Updated on 2024/04/12

写真a

 
SOU, Keitaro
 
Affiliation
Faculty of Science and Engineering, Waseda Research Institute for Science and Engineering
Job title
Senior Researcher(Professor)
Degree
博士(工学) ( 早稲田大学 )

Research Experience

  • 2023.07
    -
    Now

    Waseda University   Faculty of Science and Engineering, Waseda Research Institute for Science and Engineering   Senior Researcher (Professor)

  • 2019.03
    -
    2023.06

    Waseda University   Research Institute for Science and Engineering   Guest Researcher/Guest Associate Professor

  • 2019.06
    -
    2021.05

    Nanyang Technological University   School of Mechanical and Aerospace Engineering   Visiting Researcher

  • 2017.10
    -
    2019.02

    Waseda University   Research Institute for Science and Engineering   Adjunct Researcher

  • 2014.04
    -
    2017.09

    Waseda University   Organization for University Research Initiatives・WABIOS   Associate Professor

  • 2007
    -
     

    Waseda University   Research Institute for Science and Engineering   Associate Professor

  • 2005
    -
     

    Waseda University   Advanced Research Institute for Science and Engineering   Associate Professor

  • 2003
    -
     

    Waseda University   Advanced Research Institute for Science and Engineering   Lecture

  • 2002
    -
     

    日本公定書協会海外派遣研究員(U. Texas, San Antonio)

  • 2001
    -
     

    ヒュ-マンサイエンス振興財団海外派遣研究員(U. Texas, San Antonio)

  • 1999
    -
     

    Waseda University   Advanced Research Institute for Science and Engineering

▼display all

Education Background

  • 1995.04
    -
    2000.03

    Waseda University   Graduate School of Science and Engineering   Polymer Chemistry  

  • 1991.04
    -
    1995.03

    Waseda University   School of Science and Engineering   Applied Chemistry  

Professional Memberships

  •  
     
     

    アメリカ化学会

  •  
     
     

    日本血液代替物学会

  •  
     
     

    高分子学会

  •  
     
     

    日本化学会

Research Areas

  • Nanomaterials / Biomaterials / Biomedical engineering / Nanobioscience

Research Interests

  • Molecular assembly

  • Nanocapsule

  • Temperature-responsive

  • Liposomes

Awards

  • Young Investigator Award

    2007   International Symposium on Blood Substitutes  

  • Award for Encouragement of Research in Polymer Science; The Society of Polymer Science, Japan

    2005   The Society of Polymer Science, Japan  

  • Mizuno Toshiyuki Memorial Award

    2000   Waseda University  

 

Papers

  • Evaluation of a static mixer as a new microfluidic method for liposome formulation

    Aoba Ota, Ayaka Mochizuki, Keitaro Sou, Shinji Takeoka

    Frontiers in Bioengineering and Biotechnology   11:1229829  2023.08  [Refereed]

     View Summary

    Introduction: Microfluidic formulation of liposomes has been extensively studied as a potential replacement for batch methods, which struggle with problems in scalability and difficulty in modulating conditions. Although microfluidic devices are considered to be able to combat these issues, an adequate replacement method has yet to be established.

    Methods: This paper examines the potential of a static mixer (SM) by comparing the encapsulation efficiency, loading, lamellarity, and user-friendliness with a commonly used microfluidic device, a staggered herringbone micromixer (SHM).

    Results: In both devices, it was found that as the initial lipid concentration increased, the particle size increased; however, the overall particle size was seen to be significantly larger in the liposomes prepared with SM. PDI remained significantly smaller in SM, however, signifying that better control of the particle size was accomplished in SM. In addition, the encapsulation efficiency was slightly smaller in SM compared to SHM, and in both devices, the values increased as the initial lipid concentration increased. The increase in encapsulation efficiencies was significantly smaller than that of the theoretical encapsulation efficiency, and this was found to be due to the increase in lamellarity as the initial lipid concentration increased.

    Discussion: In terms of user-friendliness, SM demonstrated significant advantages. The mixing elements could be taken out from the device, allowing for thorough cleaning of the element and device before and after experiments and ensuring experiments are conducted at virgin state in every round. Consequently, it was found that SM not only can produce uniformly distributed liposomes but has the potential to become a more practical method for liposome formulation with modifications in the mixing elements.

    DOI

    Scopus

  • Temperature-Responsive Liposome-Linked Immunosorbent Assay for the Rapid Detection of SARS-CoV-2 Using Immunoliposomes.

    Runkai Hu, Morihiro Hotta, Taro Maruyama, Mizuki Fujisawa, Keitaro Sou, Shinji Takeoka

    ACS omega   7 ( 30 ) 26936 - 26944  2022.08  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the etiological agent of coronavirus disease 2019 (COVID-19), has infected more than 340 million people since the outbreak of the pandemic in 2019, resulting in approximately 55 million deaths. The rapid and effective diagnosis of COVID-19 patients is vital to prevent the spread of the disease. In a previous study, we reported a novel temperature-responsive liposome-linked immunosorbent assay (TLip-LISA) using biotinylated-TLip that exhibited high detection sensitivity for the prostate-specific antigen. Herein, we used immunoglobulin-TLip (IgG-TLip), in which the antibodies were directly conjugated to the liposomal surface to simplify pretreatment procedures and reduce the detection time for SARS-CoV-2. The results indicated that TLip-LISA could detect the recombinant nucleocapsid protein and the nucleocapsid protein in inactivated virus with 20 min incubation time in total, and the limit of detection was calculated to be 2.2 and 1.0 pg/mL, respectively. Therefore, TLip-LISA has high potential to be used in clinic for rapid diagnosis and disease control.

    DOI PubMed

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    3
    Citation
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  • Squaraine probes for the bimodal staining of lipid droplets and endoplasmic reticulum imaging in live cells.

    Ferdinandus, Jie Ren Tan, Jin Heng Lim, Satoshi Arai, Keitaro Sou, Chi-Lik Ken Lee

    The Analyst   147 ( 15 ) 3570 - 3577  2022.07  [Refereed]  [International journal]

     View Summary

    Lipid droplets (LDs) have emerged as a hot target for cancer therapeutics in recent years owing to findings that have shown them to be key organelles involved in maintaining cellular stability and regulating inter-organelle communication through molecular trafficking. LDs emerge from the endoplasmic reticulum (ER) as a form of cellular homeostasis control. We herein report the study of a library of asymmetric squaraines as superior fluorescence probes to track and image LDs in their native state and environment within cancer cells. The probes are highly selective towards LDs and displayed prominent bright fluorescence with just 1 μM probe concentration. They also possess bimodal LD and ER staining capability via the simple diffusion of small lipophilic molecules. The probes almost instantly stained LDs, while the ER staining rate is dependent on the probe's lipophilicity and the incubation duration. These "on-demand" organelle-selective probes are highly desirable tools for revealing the role of LDs in governing many cellular processes, especially in malignant cells.

    DOI PubMed

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    7
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  • A rapid and highly sensitive biomarker detection platform based on a temperature-responsive liposome-linked immunosorbent assay

    Runkai Hu, Keitaro Sou, Shinji Takeoka

    Scientific Reports   10 ( 1 ) 18086 - 18086  2020.10  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    The enzyme-linked immunosorbent assay (ELISA) is widely used in various fields to detect specific biomarkers. However, ELISA tests have limited detection sensitivity (≥ 1 pM), which is insufficiently sensitive for the detection of small amounts of biomarkers in the early stages of disease or infection. Herein, a method for the rapid and highly sensitive detection of specific antigens, using temperature-responsive liposomes (TLip) containing a squaraine dye that exhibits fluorescence at the phase transition temperature of the liposomes, was developed. A proof-of-concept study using biotinylated TLip and a streptavidin-immobilized microwell plate showed that the TLip bound to the plate via specific molecular recognition could be distinguished from unbound TLip within 1 min because of the difference in the heating time required for the fluorescence emission of TLip. This system could be used to detect prostate specific antigen (PSA) based on a sandwich immunosorbent assay using detection and capture antibodies, in which the limit of detection was as low as 27.6 ag/mL in a 100-μL PSA solution, 0.97 aM in terms of molar concentration. The present temperature-responsive liposome-linked immunosorbent assay provides an advanced platform for the rapid and highly sensitive detection of biomarkers for use in diagnosis and biological inspections.

    DOI PubMed

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    21
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  • Electrochemical System Encapsulated by Nanoscale Liposomes Enabling On-Demand Triggering of Electroless Deposition at Selected Areas

    Jing Zhan, Ming Lin, Satoshi Arai, Wan Wei Yang, Keitaro Sou, Hirotaka Sato

    ACS Applied Nano Materials   3 ( 6 ) 5098 - 5106  2020.06  [Refereed]

    Authorship:Corresponding author

     View Summary

    This study proposed and demonstrated an application for nanoscale thermosensitive liposomes: encapsulating chemicals (reducing agents or metal ions) to physically separate reducing agents from metal ions and temporarily prevent spontaneous reduction of the metal ion (i.e., deposition of the metal or electroless deposition). With such an electrochemical system encapsulated by nanoscale liposomes, we can trigger electroless deposition at areas of interest by heating on demand, which enables metallization at selected surface areas. We used 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) as the lipid to synthesize thermosensitive liposomes (gel-to-liquid-crystalline phase transition temperature at 40 degrees C) encapsulating hypophosphite (the reducing agent),and mixed it with a PdCl2 solution. The liposomes stably held the reducing agent for 160 days as long as it was stored in a fridge at 3 degrees C. When the temperature exceeded the phase transition temperature, the reducing agent was released from the liposomes and induced Pd deposition. This electroless deposition system encapsulated by thermosensitive liposomes was applied to metalize selected spots of the internal surface of a glass capillary tube: the mixture was injected into the tube and several spots were heated externally, and Pd metal was deposited at the spots. Furthermore, we succeeded in microscopically visualizing a single liposome thermally releasing the reducing agent and inducing metal deposition locally. Overall, on-demand triggering of electroless deposition can be accomplished by applying thermosensitive liposomes was demonstrated to be feasible. This new electrochemical system using nanoscale liposomes can be used to achieve metal coatings on various surfaces of interest.

