumor tissue differentiated from brain edema after the administration of photosensitizers.
Methods: We have performed an in vivo study of the kinetics of 5-aminolevulinic acid (5-ALA) in comparison with talaporfin sodium using the rat brain tumor model and rat vasogenic edema model produced by cold injury. The in vivo kinetics of 5-ALA and talaporfin sodium in brain tumor model and the vasogenic edema model was determined by a fluorescence macroscope and a microplate reader.
Results: The in vivo kinetic study of 5-ALA showed mild fluorescence intensity of protoporphyrin IX (PpIX) in brain tumor differentiated from vasogenic edema. The mean lesion-to-normal-brain ratio (L/N ratio) in the group of brain tumor model 2 h after the administration of 5-ALA was 7.78 +/- 4.61, which was significantly higher (P &lt; 0.01) than that of the vasogenic edema 2 h after the administration of 5-ALA (2.75 +/- 1.12). In vivo kinetic study of talaporfin sodium showed high fluorescence intensity and retention in brain tumor differentiated from vasogenic edema. The mean L/N ratio of the fluorescence intensity in the group of brain tumor model 12 h after the administration of talaporfin sodium was 23.1 +/- 11.9, which was significantly higher (P &lt; 0.01) than that of the vasogenic edema 12 h after the administration (8.93 +/- 8.03).
Conclusions: The optimization of fluorescence imaging of brain tumors differentiated from brain edema is possible in the case of 5-ALA within 6 h, and also possible in the case of talaporfin sodium beyond 12 h. (c) 2009 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.pdpdt.2009.03.005

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Language：English   Publishing type：Research paper (international conference proceedings)  

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Language：English   Publishing type：Research paper (international conference proceedings)  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (bulletin of university, research institution)  

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Language：English  

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (bulletin of university, research institution)  

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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