Details of a Researcher - Tsukada, Kosuke

Bacterial proteolytic activity improves drug delivery in tumors in a size, pharmacokinetic, and binding affinity dependent manner – A mechanistic understanding

Shirai H., Tsukada K.

Journal of Controlled Release （Journal of Controlled Release) 321 348 - 362 2020.05

ISSN 01683659

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© 2020 Elsevier B.V. Motile bacteria are able to penetrate in the distal areas of blood vessel, which makes bacteria attractive to researchers as a drug delivery vehicle carrying anti-cancer drugs to tumors. Not only therapeutic bacteria show wide anti-tumor effect but also the combination of therapeutic bacteria and conventional chemotherapy leads to dramatically large synergetic effect. We provide a mechanistic understanding of enhanced drug delivery in tumors by co-administration of chemotherapeutic agents and therapeutic bacteria. In this work, simultaneous delivery of C. novyi-NT and chemotherapeutic agents in tumors is mathematically modeled. Simulated doxorubicin concentration in tumors after Doxil administration with or without bacteria agreed reasonably well with experimental literature. Simulated doxorubicin concentration in tumors by the combination of Doxil and C. novyi-NT is over twice higher than that of Doxil alone. This enhanced doxorubicin concentration in tumors is due to the degradation of extracellular matrix of collagen by bacterial proteolytic activity, which increases hydraulic conductivity of interstitium, reduces interstitial fluid pressure, and thus increases convection through vessel walls. Additionally, it alleviates solid stress, which decompresses blood vessels, and thus increases vessel density. On the other hand, simulated doxorubicin concentration in tumors for non-liposomal free-doxorubicin is not enhanced by C. novyi-NT because vascular permeability of free-doxorubicin is larger than Doxil, and thus increased but relatively small convection across vessel walls is offset by the efflux due to increased interstitial flow. A strategy to further enhance this combination therapy is discussed along with sensitivity analysis.
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High-throughput single-cell live imaging of photobiomodulation with multispectral near-infrared lasers in cultured T cells

Katagiri W., Lee G.H., Tanushi A., Tsukada K., Choi H.S., Kashiwagi S.

Journal of Biomedical Optics （Journal of Biomedical Optics) 25 （ 3 ） 1 - 18 2020.03

ISSN 10833668

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© 2020 by ASME. Significance: Photobiomodulation is a well-established therapeutic modality. However, the mechanism of action is poorly understood, due to lack of research in the causal relationship between the near-infrared (NIR) light irradiation and its specific biological effects, hindering broader applications of this technology. Aim: Since biological chromophores typically show several absorption peaks, we determined whether specific effects of photobiomodulation are induced with a combination of two wavelengths at a certain range of irradiance only, rather than a single wavelength of NIR light. Approach: In order to analyze a wide array of combinations of multispectral NIR light at various irradiances efficiently, we developed a new optical platform equipped with two distinct wavelengths of NIR lasers by high-throughput multiple dosing for single-cell live imaging. Two wavelengths of 1064 and 1270 nm were selected based on their photobiomodulatory effects reported in the literature. Results: A specific combination of wavelengths at low irradiances (250 to 400 mW/cm2 for 1064 nm and 55 to 65 mW/cm2 for 1270 nm) modulates mitochondrial retrograde signaling, including intracellular calcium and reactive oxygen species in T cells. The time-dependent density functional theory computation of binding of nitric oxide (NO) to cytochrome c oxidase indicates that the illumination with NIR light could result in the NO release, which might be involved in these changes. Conclusions: This optical platform is a powerful tool to study causal relationship between a specific parameter of NIR light and its biological effects. Such a platform is useful for a further mechanistic study on not only photobiomodulation but also other modalities in photomedicine.
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Respiration and Heat Shock Protein After Short-Term Heating/Stretch-Fixing on Smooth Muscle Cells

Kaminota N., Ogawa E., Kumagai H., Tsukada K., Arai T.

Cardiovascular Engineering and Technology （Cardiovascular Engineering and Technology) 2020

