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We introduced complementary interactions between peptide amphiphiles and a small fluorescence dye to develop a programmable multi-component supramolecular assembly, and intracellular delivery of the dye was controlled by the dimensions of the co-assembly, which was manipulated by the peptide design.

DOI： 10.1039/c9cc02473e

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Cancer vaccines aim to prevent or inhibit tumor growth by inducing an immune response to tumor-associated antigens (TAAs) encoded by or present in the vaccine. Previous work has demonstrated that effective antitumor immunity can be induced using a codelivery system in which nonspecific immunostimulatory molecules are administered together with TAAs. In this study, we investigated the antitumor effects of a solid-in-oil (S/O) nanodispersion system containing a model TAA, ovalbumin (OVA), and resiquimod (R-848), a small molecular Toll-like receptor 7/8 ligand, which induces an antigen-nonspecific cellular immune response that is crucial for the efficacy of cancer vaccines. R-848 was contained in the outer oil phase of S/O nanodispersion. Analysis of OVA and R-848 permeation in mouse skin after application of an R-848 S/O nanodispersion indicated that R-848 rapidly permeated the skin and preactivated Langerhans cells, resulting in efficient uptake of OVA and migration of antigen-loaded Langerhans cells to the draining lymph nodes. Transcutaneous immunization of mice with an R-848 S/O nanodispersion inhibited the growth of E.G7-OVA tumors and prolonged mouse survival to a greater extent than did immunization with an S/O nanodispersion containing OVA alone. Consistent with this observation, antigen-specific secretion of the Th1 cytokine interferon-γand cytolytic activity were both high in splenocytes isolated from mice immunized with R-848 S/O. Our results thus demonstrate that codelivery of R-848 significantly amplified the antitumor immune response induced by antigen-containing S/O nanodispersions and further suggest that S/O nanodispersions may be effective formulations for codelivery of TAAs and R-848 in transcutaneous cancer vaccines.

DOI： 10.1021/acsbiomaterials.9b00260

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DOI： 10.1039/C8CC08163H

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DOI： 10.1021/acs.molpharmaceut.7b00894

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

Lipid‐based formulation of antifungal small drugs is used to mitigate drug toxicity while retaining effective antifungal activity. Our previous work demonstrated a method to enhance the antifungal properties of a chitin‐binding domain (LysM) and catalytic domain (CatD) of antifungal chitinase by microbial transglutaminase (MTG)‐mediated palmitoylation. Herein, we studied the effect of artificial cholesterylation of LysM and CatD, both of which were site‐specifically modified using an MTG‐catalyzed crosslinking. This produced protein–lipid conjugates (LysM‐cholesteryl [Chol] or ‐palmitoyl [Pal] and CatD‐Chol or ‐Pal). Although lipidation of these chitinase domains enhanced the antifungal activity against Trichoderma viride, palmitoylated proteins (LysM‐Pal and CatD‐Pal) showed stronger antifungal effects than cholesterylated proteins (LysM‐Chol and CatD‐Chol) both in the absence and presence of amphotericin B. Further characterization with lipidated LysM‐fused green fluorescent protein (LysM‐muGFP‐Pal and ‐Chol) showed that the cholesterylation of proteins promoted distribution to dextran‐rich phase in an aqueous two‐phase system consisting of polyethylene glycol and dextran. Fluorescence microscopic analyses of the phase‐separated giant unilamellar vesicles revealed distinct anchoring behavior between LysM‐muGFP‐Pal and ‐Chol to lipid membranes, which was possibly correlated with aggregate formation. These results highlight that the chemical properties of the lipid moiety are crucial to achieve effective enhancement of antifungal activity through artificial lipidation.

DOI： 10.1002/cbic.202401081

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

We have achieved a novel co-crystal in which the dual functions of the protein and single-stranded DNA are maintained by introducing a charged peptide tag at the C-terminus of the protein. The functionalities allowed the co-crystals to be modified with high selectivity. Additionally, we have confirmed that energy transfer occurs between the two molecules modified within the co-crystal. Therefore, this co-crystal has the potential as a novel biomaterial applicable to biosensors.