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    2
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  • Nanocapsule pH Regulator: Sustained Continuous Alkali Release from Thermosensitive Liposomes Reduces Acid Erosion

    Jian Rong Chong, Duc Long Le, Hirotaka Sato, Keitaro Sou

    ACS Applied Materials & Interfaces   12 ( 19 ) 21463 - 21469  2020.05  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    Thermosensitive liposomes are major drug delivery carriers, which enable targeting of drugs and burst release of the drugs from the liposomes at the site of action by applying a local heat stimulation above body temperature. Although the burst release is significant for a one-shot high-rate release of drugs at the target site, this type of release has a limited sustained action of the drugs. In this study, we report the alkali-encapsulating thermosensitive liposomes enabling environment pH regulation by sustained continuous cargo release at human body temperature. The liposomes encapsulating alkalis successfully neutralized the environmental acids for hours by releasing the alkalis and prevented acid erosion of hydroxyapatite matrix. Taken together, the present liposomes are effective for the sustained release of cargo at body temperature, specifically the alkali-encapsulating liposomes can be a preventing agent for dental caries in the oral cavity. The sustained release under endogenous body heat characteristics of thermosensitive liposomes showcased in this study can also be extended for prolonged intravenous drug exposure from targeted liposomal drug nanotherapeutics in the near future.

    DOI PubMed

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    9
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  • NANO CAPSULE BASED CHEMICAL RELEASING SYSTEM FOR INSECT-COMPUTER HYBRID ROBOT

    Long D. Le, Keitaro Sou, Hirotaka Sato

    2020 33RD IEEE INTERNATIONAL CONFERENCE ON MICRO ELECTRO MECHANICAL SYSTEMS (MEMS 2020)     433 - 436  2020  [Refereed]

     View Summary

    This study reports a nano-capsule based chemical release system capable of in vivo drug dosing. We have successfully designed thermosensitive liposomes which release the cargo at desired temperature in different released modes (single bolus, sustained slow, stepwise releases). The system was capable of delivering drug with minimal dosage repeatedly, which is suitable for brief actuator halting in insect platform control. In addition, liposomes encapsulating glucose injected to the insect automatically release fuel to boost the endurance and operating time of the insect-computer hybrid system.

  • Highly cooperative fluorescence switching of self-assembled squaraine dye at tunable threshold temperatures using thermosensitive nanovesicles for optical sensing and imaging

    Keitaro Sou, Li Yan Chan, Satoshi Arai, Chi-Lik Ken Lee

    Scientific Reports   9 ( 1 ) 17991 - 17991  2019.11  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    Thermosensitive fluorescent dyes can convert thermal signals into optical signals as a molecular nanoprobe. These nanoprobes are playing an increasingly important part in optical temperature sensing and imaging at the nano- and microscale. However, the ability of a fluorescent dye itself has sensitivity and accuracy limitations. Here we present a molecular strategy based on self-assembly to overcome such limitations. We found that thermosensitive nanovesicles composed of lipids and a unique fluorescent dye exhibit fluorescence switching characteristics at a threshold temperature. The switch is rapid and reversible and has a high signal to background ratio (>60), and is also highly sensitive to temperature (10-22%/°C) around the threshold value. Furthermore, the threshold temperature at which fluorescence switching is induced, can be tuned according to the phase transition temperature of the lipid bilayer membrane forming the nanovesicles. Spectroscopic analysis indicated that the fluorescence switching is induced by the aggregation-caused quenching and disaggregation-induced emission of the fluorescent dye in a cooperative response to the thermotropic phase transition of the membrane. This mechanism presents a useful approach for chemical and material design to develop fluorescent nanomaterials with superior fluorescence sensitivity to thermal signals for optical temperature sensing and imaging at the nano- and microscales.

    DOI PubMed

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    7
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  • Nanocapsules for Programmed Neurotransmitter Release: Toward Artificial Extracellular Synaptic Vesicles

    Keitaro Sou, Duc Long Le, Hirotaka Sato

    Small   15 ( 17 ) 1900132 - 1900132  2019.04  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    Nanocapsules present a promising platform for delivering chemicals and biomolecules to a site of action in a living organism. Because the biological action of the encapsulated molecules is blocked until they are released from the nanocapsules, the encapsulation structure enables triggering of the topical and timely action of the molecules at the target site. A similar mechanism seems promising for the spatiotemporal control of signal transduction triggered by the release of signal molecules in neuronal, metabolic, and immune systems. From this perspective, nanocapsules can be regarded as practical tools to apply signal molecules such as neurotransmitters to intervene in signal transduction. However, spatiotemporal control of the payload release from nanocapsules persists as a key technical issue. Stimulus-responsive nanocapsules that release payloads in response to external input of physical stimuli are promising platforms to enable programmed payload release. These programmable nanocapsules encapsulating neurotransmitters are expected to lead to new insights and perspectives related to artificial extracellular synaptic vesicles that might provide an experimental and therapeutic strategy for neuromodulation and nervous system disorders.

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    12
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  • Drug Delivery: Nanocapsules for Programmed Neurotransmitter Release: Toward Artificial Extracellular Synaptic Vesicles (Small 17/2019)

    Keitaro Sou, Duc Long Le, Hirotaka Sato

    Small   15 ( 17 ) 1970088 - 1970088  2019.04

    DOI

  • An Assay to Evaluate the Function of Liposomal Platelet Substitutes Delivered to Platelet Aggregates

    Suyun Janet Tan, Keiko Nakahara, Keitaro Sou, Shinji Takeoka

    Frontiers in Bioengineering and Biotechnology   7   77 - 77  2019.04  [Refereed]  [International journal]

     View Summary

    Aggregation of liposomal platelet substitutes with activated platelets is the primary endpoint to estimate hemostatic potential. Although light transmission aggregometry is a "gold standard" in assessing platelet aggregation in vitro, this method is less specific and sensitive when tested using liposomal platelet substitutes. In the current study, a new method is developed to evaluate the function of platelet substitutes. By labeling liposomes with a fluorescent dye, DiD, we evaluated their ability to target platelet aggregates using a fluorescence microscope. By incorporating an image-based 96 microtiter microplate, this method was optimized by varying the final lipid concentrations and washing times and validated using unmodified liposomes (e.g., L550 with 0 mol% of carboxylic headgroup lipid; L551 with 9 mol% of carboxylic headgroup lipid) and modified liposomes (e.g., H12-L551 with 9 mol% of carboxylic headgroup lipid and 0.3 mol% of dodecapeptide). Our results showed that 200 μM of H12-L551 liposomes and four washes represent optimal conditions for quantitative fluorescence imaging. This method allowed users to qualitatively observe the fluorescently labeled liposomes involved in platelet aggregates. The imaging analysis tool was sufficiently sensitive to quantitatively determine the significantly enhanced delivery of the modified liposomes to platelet aggregates. This enhancement was achieved using dodecapeptide, which specifically binds to activated platelets. This robust and high-throughput method enables the evaluation of liposome function and should facilitate the development of platelet substitutes with a greater ability to target platelet aggregates.

    DOI PubMed

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    2
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  • Neurotransmitter-Loaded Nanocapsule Triggers On-Demand Muscle Relaxation in Living Organism

    Duc Long Le, Ferdinandus, Chin Kiat Tnee, T. Thang Vo Doan, Satoshi Arai, Madoka Suzuki, Keitaro Sou, Hirotaka Sato

    ACS Applied Materials & Interfaces   10 ( 44 ) 37812 - 37819  2018.11  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    This paper reports the on-demand artificial muscle relaxation using a thermosensitive liposome encapsulating γ-aminobutyric acid (GABA) inhibitory neurotransmitter. Muscle relaxation is not feasible in principle, although muscle contraction can be easily induced by electrical stimulation. Herein, thermosensitive liposomes (phase transition temperature = 40 °C) were synthesized to encapsulate GABA and were injected into a leg of a living beetle. The leg was wrapped around by a Ni-Cr wire heater integrated with a thermocouple to enable the feedback control and to manipulate the leg temperature. The injected leg was temporarily immobilized by heating it up to 45 °C. The leg did not swing even by electrically stimulating the leg muscle. Subsequently, the leg recovered to swing. The result indicates that GABA was released from liposomes and fed to the leg muscle, enabling temporal muscle relaxation.

    DOI PubMed

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    19
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  • Near Infrared Fluorophore-Tagged Chloroquine in Plasmodium falciparum Diagnostic Imaging

    Li Chan, Joshua Teo, Kevin Tan, Keitaro Sou, Wei Kwan, Chi-Lik Lee

    Molecules   23 ( 10 )  2018.10  [Refereed]  [International journal]

     View Summary

    Chloroquine was among the first of several effective drug treatments against malaria until the onset of chloroquine resistance. In light of diminished clinical efficacy of chloroquine as an antimalarial therapeutic, there is potential in efforts to adapt chloroquine for other clinical applications, such as in combination therapies and in diagnostics. In this context, we designed and synthesized a novel asymmetrical squaraine dye coupled with chloroquine (SQR1-CQ). In this study, SQR1-CQ was used to label live Plasmodium falciparum (P. falciparum) parasite cultures of varying sensitivities towards chloroquine. SQR1-CQ positively stained ring, mature trophozoite and schizont stages of both chloroquine⁻sensitive and chloroquine⁻resistant P. falciparum strains. In addition, SQR1-CQ exhibited significantly higher fluorescence, when compared to the commercial chloroquine-BODIPY (borondipyrromethene) conjugate CQ-BODIPY. We also achieved successful SQR1-CQ labelling of P. falciparum directly on thin blood smear preparations. Drug efficacy experiments measuring half-maximal inhibitory concentration (IC50) showed lower concentration of effective inhibition against resistant strain K1 by SQR1-CQ compared to conventional chloroquine. Taken together, the versatile and highly fluorescent labelling capability of SQR1-CQ and promising preliminary IC50 findings makes it a great candidate for further development as diagnostic tool with drug efficacy against chloroquine-resistant P. falciparum.