ISSN 1869408X

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© 2020, Biomedical Engineering Society. Purpose: A treatment device without a stent is needed for peripheral stenotic artery treatment. We have proposed short-term heating balloon angioplasty, photo-thermo dynamic balloon angioplasty (PTDBA). Though smooth muscle cells (SMCs) after PTDBA are fixed in a stretched formation in a porcine model, influences of this stimulus on SMCs have not been investigated. SMC migration after vascular dilatation would be related to chronic restenosis. The aim of this study was to examine respiratory activity and recovery ability of SMCs after short-term heating/stretch-fixing in vitro for chronic phase treatment effect discussion. Methods: SMCs on a stretch chamber were heated for 15 s with stretching and fixed in a stretched formation. SMC migration is correlated with the cell respiratory activity. The amount of ATP production was measured using a WST-8 assay for respiratory activity evaluation. The intracellular expression of heat shock protein 70 was measured by an ELISA for recovery ability evaluation. Results: In the case of 60 °C heating, SMC respiratory activity after short-term heating/stretch-fixing decreased drastically in all stretching rates. In the case of 50 °C heating, SMC respiratory activity decreased and then increased. Alternatively, the recovery ability at 60 °C was greater than that at 50 °C. Conclusions: SMCs heated at 60 °C with stretching would have high recovery ability and low respiratory activity related to SMC migration. These results may be important evidence in determining the treatment condition in PTDBA.
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Increasing surface-enhanced Raman scattering density using gold-coated magnetic nanoparticles controlled via a magnetic field for sensitive and efficient biomarker detection

Shibusawa K., Hase T., Tsukada K.

AIP Advances （AIP Advances) 9 （ 6 ） 2019.06

ISSN 2158-3226

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© 2019 Author(s). Early detection of various diseases is expected using surface-enhanced Raman scattering (SERS). For example, a method of labeling an antibody of a disease-related molecule on metal nanoparticles and detecting the SERS signals of the particles bound to the antigen is a promising approach. However, the problems of a slow antigen-antibody reaction and low sensitivity remain unsolved. In this study, we fabricated nanoparticles that can be freely moved using an external magnetic field for rapid antigen-antibody reaction and also nanoengineered the substrate to increase the density of hotspots required for SERS. Gold-coated magnetic nanoparticles (Au-MNPs) with a core-shell structure were prepared by applying multiple coatings of gold onto magnetic iron(II,III) oxide nanoparticles, which were used as the core. A neodymium magnet easily moved and converged the Au-MNPs in the solution within a few seconds. In addition, a silver nanoparticle substrate (Ag-NS) with a hexagonal close-packed structure fixed on a polydimethylsiloxane thin film was prepared, and the stable generation of SERS was confirmed over the entire substrate. Upon aggregation of the Au-MNPs onto Ag-NS using a neodymium magnet, the total SERS strength per unit area drastically increased, suggesting that the combination of Au-MNPs and Ag-NS increased the density of the generated hotspots. In future work, with the labeling of antibodies onto Au-MNPs, we expect the proposed method to be applied in the sensitive measurement of biomarkers associated with diseases.
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Real-Time Imaging of Vaccine Biodistribution Using Zwitterionic NIR Nanoparticles

Katagiri W., Lee J.H., Tétrault M.A., Kang H., Jeong S., Evans C.L., Yokomizo S., Santos S., Jones C., Hu S., Fakhri G.E., Tsukada K., Choi H.S., Kashiwagi S.

Advanced Healthcare Materials （Advanced Healthcare Materials) 8 （ 15 ） e1900035 2019

ISSN 21922640

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© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Efficient and timely delivery of vaccine antigens to the secondary lymphoid tissue is crucial to induce protective immune responses by vaccination. However, determining the longitudinal biodistribution of injected vaccines in the body has been a challenge. Here, the near-infrared (NIR) fluorescence imaging is reported that can efficiently enable the trafficking and biodistribution of vaccines in real time. Zwitterionic NIR fluorophores are conjugated on the surface of model vaccines and tracked the fate of bioconjugated vaccines after intradermal administration. Using an NIR fluorescence imaging system, it is possible to obtain time-course imaging of vaccine trafficking through the lymphatics, observing notable uptake in lymph nodes with minimal nonspecific tissue interactions. Flow cytometry analysis confirmed that the uptake in lymph nodes by antigen presenting cells was highly dependent on the hydrodynamic diameter of vaccines. These results demonstrate that the combination of a real-time NIR fluorescence imaging system and zwitterionic fluorophores is a powerful tool to determine the fate of vaccine antigens. Since such non-specific vaccine uptake causes serious adverse reactions, this method is not only useful for optimization of vaccine design, but also for safety evaluation of clinical vaccine candidates.
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Papers, etc., Registered in KOARA 【 Display / hide 】

Flexible film-type oxygen sensor for measurement of skin and organ surfaces

Tsukada, Kōsuke

科学研究費補助金研究成果報告書 2018
Establishment of near infrared laser adjuvants : an exploration of new mechanisms in light reception

Tsukada, Kosuke

科学研究費補助金研究成果報告書 2015
Visualization of gas molecules in vivo using infrared Raman Spectroscopy and application to tumor detection

Tsukada, Kosuke

科学研究費補助金研究成果報告書 2012
Analysis of oxygen transport to malignant tumor and mechanism of enhancing effect of treatment by oxygenation of tumor tissue

Tsukada, Kosuke

科学研究費補助金研究成果報告書 2011

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Reviews, Commentaries, etc. 【 Display / hide 】