DOI： 10.1039/d4ra08326a

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

Green seaweed is currently underused compared with other major seaweed types. Many scientists have reported applications of the green seaweed Ulva in various fields in recent years, which makes it a candidate for biomass production in industrial biorefineries. Ulva contains a unique polysaccharide called ulvan, which is being considered for medicinal and pharmacological applications. Ulvan is a sulfated polysaccharide including rhamnose and glucuronic acid residues, which has a range of bioactivities, including immunomodulatory, antimicrobial, and anticoagulant properties. The biocompatibility of ulvan makes it a versatile candidate for biomaterial design. This review presents an in-depth analysis of the potential applications of ulvan, starting with extraction methods and structural/biological characterization and moving on to biomaterial design. We also highlight the advantages of ulvan over traditional seaweed polysaccharides such as agar, carrageenan, and alginate.

DOI： 10.3390/md23020056

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACS Applied Materials and Interfaces  

The rising incidence of fungal infections, compounded by the emergence of severe antifungal resistance, has resulted in an urgent need for innovative antifungal therapies. We developed an antifungal protein-based formulation as a topical antifungal agent by combining an artificial lipidated chitin-binding domain of antifungal chitinase (LysM-lipid) with recently developed ionic liquid-in-oil microemulsion formulations (MEFs). Our findings demonstrated that the lipid moieties attached to LysM and the MEFs effectively disrupted the integrity of the stratum corneum in a mouse skin model, thereby enhancing the skin permeability of the LysM-lipids. Among the MEFs incorporating LysM modified with lauric (C12), myristic (C14), and palmitic (C16) acids, the LysM-C14-loaded MEF emerged as the most promising candidate, exhibiting potent antifungal activity against Trichoderma viride growing actively beneath the skin. The stability of the MEFs was investigated after a 28 day storage period at room temperature, and both LysM-C14- and LysM-C16-loaded MEFs retained comparable antifungal activity with that of the freshly prepared MEFs. These results highlight the considerable potential of LysM-lipid-loaded MEFs as effective topical antifungal agents.

DOI： 10.1021/acsami.4c19868

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Transdermal insulin delivery is a promising method for diabetes management, providing the potential for controlled, sustained release and prolonged insulin effectiveness. However, the large molecular weight of insulin hinders its passive absorption through the stratum corneum (SC) of the skin, and high doses of insulin are required, which limits the commercial viability. We developed ethosome (ET) and trans-ethosome (TET) nanovesicle formulations containing a biocompatible lipid-based ionic liquid, [EDMPC][Lin], dissolved in 35% ethanol. TET formulations were obtained by adding isopropyl myristate (IPM), Tween-80, or Span-20 as surfactants to ET formulations. Dynamic light scattering, ζ-potential, transmission electron microscopy, and confocal laser scanning microscopy studies revealed that the nanovesicles had a stable particle size. The formulations remained stable at 4 °C for more than 3 months. ET and TET formulations containing IPM (TET1) significantly (p < 0.0001) enhanced the transdermal penetration of FITC-tagged insulin (FITC-Ins) in both mouse and pig skin, compared with that of the control FITC-Ins solution and other TET formulations, by altering the molecular structure of the SC layer. These nanovesicles were found to be biocompatible and nonirritants (cell viability >80%) in the in vitro and in vivo studies on three-dimensional (3D) artificial human skin and a diabetic mouse model, respectively. The ET and TET1 formulations were applied to the skin of diabetic mice at an insulin dosage of 30 IU/kg. The nanovesicle formulations significantly reduced blood glucose levels (BGLs) compared with the initial high BGL value (>150 mg/dL). The nanovesicle-treated mice maintained low BGLs for over 15 h, as opposed to only 2 h in the injection group. The ET and TET1 formulations reduced the BGLs by 62 and 34%, respectively, of the initial value. These ET and TET1 formulations have a high potential for use in commercial transdermal insulin patches, enhancing comfort and adherence in diabetes treatment.

DOI： 10.1021/acsbiomaterials.4c02000

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DOI： 10.1021/acssusresmgt.4c00339

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Waste and Biomass Valorization  