    DOI PubMed

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    3
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  • 温度応答性リポソームの開発と薬物送達システムへの応用

    宗 慶太郎

    人工血液   26 ( 1 ) 47 - 54  2018.10  [Refereed]

    Authorship:Corresponding author

     View Summary

    脂質分子の自発的分子集合により形成される閉鎖小胞体(リポソーム)は、タンパク質、核酸、低分子薬物などを微粒子として体内に投与するキャリアとして使われ、人工血液や薬物送達システム(DDS)への応用においてその安全性や効果が実証されている。温度に応答した薬物放出機能をもつ温度応答性リポソームは、熱刺激により薬物動態を制御するナノデバイスとして次世代DDSへの応用が期待される。本稿では、温度応答性リポソームの設計原理とDDSへの応用について概説する。温度応答性リポソームをDDS技術として生体内で安全・効果的に機能させるには、特定細胞や組織の標的化、微小空間の正確な温度制御と温度モニタリング、薬物動態や薬物放出挙動の可視化などの新しい技術開発と並行した進展が重要となる。(著者抄録)

  • Far-Red Fluorescent Liposomes for Folate Receptor-targeted Bioimaging

    Sheng Dong, Joshua Ding Wei Teo, Li Yan Chan, Chi-Lik Ken Lee, Keitaro Sou

    ACS Applied Nano Materials   1 ( 3 ) 1009 - 1013  2018.03  [Refereed]

    Authorship:Corresponding author

     View Summary

    In this paper, we describe the newly designed liposomes modified with amphiphilic far-red squaraine dye and folic acid for its application in folate receptor-targeted bioimaging. Enhanced intracellular uptake of the engineered liposomes has been demonstrated on SKOV-3 ovarian cancer cells.

    DOI

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    28
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  • Meet Our Regional Editor

    Keitaro Sou

    Current Nanomedicine   7 ( 3 )  2017.09

    DOI

  • Photo-switchable and Self-erasable Fluorescent Nanoprobe

    Keitaro Sou, Li Yan Chan, Chi-Lik Ken Lee

    Journal of Photochemistry and Photobiology A: Chemistry   332   25 - 31  2016.08  [Refereed]

    Authorship:Corresponding author

     View Summary

    Optically switchable fluorescent molecule is useful for developing photo-functional materials. However, most of the conventional fluorescent molecule is in a class of "always-on" type, which does not possess a fluorescence switching function. In this work, switchable fluorescent nanoparticles based on self assembly of amphiphilic derivative of rhodamine B is synthesized and evaluated for its optical properties. The fluorescent nanoparticles functioned as a photo-switchable and self-erasable nanoprobe by reversible intramolecular ring opening cyclization of the rhodamine B derivative in dispersion and freestanding hydrogel. (C) 2016 Elsevier B.V. All rights reserved.

    DOI

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    5
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  • Temperature Tracking in a Three-Dimensional Matrix Using Thermosensitive Liposome Platform

    Keitaro Sou, Li Yan Chan, Chi-Lik Ken Lee

    ACS Sens.   1 ( 6 ) 650 - 655  2016.05  [Refereed]

    Authorship:Corresponding author

     View Summary

    Thermosensitive lipid-based nanoparticle (liposome) is a key platform for the controlled release of functional molecules by regional heating. Temperature monitoring in a three-dimensional matrix is necessary to conduct controlled heating at the targeted region. Currently, conventional liposomes do not possess a function for temperature monitoring. Herein, an extended concept for temperature monitoring using the liposomes was examined using near-infrared (NIR) laser-induced heating of water in hydrogel. The temperature distribution in hydrogel by photothermal conversion can now be traced by fluorescence in real time, with the use of liposomes that release the fluorescence cargo at different threshold temperatures. The liposome platform, equipped with temperature-sensing capability, extend the concept of temperature monitoring for temperature-triggered drug release, as well as thermotherapy.

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    8
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  • Establishment of a total liquid ventilation system using saline-based oxygen micro/nano-bubble dispersions in rats

    Kenta Kakiuchi, Kenichi Matsuda, Norikazu Harii, Keitaro Sou, Junko Aoki, Shinji Takeoka

    J Artif Organs   18 ( 3 ) 220 - 7  2015.04  [Refereed]  [Domestic journal]

     View Summary

    Micro/nano-bubbles are practical nanomaterials designed to increase the gas content in liquids. We attempted to use oxygen micro/nano-bubble dispersions as an oxygen-rich liquid as a means for total liquid ventilation. To determine the oxygen content in the bubble dispersion, a new method based on a spectrophotometric change between oxy- and deoxy-hemoglobin was established. The oxygen micro/nano-bubble dispersion was supplied to an experimental total ventilation liquid in anesthetic rats. Though the amount of dissolving oxygen was as low as 6 mg/L in physiological saline, the oxygen content in the oxygen micro/nano-bubble dispersion was increased to 45 mg/L. The positive correlation between the oxygen content and the life-saving time under liquid ventilation clearly indicates that the life-saving time is prolonged by increasing the oxygen content in the oxygen micro/nano-bubble dispersion. This is the first report indicating that the oxygen micro/nano-bubbles containing a sufficient amount of oxygen are useful in producing oxygen-rich liquid for the process of liquid ventilation.

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    8
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  • Engineered Liposomes for Drug Delivery and Biomedical Imaging

    Keitaro Sou

    PNM   4 ( 2 ) 95 - 101  2015.03  [Refereed]

    Authorship:Corresponding author

    DOI

  • Thermosensitive nanoplatforms for photothermal release of cargo from liposomes under intracellular temperature monitoring

    Satoshi Arai, Chi-Lik Ken Lee, Young-Tae Chang, Hirotaka Sato, Keitaro Sou

    RSC Adv.   5 ( 113 ) 93530 - 93538  2015  [Refereed]

    Authorship:Corresponding author

     View Summary

    Control of cargo release from nanoscale carriers is an important technology for maximizing the benefits of nanoparticulate drug delivery systems. Herein, we attempt to trigger the release of cargo from liposomes by photothermal conversion of water with a 980 nm near-infrared (NIR) laser. This study examined liposomes of two types formulated by 1,2-dipalmitory-sn-glycero-3-phosphocholine (DPPC) or a mixture of DPPC/cholesterol with an anionic lipid and PEG-lipid as stabilizers encapsulating calcein as a cargo at different ionic strengths. Liposome formulation encapsulating a hypertonic solution with a lipid membrane shows that a gel to liquid-crystalline phase transition at around 40 degrees C effectively released the cargo from liposomes at temperature above 40 degrees C with NIR irradiation. Our proof of concept has been further demonstrated in a cancer cell with monitoring the actual "intracellular temperature" using a fluorescent thermosensor. Intracellular thermometry revealed that it was not until the intracellular temperature reached around 40 degrees C by NIR irradiation that the release of the cargo started gradually, showing good agreement with the result from the extracellular in vitro study. This targeted release of cargo from thermosensitive liposomes based on a photothermal effect using a NIR laser offers a potent nanoscale platform for the on-demand release of drugs in intracellular space with local hyperthermia. The intracellular thermometry facilitates the quantitative monitoring and control of the hyperthermia at the cellular level.

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  • Therapeutic Impact of Erythropoietin-Encapsulated Liposomes Targeted to Bone Marrow on Renal Anemia

    Yuri Miyazaki, Kazuaki Taguchi, Keitaro Sou, Hiroshi Watanabe, Yu Ishima, Toshikazu Miyakawa, Hiroaki Mitsuya, Masafumi Fukagawa, Masaki Otagiri, Toru Maruyama

    Mol. Pharmaceutics   11 ( 11 ) 141006162142007 - 141006162142007  2014.10  [Refereed]  [International journal]

     View Summary

    Bone marrow is a key element in the diagnosis of disorders of erythropoiesis, including anemia, and a potential target in their treatment. However, because efficient delivery of diagnostic and therapeutic agents to bone marrow is difficult, such delivery is achieved by administering drugs in large quantities that often have adverse effects. Here, we achieved selective delivery of recombinant human erythropoietin (rHuEPO) to bone marrow, via its encapsulation in liposomes with l-glutamic acid, N-(3-carboxy-1-oxopropyl)-, 1,5-dihexadecyl ester (SA) (liposome-EPO). The result, in a rabbit model of renal anemia, was a beneficial effect on hematopoiesis, better than with rHuEPO alone. Also, we determined that liposome-EPO delivery to bone marrow depended on specific uptake by bone marrow macrophages because of the presence of SA. These results indicate both that liposome-EPO is a new, promising erythropoietin-stimulating agent and that liposomes with SA have potential for diagnostic and therapeutic applications in diseases originating from bone marrow.

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    7
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  • エリスロポエチン骨髄デリバリーシステムの腎性貧血治療への応用

    丸山 徹, 田口 和明, 宮崎 裕理, 渡邊 博志, 宗 慶太郎, 末永 綾香, 異島 優, 小田切 優樹

    日本薬学会年会要旨集   134年会 ( 4 ) 94 - 94  2014.03  [Refereed]

  • Application of Surface–modified Liposomes with Succinic Acid for Drug Delivery System Targeting Bone Marrow

    Keitaro Sou

    MEMBRANE   39 ( 5 ) 290 - 295  2014  [Refereed]

    Authorship:Corresponding author

     View Summary

    The capsular structure of liposomes is attractive for encapsulation of pharmaceuticals to develop nanoparticle-based drug delivery systems. Here unique liposomes which are modified with succinic acid on their surface arereviewed at a point of view of drug delivery carriers. The negatively charged carboxyl group of the succinic acid onthe surface of the liposomes contributes to facilitate the formation of the unilamellar liposomes which have superiorability to efficiently encapsulate the pharmaceuticals. Interestingly, we found that the liposomes modified with suc-cinic acid are highly distributed in the bone marrow through the intravenous injection. These characteristics of thesurface–modified liposomes with succinic acid would be applicable for the drug delivery system targeting bone mar-row.