皮内投与型ワクチンの免疫賦活化に適した近赤外レーザーデバイスの開発

片桐渉, 君塚善文, 柏木哲, 塚田孝祐

日本レーザー医学会誌 ((NPO)日本レーザー医学会) 39 ( 3 ) 254 - 254 2018.09

ISSN 0288-6200
“標識しない”という新たなバイオイメージングの流れ

塚田孝祐

光学 (日本光学会) 44 ( 6 ) 215 2015.06

Introduction and explanation (scientific journal), Single Work

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Presentations 【 Display / hide 】

共焦点光学系を用いた腫瘍血管の透過性及び酸素分圧の定量化

岩本侑一郎，小田慶太郎，塚田孝祐

第43回レーザ顕微鏡研究会＆シンポジウム, 2018.01, Oral Presentation(general)
近赤外光を用いた非侵襲的ワクチンアジュバント

柏木哲，君塚善文，片桐渉，塚田孝祐

第38回日本レーザー医学会総会, 2017.11, Oral Presentation(general)
近赤外半導体レーザーデバイスによる免疫活性化作用の検証

片桐渉，君塚善文，Kashiwagi Satoshi，塚田孝祐

第38回日本レーザー医学会総会, 2017.11, Poster (general)
Quantification and imaging of vascular permeability and partial pressure of oxygen in vivo

Iwamoto Y., Oda K., Tsukada K.

Annual Meeting of BMES 2017 (Phoenix, USA) , 2017.10, Oral Presentation(general), Biomedical Engineering Society
Three-dimensional in vivo analysis of histology for low-level laser therapy

Katagiri W., Tsukada K.

Annual Meeting of BMES 2017 (Phoenix, USA) , 2017.10, Poster (general), Biomedical Engineering Society

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Research Projects of Competitive Funds, etc. 【 Display / hide 】

単一細胞の超解像酸素分圧イメージング

2019.04

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2022.03

MEXT,JSPS, Grant-in-Aid for Scientific Research, 塚田　孝祐, Grant-in-Aid for Scientific Research (C), Principal Investigator
皮膚や臓器に貼付できるフレキシブル酸素イメージングフィルム

2016.04

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Present

日本学術振興会, Principal Investigator
近赤外光による新規ワクチンアジュバントのインフルエンザ集団予防接種への適用を目的とするポータブルレーザー医療機器の創出

2016.04

-

Present

AMED, 橋渡し研究加速ネットワークプログラム, Principal Investigator
組織低酸素イメージングセンサの開発と造影剤投与不要な初期がん検出への実用

2015.04

-

2016.03

中谷医工計測技術振興財団
近赤外レーザによる物理的免疫アジュバントの確立：生体の新たな光感受機構の探求

2014.04

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2015.03

日本学術振興会, Principal Investigator

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Awards 【 Display / hide 】

Best Poster Award

2015.09, Japanese Society for Microcirculation, A cell culture microdevice with a continuous oxygen gradient for microvascular research in vitro
最優秀研究奨励賞

佐藤安沙子，内田英幸，宮山明，塚田孝祐, 2013.02, 日本微小循環学会, Development of a cell culture microdevice with oxygen gradient as a model for microvascular environment

Type of Award： Awards of National Conference, Council and Symposium
第二回先端フォトニクスシンポジウムポスター賞

Tsukada Kosuke, 2011.10, 日本学術会議総合工学委員会ICO分科会, 生体分光計測が解き明かすがんの低酸素・代謝メカニズム

Type of Award： Awards of National Conference, Council and Symposium

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Other 【 Display / hide 】

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文部科学省スーパーグローバル大学創成支援事業による海外副指導教員の受け入れ
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文部科学省スーパーグローバル大学創成支援事業による海外副指導教員の受け入れ
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文部科学省スーパーグローバル大学創成支援事業による海外副指導教員の受け入れ
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文部科学省スーパーグローバル大学創成支援事業による海外副指導教員の受け入れ

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Courses Taught 【 Display / hide 】

PRESENTATION TECHNIQUE

2020
MEDICAL PHOTONICS

2020
INDEPENDENT STUDY ON FUNDAMENTAL SCIENCE AND TECHNOLOGY

2020
INDEPENDENT STUDY FOR EXCHANGE STUDENT A

2020
GRADUATE RESEARCH ON FUNDAMENTAL SCIENCE AND TECHNOLOGY 2

2020

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Courses Previously Taught 【 Display / hide 】

物情実験C, D

Keio University, 2016, Autumn Semester
バイオメカニズム

Keio University, 2016, Autumn Semester
自然科学実験

Keio University, 2016, Spring Semester
電気回路同演習

Keio University, 2016, Spring Semester
医用光工学

Keio University, 2014, Autumn Semester, Lecture, Lecturer outside of Keio