Purpose: This work evaluated the profiles of Industrial agar seaweed waste biomass (ISWB) and pretreated ISWB by using deep eutectic solvent (DESs) and NaOH. The profiles of nanocellulose obtained from pretreated ISWB (with various types of hydrogen bond donors of choline chloride (ChCl)-based hydrated DES) were also evaluated. Methods: ISWB underwent pre-treatment with either 100% wt. DES (1:1 molar ratio of ethylene glycol: citric acid) or 10% wt. NaOH at 80 °C to 90 °C. Subsequent treatment involved 10% wt. DES or ChCl-based hydrated DES with various HBDs (oxalic acid, citric acid, and urea) in a 1:2 molar ratio to produce nanocellulose. Results: Cellulose nanofibers isolated by the CE-DES approach exhibited a substantially higher yield compared with those obtained via the CE-NaOH method. CE-DES method induced swelling of ISWB and facilitate production of cellulose nanofibers. SEM images of samples indicates the presence of fibrous nanostructures across the majority of the specimens. Fourier-transform infrared (FTIR) spectroscopy demonstrated uniformity among all samples; they exhibited a consistent fingerprint pattern. X-ray diffraction (XRD) spectra indicated the presence of cellulose Type I in cellulose nanofibers produced by CE–DES, but not definitively in nanocellulose produced by the CE–NaOH method. Conclusion: Cellulose nanofibers can be isolated from ISWB by using various DES and exhibits substantial characteristics of cellulose nanofibers from different ISWB pretreatment protocols. Graphical Abstract: (Figure presented.)

DOI： 10.1007/s12649-024-02499-z

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

Herein, we report a transdermal patch prepared using an ionic liquid-based solid in oil (IL-S/O) nanodispersion and a pressure-sensitive adhesive (PSA) to deliver the macromolecular antigenic protein, ovalbumin (OVA). The IL-S/O nanodispersion and a PSA were first mixed at an equal weight ratio, then coated onto a release liner, and covered with a support film. To evaluate the effect of the PSA, three types of PSAs, DURO-TAK 87-4098, DURO-TAK 87-4287, and DURO-TAK 87-235A, were used to obtain the corresponding IL-S/O patches SP-4098, SP-4287, and SP-235A, respectively. The prepared IL-S/O patches were characterized for surface morphology, viscoelasticity, and moisture content. In vitro skin penetration and in vivo immunization studies of the IL-S/O patches were performed using Yucatan micropig skin and the C57BL/6NJc1 mice model, respectively. The SP-4098 and SP-4287 delivered 5.49-fold and 5.47-fold higher amounts of drug compared with the aqueous formulation. Although both patches delivered a similar amount of drug, SP-4287 was not detached fully from the release liner after 30 days, indicating low stability. Mice immunized with the OVA-containing SP-4098 produced a 10-fold increase in anti-OVA IgG compared with those treated with an aqueous formulation. These findings suggested that the IL-S/O patch may be a good platform for the transdermal delivery of antigen molecules.

DOI： 10.3390/molecules29132995

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Bioscience and Bioengineering  

Antibody drugs play a vital role in diagnostics and therapy. However, producing antibodies from mammalian cells is challenging owing to cellular heterogeneity, which can be addressed by applying droplet-based microfluidic platforms for high-throughput screening (HTS). Here, we designed an integrated system based on disulfide-bonded redox-responsive hydrogel beads (redox-HBs), which were prepared through enzymatic hydrogelation, to compartmentalize, screen, select, retrieve, and recover selected Chinese hamster ovary (CHO) cells secreting high levels of antibodies. Moreover, redox-HBs were functionalized with protein G as an antibody-binding module to capture antibodies secreted from encapsulated cells. As proof-of-concept, cells co-producing immunoglobulin G (IgG) as the antibody and green fluorescent protein (GFP) as the reporter molecule, denoted as CHO(IgG/GFP), were encapsulated into functionalized redox-HBs. Additionally, antibody-secreting cells were labeled with protein L-conjugated horseradish peroxidase using a tyramide amplification system, enabling fluorescence staining of the antibody captured inside the beads. Redox-HBs were then applied to fluorescence-activated droplet sorting, and selected redox-HBs were degraded by reducing the disulfide bonds to recover the target cells. The results indicated the potential of the developed HTS platform for selecting a single cell viable for biopharmaceutical production.

DOI： 10.1016/j.jbiosc.2024.04.001

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Language：English   Publisher：(公社)日本生物工学会  