    DOI CiNii

  • Arginine-based cationic liposomes for efficient in vitro plasmid DNA delivery with low cytotoxicity

    Takeoka, Shinji, Sarker, Aoshima, Hokama, Inoue, Sou, Keitaro

    International Journal of Nanomedicine   8   1361 - 1361  2013  [Refereed]

     View Summary

    Background: Currently available gene delivery vehicles have many limitations such as low gene delivery efficiency and high cytotoxicity. To overcome these drawbacks, we designed and synthesized two cationic lipids comprised of n-tetradecyl alcohol as the hydrophobic moiety, 3-hydrocarbon chain as the spacer, and different counterions (eg, hydrogen chloride [HCl] salt or trifluoroacetic acid [TFA] salt) in the arginine head group.Methods: Cationic lipids were hydrated in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer to prepare cationic liposomes and characterized in terms of their size, zeta potential, phase transition temperature, and morphology. Lipoplexes were then prepared and characterized in terms of their size and zeta potential in the absence or presence of serum. The morphology of the lipoplexes was determined using transmission electron microscopy and atomic force microscopy. The gene delivery efficiency was evaluated in neuronal cells and HeLa cells and compared with that of lysine-based cationic assemblies and Lipofectamine (TM) 2000. The cytotoxicity level of the cationic lipids was investigated and compared with that of Lipofectamine (TM) 2000.Results: We synthesized arginine-based cationic lipids having different counterions (ie, HCl-salt or TFA-salt) that formed cationic liposomes of around 100 nm in size. In the absence of serum, lipoplexes prepared from the arginine-based cationic liposomes and plasmid (p) DNA formed large aggregates and attained a positive zeta potential. However, in the presence of serum, the lipoplexes were smaller in size and negative in zeta potential. The morphology of the lipoplexes was vesicular. Arginine-based cationic liposomes with HCl-salt showed the highest transfection efficiency in PC-12 cells. However, arginine-based cationic liposomes with TFA salt showed the highest transfection efficiency in HeLa cells, regardless of the presence of serum, with very low associated cytotoxicity.Conclusion: The gene delivery efficiency of amino acid-based cationic assemblies is influenced by the amino acids (ie, arginine or lysine) present as the hydrophilic head group and their associated counterions.

    DOI DOI2

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  • Cationic Amino Acid Based Lipids as Effective Nonviral Gene Delivery Vectors for Primary Cultured Neurons

    Aoshima, Yumiko, Hokama, Ryosuke, Sou, Keitaro, Sarker, Satya Ranjan, Iida, Kabuto, Nakamura, Hideki, Inoue, Takafumi, Takeoka, Shinji

    ACS Chemical Neuroscience   4 ( 12 ) 131011153804008 - 131011153804008  2013  [Refereed]  [International journal]

     View Summary

    The delivery of specific genes into neurons offers a potent approach for treatment of diseases as well as for the study of neuronal cell biology. Here we investigated the capabilities of cationic amino acid based lipid assemblies to act as nonviral gene delivery vectors in primary cultured neurons. An arginine-based lipid, Arg-C3-Glu2C14, and a lysine-based lipid, Lys-C3-Glu2C14, with two different types of counterion, chloride ion (Cl-) and trifluoroacetic acid (TFA-), were shown to successfully mediate transfection of primary cultured neurons with plasmid DNA encoding green fluorescent protein. Among four types of lipids, we optimized their conditions such as the lipid-to-DNA ratio and the amount of pDNA and conducted a cytotoxicity assay at the same time. Overall, Arg-C3-Glu2C14 with TFA- induced a rate of transfection in primary cultured neurons higher than that of Lys-C3-Glu2C14 using an optimal weight ratio of lipid-to-plasmid DNA of 1. Moreover, it was suggested that Arg-C3-Glu2C14 with TFA- showed the optimized value higher than that of Lipofectamine2000 in experimental conditions. Thus, Arg-C3-Glu2C14 with TFA- is a promising candidate as a reliable transfection reagent for primary cultured neurons with a relatively low cytotoxicity.

    DOI PubMed

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    18
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  • Arginine-based cationic liposomes for efficient in vitro plasmid DNA delivery with low cytotoxicity.

    Satya Ranjan Sarker, Yumiko Aoshima, Ryosuke Hokama, Takafumi Inoue, Keitaro Sou, Shinji Takeoka

    International journal of nanomedicine   8   1361 - 75  2013  [Refereed]  [International journal]

     View Summary

    BACKGROUND: Currently available gene delivery vehicles have many limitations such as low gene delivery efficiency and high cytotoxicity. To overcome these drawbacks, we designed and synthesized two cationic lipids comprised of n-tetradecyl alcohol as the hydrophobic moiety, 3-hydrocarbon chain as the spacer, and different counterions (eg, hydrogen chloride [HCl] salt or trifluoroacetic acid [TFA] salt) in the arginine head group. METHODS: Cationic lipids were hydrated in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer to prepare cationic liposomes and characterized in terms of their size, zeta potential, phase transition temperature, and morphology. Lipoplexes were then prepared and characterized in terms of their size and zeta potential in the absence or presence of serum. The morphology of the lipoplexes was determined using transmission electron microscopy and atomic force microscopy. The gene delivery efficiency was evaluated in neuronal cells and HeLa cells and compared with that of lysine-based cationic assemblies and Lipofectamine™ 2000. The cytotoxicity level of the cationic lipids was investigated and compared with that of Lipofectamine™ 2000. RESULTS: We synthesized arginine-based cationic lipids having different counterions (ie, HCl-salt or TFA-salt) that formed cationic liposomes of around 100 nm in size. In the absence of serum, lipoplexes prepared from the arginine-based cationic liposomes and plasmid (p) DNA formed large aggregates and attained a positive zeta potential. However, in the presence of serum, the lipoplexes were smaller in size and negative in zeta potential. The morphology of the lipoplexes was vesicular. Arginine-based cationic liposomes with HCl-salt showed the highest transfection efficiency in PC-12 cells. However, arginine-based cationic liposomes with TFA salt showed the highest transfection efficiency in HeLa cells, regardless of the presence of serum, with very low associated cytotoxicity. CONCLUSION: The gene delivery efficiency of amino acid-based cationic assemblies is influenced by the amino acids (ie, arginine or lysine) present as the hydrophilic head group and their associated counterions.

    DOI PubMed

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  • Advanced Drug Carriers Targeting Bone Marrow

    Keitaro Sou

       2012.10

    DOI

  • Curcumin Towards Nanomedicine

    Keitaro Sou

       2012.07  [Refereed]

    Authorship:Corresponding author

    DOI

  • Cardiopulmonary hemodynamic responses to the small injection of hemoglobin vesicles (artificial oxygen carriers) in miniature pigs

    Sakai, H., Suzuki, Y., Sou, K., Kano, M.

    Journal of Biomedical Materials Research - Part A   100 A ( 10 ) 2668 - 77  2012  [Refereed]  [International journal]

     View Summary

    Intravenous injection of liposomes into pigs reportedly induces anaphylactoid reactions at a small dose, resulting in circulatory disorder. Hemoglobin vesicles (HbVs) are artificial oxygen carriers encapsulating Hb solution in liposomes. It is not known how pigs respond to HbV injection. We aimed to analyze the cardiopulmonary responses to small injections of HbV and empty vesicle (EV) and compare them with a conventional liposome (CL) with a different lipid composition containing phosphatidylglycerol (PG). PG is known to induce an anaphylactoid reaction in pigs. Nine male miniature pigs were used for HbV, EV, and CL injections. The anesthetized pig received 0.05 and 0.5 mL/kg of a test fluid for the first and second injection with a 70 min interval. Results show that CL repeatedly induced significant increases in systemic and pulmonary arterial pressures and vascular resistances and decreases in heart rate and cardiac output (CO). HbV and EV at the first injection-induced pulmonary hypertension, with significantly smaller changes in systemic arterial pressure and CO. No remarkable response was visible at the second injection in spite of a larger dosage. Only CL repeatedly induced thrombocytopenia, leukocytopenia, and plasma thromboxane B(2) increase resulting from complement activation, although HbV and EV showed smaller changes. Transmittance electron micrograph of pulmonary intravascular macrophages (PIMs) showed phagocytosis of HbV, indicating the possibility that nonspecific phagocytosis by PIMs relates to the responses observed after the first injection. HbV does not induce a significant anaphylactoid reaction in pigs compared with CL because of the different lipid composition.

    DOI PubMed

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  • Removal of Cellular-Type Hemoglobin-Based Oxygen Carrier (Hemoglobin-Vesicles) From Blood Using Centrifugation and Ultrafiltration

    Sakai, H., Sou, K., Horinouchi, H., Tsuchida, E., Kobayashi, K.

    Artificial Organs   36 ( 2 ) 202 - 9  2012  [Refereed]  [International journal]

     View Summary

    The hemoglobin-vesicle (HbV) is an artificial oxygen carrier encapsulating a concentrated hemoglobin solution in a phospholipid vesicle (liposome). During or after transporting oxygen, macrophages capture HbVs in the reticuloendothelial system (RES) with an approximate circulation half-life of 3 days. Animal studies show transient splenohepatomegaly after large doses, but HbVs were completely degraded, and the components were excreted in a few weeks. If a blood substitute is used for emergency use until red blood cell transfusion becomes available or for temporary use such as a priming fluid for an extracorporeal circuit, then one option would be to remove HbVs from the circulating blood without waiting a few weeks for removal by the RES. Using a mixture of beagle dog whole blood and HbV, we tested the separation of HbV using a centrifugal Fresenius cell separator and an ultrafiltration system. The cell separator system separated the layers of blood cell components from the HbV-containing plasma layer by centrifugal force, and then the HbV was removed from plasma phase by the ultrafiltration system. The HbVs (250-280 nm) are larger than plasma proteins (< 22 nm diameter) but smaller than blood cell components (> 3 µm). The size of HbVs is advantageous to be separated from the original blood components, and the separated blood components can be returned to circulation.

    DOI PubMed

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    3
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  • Radiolabeled liposomes as theranostic agents

    William T. Phillips, Beth Goins, Keitaro Sou, Ande Bao

    Nanoimaging     71 - 108  2011.08  [Refereed]

    DOI

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  • Tc-99m-bone marrow-targeted liposomal carriers: Comparison between rat, mice, hamster, rabbit and rhesus monkey

    Keitaro Sou, Beth Goins, Babatunde Oyajobi, Bruno Travi, William Phillips

    JOURNAL OF NUCLEAR MEDICINE   52  2011.05

  • リポソーム技術を基盤とする骨髄指向性薬物送達キャリアー

    宗 慶太郎

    人工血液   18 ( 4 ) 134 - 141  2011.03  [Refereed]

    Authorship:Corresponding author

     View Summary

    リポソームは細胞型人工酸素運搬体としての応用のほか,各種薬物や遺伝子の運搬体としての応用が期待されている.人工酸素運搬体に利用されるリポソームは大量投与を想定して開発され,薬物キャリアーとして少量投与で使用される血中滞留性リポソームとは粒子径や脂質組成などで異なる特徴を有している.このリポソームにヘモグロビンを内包させた人工酸素運搬体(Hb小胞体)を大量投与(680mg lipid/kg body weight)すると,主に肝臓,脾臓,骨髄に捕捉され,2〜3日程度の半減期で血中から消失する.一方,薬物送達の対象となる少投与量(15mg lipid/kg body weight)では,興味深いことに骨髄に集中した体内分布が観測される.この体内動態特性により,骨髄に薬剤を効率的に運搬できる薬物送達システムとしての新しい応用が期待できる.(著者抄録)

  • Bone marrow-targeted liposomal carriers

    Sou, K., Goins, B., Oyajobi, B.O., Travi, B.L., Phillips, W.T.

    Expert Opinion on Drug Delivery   8 ( 3 )  2011  [Refereed]

    Authorship:Corresponding author

    DOI

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  • Phagocytosis of liposome particles by rat splenic immature monocytes makes them transiently and highly immunosuppressive in ex vivo culture conditions

    Takahashi, D., Azuma, H., Sakai, H., Sou, K., Wakita, D., Abe, H., Fujihara, M., Horinouchi, H., Nishimura, T., Kobayashi, K., Ikeda, H.

    Journal of Pharmacology and Experimental Therapeutics   337 ( 1 ) 42 - 9  2011  [Refereed]  [International journal]

     View Summary

    Liposomes reportedly accumulate in monophagocytic systems (MPSs), such as those of the spleen. Accumulation of considerable amounts of liposome in a MPS can affect immunologic response. While developing a liposomal oxygen carrier containing human hemoglobin vesicle (HbV), we identified its suppressive effect on the proliferation of rat splenic T cells. The aim of this study was to elucidate the mechanism underlying that phenomenon and its effect on both local and systemic immune response. For this study, we infused HbV intravenously at a volume of 20% of whole blood or empty liposomes into rats, removed their spleens, and evaluated T cell responses to concanavalin A (Con A) or keyhole limpet hemocyanin (KLH) by measuring the amount of [(3)H]thymidine incorporated into DNA. Cells that phagocytized liposomal particles were sorted using flow cytometry and analyzed. Serum anti-KLH antibody was measured after immunizing rats with KLH. Results showed that T cell proliferation in response to Con A or KLH was inhibited from 6 h to 3 days after the liposome injection. Direct cell-to-cell contact was necessary for the suppression. Both inducible nitric-oxide synthase and arginase inhibitors restored T cell proliferation to some degree. The suppression abated 7 days later. Cells that trapped vesicles were responsible for the suppression. Most expressed CD11b/c but lacked class II molecules. However, the primary antibody response to KLH was unaffected. We conclude that the phagocytosis of the large load of liposomal particles by rat CD11b/c+, class II immature monocytes temporarily renders them highly immunosuppressive, but the systemic immune response was unaffected.

    DOI PubMed

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  • Electrostatics of carboxylated anionic vesicles for improving entrapment capacity

    Sou, K.

    Chemistry and Physics of Lipids   164 ( 3 ) 211 - 5  2011  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    Electrostatic interaction is an important secondary force affecting the structure, stability, and function of lipid vesicles (liposomes). For this study, a negatively charged lipid with carboxylic acid was mixed with phospholipid to produce anionic vesicles. The electrostatics of the carboxylated anionic vesicle (ca. 200 nm diameter) was determined and correlated with entrapment capacity of the vesicles. Correlative analysis revealed the zeta potential of the vesicles as a factor quantitatively affecting the entrapment capacity for a water-soluble marker, in which the entrapment capacity reached its maximum level in less than -30 mV of zeta potential. Transmission electron microscopy (TEM) revealed that the vesicles with high entrapment capacity are composed of a unilamellar membrane. This finding is expected to be useful for efficient encapsulation of water-soluble pharmaceuticals within vesicles.

    DOI PubMed

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  • Bone marrow-targeted liposomal carriers: A feasibility study in nonhuman primates

    Sou, K., Goins, B., Lel, , M.M., Tsuchida, E., Phillips, W.T.

    Nanomedicine   5 ( 1 ) 41 - 9  2010  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    BACKGROUND & AIMS: Recently, we described a novel surface-modified lipid vesicle formulation (liposome) that had very high targeting to bone marrow in normal rabbits. Because the bone marrow is the site of hematopoiesis, bone marrow-targeted drug-delivery systems have many potential applications. In this study we investigated whether these bone marrow-targeted vesicles are also similarly effective for bone marrow targeting in rhesus monkeys, a primate animal model that is more relevant to humans. MATERIALS & METHODS: The preformed vesicles encapsulating 30 mM glutathione were labeled with technetium-99m ((99m)Tc) for scintigraphic imaging. The vesicles were 216 +/- 21 nm in diameter with a negative surface charge composed of DPPC, cholesterol, anionic amphiphile and poly(ethylene glycol)-DSPE (1:1:0.2:0.013 molar ratio). RESULTS: The whole-body images of rhesus monkeys receiving intravenous (99m)Tc vesicles revealed high uptake of the (99m)Tc vesicles in bone marrow. Based on image analysis, we estimated that approximately 70% of the injected dose of the (99m)Tc vesicles was taken up by the bone marrow. CONCLUSION: This finding increases the feasibility of using this bone marrow-specific drug-delivery system for clinical applications.

    DOI PubMed

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    22
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  • Hemoglobin-vesicle, a cellular artificial oxygen carrier that fulfils the physiological roles of the red blood cell structure

    Sakai, H., Sou, K., Horinouchi, H., Kobayashi, K., Tsuchida, E.

    Advances in Experimental Medicine and Biology   662   433 - 8  2010  [Refereed]  [International journal]

     View Summary

    Hb-vesicles (HbV) are artificial O(2) carriers encapsulating concentrated Hb solution (35 g/dL) with a phospholipid bilayer membrane (liposome). The concentration of the HbV suspension is extremely high ([Hb] = 10 g/dL) and it has an O(2) carrying capacity that is comparable to that of blood. HbV is much smaller than RBC (250 vs. 8000 nm), but it recreates the functions of RBCs; (i) the slower rate of O(2) unloading than Hb solution; (ii) colloid osmotic pressure is zero; (iii) the viscosity of a HbV suspension is adjustable to that of blood; (iv) HbV is finally captured by and degraded in RES; (v) co-encapsulation of an allosteric effector to regulate O(2) affinity; (vi) the lipid bilayer membrane prevents direct contact of Hb and vasculature; (vii) NO-binding is retarded to some extent by an intracellular diffusion barrier, and HbV does not induce vasoconstriction. (viii) Both RBC and HbV can be a carrier of not only O(2) but also exogenous CO. However, HbV has limitations such as a shorter functional half-life when compared with RBCs. On the other hand, the advantages of HbV are that it is pathogen-free and blood-type-antigen-free; moreover, it can withstand long-term storage of a few years, none of which can be achieved by the RBC transfusion systems.

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  • Clinical laboratory test of blood specimens containing hemoglobin-vesicles. -Interference avoidance by addition of dextran-.

    K. Sou, R. Komine, H. Sakai, K. Kobayashi, E. Tsuchida, M. Murata

    Artif. Blood   17 ( 1 ) 6 - 15  2009.06  [Refereed]

  • Characterization and cytotoxicity of self-organized assemblies of curcumin and amphiphatic poly(ethylene glycol).

    Sou K, Oyajobi B, Goins B, Phillips WT, Tsuchida E

    Journal of Biomedical Nanotechnology   5 ( 2 ) 202 - 8  2009.04  [Refereed]  [International journal]

    Authorship:Corresponding author

     View Summary

    Polymer-conjugated nanoparticles are an important technology to control the stability, safety, and efficacy in drug delivery systems. Herein, we investigate self-organized mixed assemblies of a lipophilic drug candidate, curcumin (Cm), and a poly(oxyethylene) cholesteryl ether (PEG-Chol). Cm was assembled together with PEG-Chol to form nano-sized assemblies (around 10 nm) of assumed micelles. In contrast with the rapid decomposition of free Cm due to the hydrolysis, the Cm was highly stabilized in the nanoparticles, especially at below 40 mol% Cm. Cell viability assay revealed that the cytotoxic activity of the Cm/PEG-Chol nanoparticles against myeloma cells is higher than those of free Cm in a comparison at 1 microM. On the other hand, both the Cm/PEG-Chol nanoparticles and PEG-Chol micelles had significant cytotoxicity to the myeloma cells at 5 microM. Taken together, the present Cm/PEG-Chol system offers a stable nanoparticle encapsulating Cm which can be injected as a liquid. Cm and vehicle micelles will damage the cancer cells cooperatively.

    DOI PubMed

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    28
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  • Chapter 19 Hemoglobin-Vesicles as an Artificial Oxygen Carrier

    Sakai, Hiromi, Sou, Keitaro, Tsuchida, Eishun

    Methods in Enzymology   465 ( C ) 363 - 84  2009  [Refereed]  [International journal]

     View Summary

    Hemoglobin-vesicles (HbV) or liposome-encapsulated hemoglobin (LEH) are artificial oxygen carriers that mimic the cellular structure of RBCs. In contrast to other liposomal products containing antifungal or anticancer drugs, one injection of HbV in place of a blood transfusion is estimated as equivalent to a massive dose, such as several hundred milliliters or a few liters of normal blood contents. The fluid must therefore contain a sufficient amount of Hb, the binding site of oxygen, to carry oxygen like blood. Encapsulation of Hb can shield various toxic effects of molecular Hbs. On the other hand, the liposomal structure, surface property, and the balance between the stability for storage and blood circulation and instability for the prompt degradation in the reticuloendothelial system must be considered to establish an optimal transfusion alternative.

    DOI DOI2 PubMed

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  • Artificial oxygen carriers, hemoglobin vesicles and albumin-hemes, based on bioconjugate chemistry

    Tsuchida, E., Sou, K., Nakagawa, A., Sakai, H., Komatsu, T., Kobayashi, K.