抗体を高レベルで分泌しているチャイニーズハムスター卵巣(CHO)細胞を分画、スクリーニング、選別、回収し、選別後に回復させるのに用いる、ハイスループットスクリーニング(HTS)向けの統合システムを設計してその性能を検証した。本システムの主要要素は、ジスルフィド結合で酸化還元応答性を持たせた親水性ゲルビーズとし、それに細胞を内包させることを試みた。概念実証実験には免疫グロブリンGと蛍光蛋白を共発現するCHO細胞を使用した。同細胞とゲルの材料をマイクロ流体デバイスで混ぜ合わせて油中水型乳剤を調製し、実際に細胞がこのビーズ内に包まれた状態となることを確認した。この乳剤に酵素を作用させ親水性ゲル化反応を起こさせてビーズとした。ゲルには、抗体と結合するprotein Gをジスルフィド結合で固定する機能化を施した。さらにprotein Lを結合させた西洋ワサビペルオキシダーゼで標識することで、ビーズ内部で捕捉された抗体を蛍光染色することが可能になった。このビーズに蛍光活性化細胞選別法を適用し、選別されたビーズのジスルフィド結合を還元分解することで、抗体を産生している標的細胞を回収した。本研究で開発したHTSプラットフォームは、バイオ医薬品を産み出す見込みのある単一細胞を選別するのに有用となる可能性があることが示された。

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

Ulva is an unutilized green seaweed that grows in the intertidal zone around the coast of Java Island, Indonesia. In this study, U. lactuca samples collected from three regions in south of Java Island (Cihara, Surade, and Tepus) were studied in terms of their chemical composition, physical properties and its bioactivity, to determine the best regions for establishing seaweed industries. The chemical characteristics differed significantly among different regions, where the seaweed from Tepus, Surade and Cihara had the highest content of protein (22.93%), carbohydrate (61.58%), and mineral (28.72%), respectively. The amino acids were dominated with L-aspartic acid and L-glutamic acid. All U. lactuca samples contained abundant pigments, such as chlorophylls and carotenoids, especially samples from Tepus. The highest content of crude ulvan was found in Surade seaweed (26.9%). Chemical and physical analyses showed the presence of S = O and C–O–S functional groups in ulvan, a sulfated polysaccharide unique to Ulva sp., with thermal degradation up to 220 °C. Crude ulvan from Surade and Tepus seaweed exhibited bioactivity to support proliferation of fibroblast cells at 100 and 1000 ppm, respectively. Based on the properties of U. lactuca, Tepus and Surade were identified as potential sites to establish aquaculture and/or processing industries.

DOI： 10.1007/s12562-024-01799-6

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Publisher：ASEAN Journal of Chemical Engineering  

Ulva lactuca is a green seaweed commonly called sea lettuce and contains sulphated polysaccharides that have biological activity. Despite its lack of ecological sustainability, strong acids (HCl) and strong bases (NaOH) are widely used as solvents in the conventional extraction process for ulvan. Deep eutectic solvent (DES) is an alternative to ulvan extraction solvent, which is more environmentally friendly and has low toxicity. This study aims to assess the efficacy of peracetic acid (PAA) pretreatment and post-treatment in enhancing the quality of extracted ulvan using a DES-based solvent in the extraction process. Ulvan extraction using DES with a temperature of 85-95°C for 1 hour and adding 2% PAA pretreatment, 0.1%, 0.5%, and 2% PAA post-treatment were conducted. PAA pre-and post-treatment was carried out with a 1:10 (w/v) ratio at room temperature for 30 minutes. The analysis included moisture content, yield, functional groups, sulphate content, and color. The test results revealed that ulvan treated with 2% PAA pretreatment had the highest moisture content and sulphate content, at 18.71% and 33.39%, respectively, while ulvan treated with 0.1% PAA post-treatment had the highest yield, at 41.96%. Adding peracetic acid concentration can increase the color quality of the ulvan. PAA pre-and post-treatment had a significant effect on all ulvan quality parameters.

DOI： 10.22146/ajche.12272

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：International Journal of Molecular Sciences  

Candida albicans is a prevalent fungal pathogen that displays antibiotic resistance. The polyene antifungal amphotericin B (AmB) has been the gold standard because of its broad antifungal spectra, and its liposomal formulation, AmBisome, has been used widely and clinically in treating fungal infections. Herein, we explored enhancing the antifungal activity of AmBisome by integrating a small chitin-binding domain (LysM) of chitinase A derived from Pteris ryukyuensis. LysM conjugated with a lipid (LysM–lipid) was initially prepared through microbial transglutaminase (MTG)-mediated peptide tag-specific conjugation of LysM with a lipid–peptide substrate. The AmBisome formulation modified with LysM–lipid conjugates had a size distribution that was comparable to the native liposomes but an increased zeta potential, indicating that LysM–lipid conjugates were anchored to AmBisome. LysM–lipid-modified AmBisome exhibited long-term stability at 4 °C while retaining the capacity to bind chitin. Nevertheless, the antifungal efficacy of LysM–lipid-modified AmBisome against C. albicans was modest. We then redesigned a new LysM–lipid conjugate by introducing a peptide linker containing a thrombin digestion (TD) site at the C-terminus of LysM (LysM–TD linker–lipid), thereby facilitating the liberation of the LysM domain from AmBisome upon the addition of thrombin. This new AmBisome formulation anchored with LysM–TD linker–lipid exhibited superior performance in suppressing C. albicans growth in the presence of thrombin compared with the LysM–lipid formulation. These results provide a platform to design stimuli-responsive AmBisome formulations that respond to external environments and thus advance the treatment of pathogenic fungi infections.

DOI： 10.3390/ijms25073567

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DOI： 10.1101/2024.03.04.583322

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

Herein, we report ethosome (ET) formulations composed of a safe amount of 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine (DMPC)-based ionic liquid with various concentrations of ethanol as a carrier for the transdermal delivery of a high molecular weight drug, insulin. The Insulin-loaded ET vesicles exhibited long-term stability compared to conventional DMPC ETs, showing significantly higher drug encapsulation efficiency and increased skin permeation ability.

DOI： 10.1039/d3cc06130b

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Journal of Molecular Liquids  

Ionic liquid (IL)-based transdermal formulations have gained significant attention because of their high skin penetration efficiency and ease of design. However, many IL-based formulations exhibit low viscosity, which hinders direct administration and leads to less efficient drug delivery. Therefore, there is a pressing need for specialized formulations with improved viscosity and efficacy as a drug delivery platform. In this study, we report a ready-to-use transdermal patch system utilizing IL-in-oil (IL/O) microemulsions to deliver acyclovir, a sparingly soluble antiviral drug. To prepare the patch system, a mixture containing equal weights of IL/O microemulsions and adhesive (Durotak 87–4098) was homogenized, subsequently coated on a liner, and covered by a support film. These patches were produced with varying thicknesses (100 μm, 200 μm, 300 μm, and 500 μm) via a solvent evaporation technique. A 24-hour in vitro skin permeation study revealed that the thinnest patch (100 μm) delivered more than 45 % of the loaded drug. Drug delivery rate gradually reduced as the patch thickness increased, accounting for 22 % and 14 % drug permeation by 200 μm and 300 μm patches respectively. A 30-day stability study at room temperature demonstrated that neither the physical appearance nor the active ingredient content changed, validating the physical and chemical stability of the patches. Skin permeation mechanism by Fourier transform infrared spectroscopic analysis of the skin suggested that the IL/O patch possesses the capability to modify the lipid barrier in the stratum corneum thus facilitating drug diffusion. In vitro skin irritation studies on reconstructed human epidermal tissue and Yucatan micropig skin revealed that the patch exhibits no skin irritation. We believe that the adhesive nature of this newly developed IL-based patch holds significant promise as a transdermal drug delivery platform.

DOI： 10.1016/j.molliq.2024.124184

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

Microbial transglutaminase (MTG) from Streptomyces mobaraensis is a powerful biocatalytic glue for site-specific cross-linking of a range of biomolecules and synthetic molecules that have an MTG-reactive moiety. The preparation of active recombinant MTG requires post-translational proteolytic digestion of a propeptide that functions as an intramolecular chaperone to assist the correct folding of the MTG zymogen (MTGz) in the biosynthesis. Herein, we report engineered active zymogen of MTG (EzMTG) that is expressed in soluble form in the host Escherichia coli cytosol and exhibits cross-linking activity without limited proteolysis of the propeptide. We found that the saturation mutagenesis of residues K10 or Y12 in the propeptide domain generated several active MTGz mutants. In particular, the K10D/Y12G mutant exhibited catalytic activity comparable to that of mature MTG. However, the expression level was low, possibly because of decreased chaperone activity and/or the promiscuous substrate specificity of MTG, which is potentially harmful to the host cells. The K10R/Y12A mutant exhibited specific substrate-dependent reactivity toward peptidyl substrates. Quantitative analysis of the binding affinity of the mutated propeptides to the active site of MTG suggested an inverse relationship between the binding affinity and the catalytic activity of EzMTG. Our proof-of-concept study provides insights into the design of a new biocatalyst using the MTGz as a scaffold and a potential route to high-throughput screening of EzMTG mutants for bioconjugation applications.