    Bioconjugate Chemistry   20 ( 8 ) 1419 - 40  2009  [Refereed]  [Invited]  [International journal]

     View Summary

    Hemoglobin (Hb, Mw: 64 500) and albumin (Mw: 66 500) are major protein components in our circulatory system. On the basis of bioconjugate chemistry of these proteins, we have synthesized artificial O(2) carriers of two types, which will be useful as transfusion alternatives in clinical situations. Along with sufficient O(2) transporting capability, they show no pathogen, no blood type antigen, biocompatibility, stability, capability for long-term storage, and prompt degradation in vivo. Herein, we present the latest results from our research on these artificial O(2) carriers, Hb-vesicles (HbV) and albumin-hemes. (i) HbV is a cellular type Hb-based O(2) carrier. Phospholipid vesicles (liposomes, 250 nm diameter) encapsulate highly purified and concentrated human Hb (35 g/dL) to mimic the red blood cell (RBC) structure and eliminate side effects of molecular Hb such as vasoconstriction. The particle surface is modified with PEG-conjugated phospholipids, thereby improving blood compatibility and dispersion stability. Manipulation of physicochemical parameters of HbV, such as O(2) binding affinity and suspension rheology, supports the use of HbV for versatile medical applications. (ii) Human serum albumin (HSA) incorporates synthetic Fe(2+)porphyrin (FeP) to yield unique albumin-based O(2) carriers. Changing the chemical structure of incorporated FeP controls O(2) binding parameters. In fact, PEG-modified HSA-FeP showed good blood compatibility and O(2) transport in vivo. Furthermore, the genetically engineered heme pocket in HSA can confer O(2) binding ability to the incorporated natural Fe(2+)protoporphyrin IX (heme). The O(2) binding affinity of the recombinant HSA (rHSA)-heme is adjusted to a similar value to that of RBC through optimization of the amino acid residues around the coordinated O(2).

    DOI PubMed

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  • Review of hemoglobin-vesicles as artificial oxygen carriers

    Sakai, H., Sou, K., Horinouchi, H., Kobayashi, K., Tsuchida, E.

    Artificial Organs   33 ( 2 ) 139 - 45  2009  [Refereed]  [International journal]

     View Summary

    Blood transfusion systems have greatly benefited human health and welfare. Nevertheless, some problems remain: infection, blood type mismatching, immunological response, short shelf life, and screening test costs. Blood substitutes have been under development for decades to overcome such problems. Plasma component substitutes have already been established: plasma expanders, electrolytes, and recombinant coagulant factors. Herein, we focus on the development of red blood cell (RBC) substitutes. Side effects hindered early development of cell-free hemoglobin (Hb)-based oxygen carriers (HBOCs) and underscored the physiological importance of the cellular structure of RBCs. Well-designed artificial oxygen carriers that meet requisite criteria are expected to be realized eventually. Encapsulation of Hb is one idea to shield the toxicities of molecular Hbs. However, intrinsic issues of encapsulated Hbs must be resolved: difficulties related to regulating the molecular assembly, and management of its physicochemical and biochemical properties. Hb-vesicles (HbV) are a cellular type of HBOC that overcome these issues. The in vivo safety and efficacy of HbV have been studied extensively. The results illustrate the potential of HbV as a transfusion alternative and promise its use for other clinical applications that remain unattainable using RBC transfusion.

    DOI PubMed

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  • Static structures and dynamics of hemoglobin vesicle (HbV) developed as a transfusion alternative

    Sato, T., Sakai, H., Sou, K., Medebach, M., Glatter, O., Tsuchida, E.

    Journal of Physical Chemistry B   113 ( 24 ) 8418 - 28  2009  [Refereed]  [International journal]

     View Summary

    Hemoglobin vesicle (HbV) is an artificial oxygen carrier that encapsulates solution of purified and highly concentrated (ca. 38 g dL(-1)) human hemoglobin. Its exceptionally high concentration as a liposomal product (ca. 40% volume fraction) achieves an oxygen-carrying capacity comparable to that of blood. We use small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS) to investigate the hierarchical structures and dynamics of HbVs in concentrated suspensions. SAXS data revealed unilamellar shell structure and internal density profile of the artificial cell membrane for Hb encapsulation. The SAXS intensity of HbV at scattering vector q > 0.5 nm(-1) manifests dissolution states of the encapsulated Hbs in the inner aqueous phase of the vesicle having ca. 240 nm diameter. The peak position as well as the height and width of static structure factor of Hb before and after encapsulation are almost identical, demonstrating the preserved protein-protein interactions in the confined space. To overcome multiple scattering from turbid samples, we employed thin layer-cell DLS combined with the so-called bruteforce and echo techniques, which allows us to observe collective diffusion dynamics of HbVs without dilution. A pronounced slowdown of the HbV diffusion and eventual emergence of dynamically arrested state in the presence of high-concentration plasma substitutes (water-soluble polymers), such as dextran, modified fluid gelatin, and hydroxylethyl starch, can be explained by depletion interaction. A significantly weaker effect of recombinant human serum albumin on HbV flocculation and viscosity enhancement than those induced by other polymers is clearly attributed to the specificity as a protein; its compact structure efficiently reduces the reservoir polymer volume fraction that determines the depth of the attractive potential between HbVs. These phenomena are technically essential for controlling the suspension rheology, which is advantageous for versatile clinical applications.

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  • Hemoglobin vesicles as a transfusion alternative.

    H. Sakai, K. Sou, E. Tsuchida

    Methods Enzymol.   465   363-384  2009

  • 輸血代替としての利用法 Beagle犬を用いた40%脱血ショックにおけるHb小胞体の蘇生効果および中長期生存後の安全性の検討

    池田 達彦, 堀之内 宏久, 井澤 菜緒子, 河野 光智, 泉 陽太郎, 渡辺 真純, 川村 雅文, 宗 慶太郎, 酒井 宏水, 土田 英俊, 小林 紘一

    人工血液   16 ( 2 ) 47 - 47  2008.10

  • Loading of curcumin into macrophages using lipid-based nanoparticles

    Keitaro Sou, Shunsuke Inenaga, Shinji Takeoka, Eishun Tsuchida

    International Journal of Pharmaceutics   352 ( 1-2 )  2008.03  [Refereed]

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  • Haemoglobin-vesicles as artificial oxygen carriers: Present situation and future visions

    Sakai, H., Sou, K., Horinouchi, H., Kobayashi, K., Tsuchida, E.

    Journal of Internal Medicine   263 ( 1 )  2008  [Refereed]

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  • 人工酸素運搬体の適応 Beagle犬を用いた40%脱血ショックにおけるHb小胞体の蘇生効果および中長期生存の評価

    池田 達彦, 堀之内 宏久, 井澤 菜緒子, 河野 光智, 泉 陽太郎, 渡辺 真純, 川村 雅文, 宗 慶太郎, 酒井 宏水, 土田 英俊, 小林 紘一

    人工血液   15 ( 1 ) 18 - 18  2007.06

  • Molecular to cooperative dynamics and static structures of PEG-conjugated phospholipid in aqueous micellar solutions: dielectric spectroscopy and SAXS study.

    T. Sato, H. Sakai, K. Sou, E. Tsuchida

    J. Phys. Chem. B.   111   1393-1401  2007.02  [Refereed]

  • Selective uptake of surface-modified phospholipid vesicles by bone marrow macrophages in vivo

    Sou, K., Goins, B., Takeoka, S., Tsuchida, E., Phillips, W.T.

    Biomaterials   28 ( 16 )  2007  [Refereed]

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  • Poly(ethylene glycol)-conjugated phospholipids in aqueous micellar solutions: hydration, static structure, and interparticle interactions

    Sato, T., Sakai, H., Sou, K., Buchner, R., Tsuchida, E.

    Journal of Physical Chemistry B   111 ( 6 )  2007  [Refereed]

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  • Solution to the problems of acellular hemoglobins by encapsulation and the intrinsic issues of hemoglobin vesicles as a molecular assembly

    SAKAI, HIROMI, SOU, KEITARO, TSUCHIDA, EISHUN

    Transfusion Alternatives in Transfusion Medicine   9 ( 4 ) 226-236  2007  [Refereed]

    DOI DOI2

  • Preparation and evaluation of o/w emulsions with an anionic lipid, containing lipophilic drug

    Inenaga, S., Sou, K., Takeoka, S., Tsuchida, E.

    Polymer Preprints, Japan   55 ( 2 )  2006

  • Drug delivery to bone marrow using surface-modified vesicles

    Sou, K., Tsuchida, E.

    Polymer Preprints, Japan   55 ( 2 )  2006

  • Hemoglobin Vesicles as a Molecular Assembly

    Sakai, Hiromi, Sou, Keitaro, Takeoka, Shinji, Kobayashi, Koichi, Tsuchida, Eishun

    Blood Substitutes     514 - 522  2006  [Refereed]

     View Summary

    Liposome encapsulated hemoglobin is a long-sought goal in Japan, where the product is called hemoglobin vesicles (HbV), which distinguishes this product from the one developed primarily in the US, whose designation is liposome-encapsulated Hb (LEH). HbV is the result of a long series of studies in which the size of the vesicles, including the number of lipid layers, the surface composition and materials co-encapsulated have been optimized. HbV is produced by an extrusion process that has commercial potential, although at this time the product has not yet been produced in quantities sufficient for clinical trials. Sterilization of the hemoglobin, prior to encapsulation, is performed using heat, and antioxidants are co-encapsulated to retard hemoglobin oxidation. Oxygen affinity is regulated to any desired P50 by co-encapsulation of allosteric effectors, and this group has contributed important studies on the effect of different P 50 on oxygen delivery to tissues by HbV. The product is claimed to be stable when stored for up to 2 years. A commercial effort has been launched in Japan, and it is hoped that HbV could be in human clinical trials within the next few years. This chapter summarizes the characteristics of the preparation process of HbV based on the sciences of molecular assembly to induce their excellent performances. © 2006 Elsevier Ltd. All rights reserved.

    DOI DOI2

    Scopus

    4
    Citation
    (Scopus)
  • Circulation kinetics and organ distribution of Hb-vesicles developed as a red blood cell substitute

    Sou, K., Klipper, R., Goins, B., Tsuchida, E., Phillips, W.T.

    Journal of Pharmacology and Experimental Therapeutics   312 ( 2 )  2005  [Refereed]

    DOI

    Scopus

    71
    Citation
    (Scopus)
  • Physiologic capacity of reticuloendothelial system for degradation of Hb-vesicles (artificial oxygen carriers) after massive intravenous doses by daily repeated infusions for 14 days

    Sakai, H., Sou, K., Takeoka, S., Horinouchi, H., Kobayashi, K., Tsuchida, E.