DOI： 10.1021/acs.bioconjchem.3c00544

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACS Biomaterials Science and Engineering  

Droplet-based high-throughput screening systems are an emerging technology that provides a quick test to screen millions of cells with distinctive characteristics. Biopharmaceuticals, specifically therapeutic proteins, are produced by culturing cells that secrete heterologous recombinant proteins with different populations and expression levels; therefore, a technology to discriminate cells that produce more target proteins is needed. Here, we present a droplet-based microfluidic strategy for encapsulating, screening, and selecting target cells with redox-responsive hydrogel beads (HBs). As a proof-of-concept study, we demonstrate the enrichment of hybridoma cells with enhanced capability of antibody secretion using horseradish peroxidase (HRP)-catalyzed hydrogelation of tetra-thiolate poly(ethylene glycol); hybridoma cells were encapsulated in disulfide-bonded HBs. Recombinant protein G or protein M with a C-terminal cysteine residue was installed in the HBs via disulfide bonding to capture antibodies secreted from the cells. HBs were fluorescently stained by adding the protein L-HRP conjugate using a tyramide signal amplification system. HBs were then separated by fluorescence-activated droplet sorting and degraded by reducing the disulfide bonds to recover the target cells. Finally, we succeeded in the selection of hybridoma cells with enhanced antibody secretion, indicating the potential of this system in the therapeutic protein production.

DOI： 10.1021/acsbiomaterials.3c01386

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Language：English   Publisher：Japan Association of Solvent Extraction  

<p>We synthesized low-toxicity L-leucine propyl ester linoleate and L-leucine propyl ester oleate pseudo-protic ionic liquids (ILs) for benign extraction of Ni(II), Co(II), and Mn(II). The extraction ability order for both ILs was Ni(II) > Co(II) > Mn(II). In addition, we developed a machine learning model with an eXtreme Gradient Boosting regressor algorithm to evaluate and predict the ecotoxicity level of the ILs. An evaluation of the proposed regression model by cross-validation indicates that the model is reliable, with an R² value of 0.71. The prediction results indicate that the newly synthesized ILs are much less toxic than a commercially available IL (methyltrioctylammonium chloride) that is often used for metal extraction. </p>

DOI： 10.15261/serdj.31.31

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Language：Japanese   Publisher：(公財)上原記念生命科学財団  

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Squalen Bulletin of Marine and Fisheries Postharvest and Biotechnology  

Ulva lactuca, a green seaweed that is widely distributed in Indonesia, is abundant but still underutilized. Even though this seaweed contains a sulfated polysaccharide called ulvan as much as 30-40% of its dry biomass and secondary metabolite. These components can be applied in various fields including as a reducing agent for silver ions in the bottom up synthesis of silver nanoparticles. The utilization of seaweed extract combined with ultrasonication is expected to enhance the efficacy of environmentally friendly silver nanoparticle synthesis. The objective of this study was to obtain the crude extract of U. lactuca and to investigate the impact of extract concentration and ultrasonication duration on the synthesis of silver nanoparticles. The study consists of two main phases: bio-synthesis employing different concentrations of the U. lactuca crude extract and bio-synthesis using selected extract concentrations combined with ultrasonic assistance for varying durations. The results of this study indicate that the crude extract of U. lactuca is a crude ulvan polysaccharide with a yield value and sulfate content of 26.9 ± 0.90% and 20.04 ± 1.02%, respectively. A reddish-brown color indicates the formation of silver nanoparticles. Based on the absorbance intensity, a 10% (v/v) concentration of ulvan crude extract produced the highest absorbance intensity (0.038 a.u). In addition, the ultrasonication duration of 60 minutes has succeeded in producing the smallest particle size (267.40 ± 6.52 nm) with a homogeneous particle distribution (PdI 0.265 ± 0.05). Scanning electron microscope (SEM) images depicted oval-shaped silver nanoparticles, while the Fourier-transform infrared (FTIR) spectrum indicated the degradation of sulfate and polysulfide functional groups in the crude extract during the synthesis process. These findings highlight the significant role of sulfate/sulfide groups present in the U. lactuca crude extract in the synthesis of silver nanoparticles.

DOI： 10.15578/squalen.802

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：ACS Applied Materials and Interfaces  

Nucleic acid drugs, including antisense oligonucleotides (ASOs), have received considerable attention as novel therapeutics for the treatment of intractable diseases. Despite their potential benefits, ASOs are currently administered via injection, which can negatively impact patient quality of life because of the prevalence of severe injection site reactions. Non-invasive transdermal administration of ASOs is desirable but highly challenging owing to the strong barrier imposed by the stratum corneum, which only permits the penetration of small molecules under 500 Da. For ASOs to exert their antisense effect, they must traverse the negatively charged cell membrane and reach the cytoplasm. In this study, we used the solid-in-oil (S/O) dispersion technology to facilitate the skin permeation of ASOs by coating the drug with a hydrophobic surfactant molecule, specifically lipid-based ionic liquid (IL) surfactants with high biocompatibility and transdermal penetration-enhancing properties. To induce the antisense effect, it was important to achieve simultaneous transdermal delivery and intracellular entrapment of ASOs. In vitro investigations indicated that the newly prepared IL-S/O enhanced the transdermal penetration and intracellular delivery of ASOs, thus inhibiting mRNA translation of the target TGF-β. In addition, in vivo investigations of tumor-bearing mice suggested that the anti-tumor effect of the IL-S/O was similar to that of injection. This study demonstrates the potential of non-invasive transdermal delivery carriers based on biocompatible ILs, which can be applied to a variety of nucleic acid drugs.

DOI： 10.1021/acsami.3c03900

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Transcutaneous vaccination is one of the successful, affordable, and patient-friendly advanced immunization approaches because of the presence of multiple immune-responsive cell types in the skin. However, in the absence of a preferable facilitator, the skin’s outer layer is a strong impediment to delivering biologically active foreign particles. Lipid-based biocompatible ionic-liquid-mediated nanodrug carriers represent an expedient and distinct strategy to permit transdermal drug delivery; with acceptable surfactants, the performance of drug formulations might be further enhanced. For this purpose, we formulated a lipid-based nanovaccine using a conventional (cationic/anionic/nonionic) surfactant loaded with an antigenic protein and immunomodulator in its core to promote drug delivery by penetrating the skin and boosting drug delivery and immunogenic cell activity. In a follow-up investigation, a freeze–dry emulsification process was used to prepare the nanovaccine, and its transdermal delivery, pharmacokinetic parameters, and ability to activate autoimmune cells in the tumor microenvironment were studied in a tumor-budding C57BL/6N mouse model. These analyses were performed using ELISA, nuclei and HE staining, flow cytometry, and other biological techniques. The immunomodulator-containing nanovaccine significantly (p < 0.001) increased transdermal drug delivery and anticancer immune responses (IgG, IgG1, IgG2, CD8+, CD207+, and CD103+ expression) without causing cellular or biological toxicity. Using a nanovaccination approach, it is possible to create a more targeted and efficient delivery system for cancer antigens, thereby stimulating a stronger immune response compared with conventional aqueous formulations. This might lead to more effective therapeutic and preventative outcomes for patients with cancer.

DOI： 10.3390/molecules28072969

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Journal of Pharmaceutical Sciences  

Malaria is a mosquito-borne infectious disease that is widespread in developing countries. Malaria vaccines are important in efforts to eradicate malaria; however, vaccines are usually administered by injection, which requires medical personnel and has a risk of causing infection. Transdermal vaccines can be administered without damaging the skin and thus are ideal for the prevention of malaria. However, the stratum corneum forms a "brick and mortar" like structure in which stratum corneum cells are embedded in a hydrophobic matrix composed of lipids, which strongly inhibits the permeation of hydrophilic substances. In the present study, we designed a transdermal vaccine against vivax malaria using a solid-in-oil (S/O) dispersion. The S/O dispersion of a transmission blocking vaccine candidate, Pvs25 from Plasmodium vivax, showed higher skin penetration than that of the aqueous solution. Mice immunized with the S/O dispersion generated antibodies at similar titers as the mice immunized by injection, over the mid- to long-term. These results provide information for the development of transdermally administered malaria vaccines toward the eradication of malaria.

DOI： 10.1016/j.xphs.2022.10.031

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：THE JAPAN SOCIETY OF DRUG DELIVERY SYSTEM  

DOI： 10.2745/dds.38.80

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：American Chemical Society (ACS)  

To reduce the exploitation of mine resources and decrease the harm to the environment caused by urban electronic wastes, the recovery of critical metals in secondary resources is crucial. In this study, we have successfully developed an eco-friendly process to integrate the leaching and separation of cobalt (Co) from a spent lithium-ion battery (LIB) cathode using an amino acid-based aqueous biphasic system (ABS). We, for the first time, demonstrated a simple method for leaching a LIB cathode using only amino acids. In addition, we have investigated the leaching mechanism using the typical cathode active material lithium cobalt oxide (LiCoO2). Then, the Co was selectively extracted by a biphasic system (amino acid− PPG400−H2O). This novel process has an excellent prospect in the field of spent-battery recycling because of its eco-friendly and process-simplified advantages.