    Polymer Preprints, Japan   54 ( 1 )  2005

  • Pharmacokinetics properties of surface-modified vesicles

    Sou, K., Coins, B., Phillips, W.T., Takeoka, S., Tsuchida, E.

    Polymer Preprints, Japan   54 ( 2 )  2005

  • Ligand exchange of hemoglobin vesicle with the model device optimized its light response to gas-liquid boundary face more efficient

    Suzuki, D., Takeoka, S., Sou, K., Tsuchida, E.

    Polymer Preprints, Japan   54 ( 2 )  2005

  • Circulatory half-life time of artificial red blood cell (hemoglobin-vesicles) and their distribution to metabolic organs

    Sou, K., Goins, B., Phillips, W.T., Sakai, H., Takeoka, S., Tsuchida, E.

    Polymer Preprints, Japan   54 ( 1 )  2005

  • Hemoglobin-Vesicles (HbV) as Artificial Oxygen Carriers

    Sakai, Hiromi, Sou, Keitaro, Takeoka, Shinji, Kobayashi, Koichi, Tsuchida, Eishun

    ARTIFICIAL OXYGEN CARRIER: ITS FRONT LINE   12   135 - 168  2005  [Refereed]

     View Summary

    Considering the physiological significance of the cellular structure of a red blood cell (RBC), it may be reasonable to mimic its structure for designing a hemoglobin (Hb)-based oxygen carrier. In this chapter, we have summarized the characteristics and performances of Hb-vesicles (HbV) that have been developed on the basis of molecular assembly. Collaborative in vitro and in vivo studies have revealed sufficient safety and efficacy of HbV.

    DOI

  • Oxygen infusions (hemoglobin-vesicles and albumin-hemes) based on nano-molecular sciences

    Tsuchida, E., Sakai, H., Komatsu, T., Takeoka, S., Huang, Y., Sou, K., Nakagawa, A., Teramura, Y., Kobayashi, K.

    Polymers for Advanced Technologies   16 ( 2-3 ) 73-83 - 83  2005  [Refereed]

     View Summary

    Since the discovery of a red-colored saline solution of a heme derivative that reversibly binds and releases oxygen (1983), significant efforts have been made to realize an oxygen infusion as a red cell substitute based on the sciences of both molecular assembling phenomena and macromolecular metal complexes. The authors have specified that hemoglobin (Hb)-vesicles (HbV) and recombinant human serum albumin-hemes (rHSA-heme) would be the best systems that meet the clinical requirements. (A) Hb is rigorously purified from outdated, donated red cells via pasteurization and ultrafiltration, to completely remove blood type antigen and pathogen. The HbV encapsulates thus purified concentrated Hb solution with a phospholipid bimolecular membrane (diameter, 250 nmø), and its solution properties can be adjusted comparable with blood. Surface modification of HbV with a water-soluble polymer ensures stable dispersion state and storage over a year at 20°C. In vivo tests have clarified the efficacy for extreme hemodilution and resuscitation from hemorrhagic shock, and safety in terms of biodistribution, metabolism in reticuloendothelial system (RES), clinical chemistry, blood coagulation, etc. The HbV does not induce vasoconstriction thus maintains blood flow and tissue oxygenation. (B) rHSA is now manufactured in Japan as a plasma-expander. The rHSA can incorporate eight heme derivatives (axial base substituted hemes) as oxygen binding sites, and the resulting rHSA-heme is a totally synthetic O2-carrier. Hb binds endothelium-derived relaxation factor, NO, and induces vasoconstriction. The rHSA-heme binds NO as Hb does, however, it does not induce vasoconstriction due to its low pI (4.8) and the resulting low permeability across the vascular wall (1/100 of Hb). A 5%-albumin solution possesses a physiologic oncotic pressure. Therefore, to increase the O2-transporting capacity, albumin dimer is effective. Albumin dimer can incorporate totally 16 hemes with a regulated oncotic pressure. The rHSA-heme is effective not only as a red cell substitute but also for oxygen therapeutics (e.g. oxygenation for tumor). Significant efforts have been made to produce HbV and rHSA-heme with a facility of Good Manufacturing Practice (GMP) standard, and to start preclinical and finally clinical trials. Copyright © 2005 John Wiley & Sons, Ltd.

    DOI

    Scopus

    6
    Citation
    (Scopus)
  • Physiological capacity of the reticuloendothelial system for the degradation of hemoglobin vesicles (artificial oxygen carriers) after massive intravenous doses by daily repeated infusions for 14 days

    Sakai, H., Masada, Y., Horinouchi, H., Ikeda, E., Sou, K., Takeoka, S., Suematsu, M., Takaori, M., Kobayashi, K., Tsuchida, E.

    Journal of Pharmacology and Experimental Therapeutics   311 ( 3 )  2004  [Refereed]

    DOI

    Scopus

    58
    Citation
    (Scopus)
  • Detection of Lipopolysaccharide in Hemoglobin-Vesicles by Limulus Amebocyte Lysate Test with Kinetic-Turbidimetric Gel Clotting Analysis and Pretreatment of Surfactant

    Sakai, H., Hisamoto, S., Fukutomi, I., Sou, K., Takeoka, S., Tsuchida, E.

    Journal of Pharmaceutical Sciences   93 ( 2 )  2004  [Refereed]

    DOI

    Scopus

    35
    Citation
    (Scopus)
  • [Safety of artificial oxygen carrier (synthetic erythrocytes) and the ability to supply oxygen to tissues].

    Horinouchi H, Kobayashi K, Komatsu K, Sakai H, Sou K, Suematsu M, Takeoka S, Tsuchida E

    Masui. The Japanese journal of anesthesiology   52 Suppl   S55-66  2003.12  [Domestic journal]

    PubMed

  • 酸素輸液ヘモグロビン小胞体に混在するリポポリサッカライドの定量法

    久本 秀治, 酒井 宏水, 福富 一平, 宗 慶太郎, 武岡 真司, 土田 英俊

    人工血液   11 ( 3 ) 173 - 178  2003.11  [Refereed]

     View Summary

    ヘモグロビン(Hb)を濃度高くリン脂質小胞体の内水相に内包したヘモグロビン小胞体(HbV)が人工酸素運搬体として開発され,赤血球と同等の酸素運搬機能と安全性が動物投与試験から明らかにされた.界面活性剤deca(oxyethylene)dodecyl ether(C12E10))でHbVを溶解してリポポリサッカライド(LPS)を遊離させた後,リムルステスト試薬と混合し,ゲル化反応を比濁時間分析法によって解析する方法を検討した.0.1EU/mLまでの検出限界を得ることができ,添加回収法によりその妥当性を検証することができた

  • 【先端外科医療の最前線】酸素輸液(人工赤血球)

    土田 英俊, 酒井 宏水, 武岡 真司, 宗 慶太郎, 小林 紘一

    医学のあゆみ   205 ( 9 ) 558 - 566  2003.05

  • Effective Encapsulation of Proteins into Size-Controlled Phospholipid Vesicles Using Freeze-Thawing and Extrusion

    Sou, K., Naito, Y., Endo, T., Takeoka, S., Tsuchida, E.

    Biotechnology Progress   19 ( 5 )  2003  [Refereed]

    DOI

    Scopus

    88
    Citation
    (Scopus)
  • 人工血液1

    池田 久實, 菅原 武, 阿部 英樹, 宗 慶太郎, 酒井 宏水

    人工臓器   31 ( 2 ) s165 - s167  2002

    DOI CiNii

  • Physical properties and packing states of molecular assemblies of synthetic glycolipids in aqueous dispersions

    Keitaro Sou

    Journal of the Chemical Society - Faraday Transactions   94 ( 15 )  1998  [Refereed]

    DOI

    Scopus

    10
    Citation
    (Scopus)
  • Disk-like assemblies of a synthetic glycolipid and their association with concanavalin A

    Takeoka, Shinji, Sou, Keitarou, Ohgushi, Takeru, Tsuchida, Eishun

    Supramolecular Science   5 ( 1-2 )  1998  [Refereed]

    DOI

    Scopus

    4
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    (Scopus)
  • 人工血液(1)

    高橋 恒夫, 柳田 尚之, 田中 三津子, 玉置 透, 川村 明夫, 石崎 彰, 岡野 正裕, 高橋 昌宏, 目黒 順一, 久木田 和丘, 米川 元樹, 緒方 嘉貴, 福井 秀男, 安藤 克利, 川合 宣行, 前島 浩光, 武岡 真司, 西出 宏之, 土田 英俊, 朴 晟翼, 武岡 真司, 酒井 宏水, 宗慶 太郎, 巨勢 丈裕, 西出 宏之, 土田 英俊, 泉 陽太郎, 吉津 晃, 小林 紘一

    人工臓器   25   S143 - S144  1996

    DOI CiNii

  • Critical Molecular Weight Effects in the Aggregation of Phospholipid Vesicles Triggered by Water-Soluble Polymers and an Integrated Glycolipid

    Takeoka, Shinji, Sou, Keitaro, Arase, Shinya, Ohgushi, Takeru, Tsuchida, Eishun

    Macromolecules   29 ( 25 ) 8132 - 8136  1996  [Refereed]

     View Summary

    The intervesicular aggregation of phospholipid vesicles is induced by the addition of water-soluble polymers such as poly(ethylene glycol), dextran, etc. due to the interaction between the vesicular surface and the water-soluble polymers. The interaction can be expressed by the critical molecular weight (M(c)) of the water-soluble polymers for the aggregation of vesicles. The surface modification of vesicles with glycolipids (O-1,O-5-bis(octadecyl) N-maltooligonoyl-L-glutamate) accelerates the aggregation of vesicles induced by dextran; therefore, M(c) significantly decreased due to the surface modification. No dependence of phospholipid concentration and dextran concentration in an aqueous phase on the M(c) indicates that dextran does not act as a cross-linking agent among the vesicles. A clear dependence of the density of the saccharide chains on the vesicular surface on the M(c) suggests that dextran should adsorb on the surface of the vesicles by the interaction with the oligosaccharide chains on the surface and cause vesicular aggregation. A lower critical solution temperature was observed for this kind of interaction, and the critical temperature was controlled by changing the molecular weight of dextran.

    DOI

    Scopus

    6
    Citation
    (Scopus)
  • Effect of surface modification of hemoglobin-vesicles (HbV) with polyethyleneglycol-lipid or glycolipid.

    S.I. Park, K. Sou, H. Sakai, S. Takeoka, H. Nishide, E. Tsuchida

    Artif Blood   4   9-13  1996  [Refereed]

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Books and Other Publications

  • DDS先端技術の製剤への応用開発

    宗 慶太郎, 田口和明( Part: Contributor, 第6章 6節 リポソーム製剤の骨髄へのDDS応用)

    技術情報協会  2017.06 ISBN: 9784861046636

  • Drug delivery applications of noninvasive imaging : validation from biodistribution to sites of action

    William T Phillips, Ande Bao, Keitaro Sou, Shihong Li, Beth Goins( Part: Contributor, Chapter 11 Radiolabeled liposomes as drug delivery nano-theranostics)

    Wiley  2014 ISBN: 9780470633472

  • Recent Advances in Novel Drug Carrier Systems

    Keitaro Sou( Part: Contributor, Chapter 15 Advanced drug carriers targeting bone marrow)

    InTech  2012

  • 医療分野における材料と機能膜

    酒井宏水, 宗 慶太郎, 武岡真司, 小林紘一, 土田英俊( Part: Contributor, 第5章 人工赤血球)

    シーエムシー出版  2011.06 ISBN: 9784781303352

  • Nanoimaging

    William T Phillips, Beth Goins, Keitaro Sou, Ande Bao( Part: Contributor, Chapter 4 Radiolabeled liposomes as theranostic agents)

    Pan Stanford Publishing Pte Ltd.  2011

  • 医療用マテリアルと機能膜

    酒井宏水, 宗 慶太郎, 武岡真司, 小林紘一, 土田英俊( Part: Contributor, 第5章 人工赤血球)

    シーエムシー出版  2005.05 ISBN: 4882315033

  • Artificial Oxygen Carrier, Its Front line

    Koichi Kobayashi, Hirohisa Horinouchi, Masazumi Watanabe, Yotaro Izumi, Yuji Teramura, Akito Nakagawa, Yubin Huang, Keitaro Sou, Hiromi Sakai, Teruyuki Komatsu, Shinji Takeoka, Eishun Tsuchida( Part: Contributor, Safety and efficacy of hemoglobin-vesicles and albumin-hemes)

    Springer-Verlag  2005

  • Artificial Oxygen Carrier, Its Front line

    Hiromi Sakai, Keitaro Sou, Shinji Takeoka, Koichi Kobayashi, Eishun Tsuchida( Part: Contributor, Hemoglobin-vesicles (HbV) as artificial oxygen carriers)

    Springer-Verlag  2005

  • Blood Substitutes

    Hiromi Sakai, Keitaro Sou, Shinji Takeoka, Koichi Kobayashi, Eishun Tsuchida( Part: Contributor, Chapter 44 Hemoglobin-vesicles as a molecular assembly: characteristics of preparation process and performances as artificial oxygen carriers)

    Elsevier, Academic Press  2005

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Research Projects

  • Development of temperature-responsive lipid nano-devices for spatiotemporally controlled payload release

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Project Year :

    2016.04
    -
    2019.03
     

    Sou Keitaro, Arai Satoshi

     View Summary

    The aim of this study is to develop nano-devices that release a payload timely at a target region to apply them for delivery and controlled release of functional molecules such as drugs. To this end, temperature-responsive lipid nano-capsules that release the payloads when heated to a threshold temperature have been developed. These nano-capsules successfully released the drugs at target region by heating the tissue up to the threshold temperature in living organism. In addition, a technique for spatial temperature monitoring to precisely control the temperature at small space where the conventional thermometers can not be applied has been investigated.

  • Drug delivery control based on assembly mediated by surface modification of phospholipid vesicles

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)

    Project Year :

    2005
    -
    2007
     

    SOU Keitaro

     View Summary

    Nanoparticulate phospholipid vesicles(liposomes) are in wide use as carriers of drugs, proteins, and genes etc. for the therapeutic purposes. However, conventional nanoparticles including vesicles were mostly distributed into liver and spleen after injection. This study provided novel concept to achieve targeting of bone marrow by using phospholipids vesicles as carrier in vivo. Two compounds, an original anionic amphiphile and conventional polyethylene glycol(PEG)-lipid, were key materials to modify the surface of vesicles for significant targeting to bone marrow macrophages in vivo. We demonstrated that more than 60% of intravenous injected vesicles selectively accumulated into bone marrow within 6h after injection in rabbits.
    In addition, our observations indicated that the responsible cellar pathway into bone marrow from blood circulation is the endocytosis by bone marrow macrophages. There is no effective drug delivery system which can target bone marrow right now. The efficient delivery of encapsulated scintigraphic and fluorescent imaging agents to bone marrow macrophages suggests that vesicles are promising carriers for the specific targeting of bone marrow macrophages and may be useful for delivering a wide range of therapeutic agents to bone marrow.

  • Research on Porphyrin-Chlorin Co-assemblies and Revival of Their Dioxygen-coordination Abilities Photoirradiation

    Japan Society for the Promotion of Science  Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)

    Project Year :

    2001
    -
    2002
     

    KAMATSU Teruyuki, TSUCHIDA Eishun, SO Keitaro

     View Summary

    The aim of this investigation is to revive the dioxygen-coordination ability of the auto-oxidized amphiphilic porphyrinatoiron(III) (lipidporphyrinatoiron(III)) by photoirradiation of the co-assembled free-base chlorine or porphyrin derivatives.
    In the first year, a new lipidporphyrin with four phospholipid-like substituents was synthesizes, It can be easily dispersed and self-assembled in aqueous system, to give spherical bi layer membranes with a diameter of 100 nm. The obtained lipidporphyrin vesicles can reversibly bind and release dioxygen under physiological conditions. The IR and MCD spectroscopies showed the coordination structure of the dioxygen. The dioxygen-binding affinity and dioxygen association and dissociation rate constants were also carefully measured.
    In the second year. electron transfer process from the excited state of the incorporated protoporphyrin derivative in the lipidporphyrin bilayer membrane to the iron(III) center was investigated. Under the co-existence of the electron donor (sacrificial regent) in outer aqueous phase, this reaction became irreversible, which is photoreduction system of the lipidporphyrinatoiron(III).
    During the research period, we found some new phenomena related on this project. For example, in co-assembled bi layer vesicles made of Zn(II) complex and free-base lipidporphyrins, high-efficient energy transfer took place from the singlet state of the porphyricatozinc(II). It could be a new light-harvesting model in aqueous medium.

  • リン脂質小胞体の表面修飾を用いる分子間情報伝達を集合現象から観測する方法の確立

    日本学術振興会  科学研究費助成事業 若手研究(B)

    Project Year :

    2001
    -
    2002
     

    宗 慶太郎

     View Summary

    本年度は前年度合成した両イオン性(カルボキシル基とアミノ基)、アニオン性(カルボキシル基)、あるいはポリエチレングリコール(PEG)を親水部とする一連のアミノ酸型脂質によりリン脂質小胞体の表面を修飾した試料について、小胞体の表面状態と生体適合性の関連を明確にすることを目的とした。
    リン脂質小胞体の成分としてアニオン性、あるいはPEG脂質を混合した小胞体を調製した。ラットの尾静脈より投与(全血液量に対して10%)し、血球数の推移、補体価(CH50)の計測から生体適合性を評価した。何れの小胞体の投与においても赤血球数には影響を与えなかった。アニオン性リン脂質(DPPG)は血漿蛋白質の補体成分に作用し補体活性を引き起こすことが明らかになった。これにより著しい血小板減少、白血球増大を惹起する。一方、アニオン性アミノ酸型脂質では補体活性、血小板減少は観測されず、リン脂質小胞体の表面修飾剤として有効である。この脂質組成の小胞体内水相にヘモグロビンを内包させる工程を確立、ウサギへの投与試験からの高い安全度を確認した。投与2時間後に白血球数の一過性の増大が認められたが、これは細網内皮系による小胞体の貧食作用に関連していると考えられる。両イオン性アミノ酸型脂質の形成する小胞体はアニオン性、PEGアミノ酸型脂質で表面修飾することにより水溶性高分子との相互作用による凝集が著しく抑制された。この小胞体はリン脂質成分を含まない新しい小胞体であり、リン脂質小胞体とは異なる表面状態を有している。血液と混合しても凝集は生起しない。ラットへの投与試験では、投与直後に一過性の血小板減少の傾向が認められたが、PEGアミノ酸型脂質の導入量を増大させることにより回避できた。生体適合性、代謝などより詳細検討が必要であるが、新しい小胞体として新しい展開が期待できる。

  • 脂質小胞体の体内動態評価

  • 脂質類(リン脂質,糖脂質,アミノ酸脂質、高分子結合脂質)の合成、分子集合制御、機能発現

  • 分子集合を利用した酸素輸液の製造 と その機能評価

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Misc

  • Rheological properties of PEG-modified HB-vesicles (HBVS) and their oxygen transporting capacity in vivo.

    H Sakai, K Sou, S Takeoka, K Kobayashi, E Tsuchida

    ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY   227   U541 - U542  2004.03

    Research paper, summary (international conference)  

  • Physicochemical properties of Hb-vesicles (HbV) and their O2 transporting efficiency in vivo

    9th Liposome Research Days Conference    2004

  • Circulation kinetics and biodistribution of hemoglobin-vesicles

    9th Liposome Research Days Conference    2004

  • Pharmacokinetics of the hemoglobin-vesicles (HbV) in rats

    Artificial Blood/The 9th International Symposium on Blood Substitutes (ISBS)   11(1), p.117  2003

  • Effect of the synthetic amino-lipids formulating hemoglobin-vesicles (HbV) on the circulation level of the blood cells

    Artificial blood/The 9th International Symposium on Blood Substitutes (ISBS)   11(1), p.91  2003

  • Encapsulation effecs of concentrated hemoglobin with phospholipid membrane

    Artificial Blood/The 9th International Symposium on Blood Substitutes (ISBS)   11(1), p.63  2003

  • Synthesis and molecular assembly of aminolipids to form stable hemoglobin-vesicles (HbV)

    7th International Symposium on Polymers for Advanced Technologies (PAT) 2003    2003

  • 8th International Symposium on Blood Substitutes

    Artificial Blood   9, p. 30-31  2001

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