DOI： 10.1021/acsomega.2c06654

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：ACS Applied Materials and Interfaces  

The transdermal delivery of hydrophilic drugs remains challenging owing to their poor ability to permeate the skin; formulation with oil media is difficult without adding chemical permeation enhancers or co-solvents. Herein, we synthesized 12 oil-miscible ionic liquid (IL) drugs comprising lidocaine-, imipramine-, and levamisole (Lev)-hydrochloride with fatty acid permeation enhancers, i.e., laurate, oleate, linoleate, and stearate as counterions. A set of in vitro and in vivo studies was performed to investigate the potency and deliverability of the transdermal drug formulations. All of the synthesized compounds were freely miscible with pharmaceutically acceptable solvents/agents (i.e., ethanol, N-methyl pyrrolidone, Tween 20, and isopropyl myristate (IPM)). In vitro permeation studies revealed that the oleate-based Lev formulation had 2.6-fold higher skin permeation capability than the Lev salts and also superior ability compared with the laurate-, linoleate-, and stearate-containing samples. Upon in vivo transdermal administration to mice, the peak plasma concentration, elimination half-life, and area under the plasma concentration curve values of Lev-IL were 4.6-, 2.9-, and 5.4-fold higher, respectively, than those of the Lev salt. Furthermore, in vitro skin irritation and in vivo histological studies have demonstrated that Lev-IL has excellent biocompatibility compared with a conventional ionic liquid-based carrier. The results indicate that oil-miscible IL-based drugs provide a simple and scalable strategy for the design of effective transdermal drug delivery systems.

DOI： 10.1021/acsami.2c15636

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Organic and Biomolecular Chemistry  

Cytoplasm contains high concentrations of biomacromolecules. Protein behavior under such crowded conditions is reportedly different from that in an aqueous buffer solution, mainly owing to the effect of volume exclusion caused by the presence of macromolecules. Using a crosslinking reaction catalyzed by microbial transglutaminase (MTG) as a model, we herein systematically determined how the substrate size affects enzymatic activity in both dilute and crowded solutions of dextran. We first observed a threefold reduction in MTG-mediated crosslinking of a pair of small peptide substrates in 15 wt% dextran solution. In contrast, when proteinaceous substrates were involved, the crosslinking rates in 15 wt% dextran solutions accelerated markedly to levels comparable with the level in the absence of dextran. Our results provide new insights into the action of enzymes with regard to macromolecular substrates under crowded conditions, of which the potential utility was demonstrated by the formation of highly crosslinked protein polymers.

DOI： 10.1039/d2ob01549h

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

Single-walled carbon nanotubes (SWCNTs) emit photoluminescence (PL) in the near-infrared (NIR) region (>900 nm). To enhance their PL properties, defect doping via local chemical functionalization has been developed. The locally functionalized SWCNTs (lf-SWCNTs) emit red-shifted and bright E11* PL originating from the excitons localized at the defect-doped sites. Here, we observe the E11* PL energy shifts induced by protein adsorption via the avidin-biotin interactions at the doped sites of lf-SWCNTs. We establish that the difference in the structures of the avidin derivatives notably influences the energy shifts. First, lf-SWCNT-tethering biotin groups (lf-SWCNTs-b) are synthesized based on diazonium chemistry, followed by post-modification. The responsiveness of the lf-SWCNTs-b to different microenvironments is investigated, and a correlation between the E11* PL energy shift and the induction-polarity parameters of surrounding solvents is established. The adsorption of neutravidin onto the lf-SWCNTs-b induces an increase in the induction-polarity parameters around the biotin-doped sites, resulting in the red-shift of the E11* PL peak. The E11* PL shift behaviors of the lf-SWCNTs-b change noticeably when avidin and streptavidin are introduced compared to the case with neutravidin. This is due to the different microenvironments formed at the biotin-doped sites, attributed to the difference in the structural features of the introduced avidin derivatives. Moreover, we successfully enhance the detection signals of lf-SWCNTs-b (>three fold) for streptavidin detection using a fabricated film device. Therefore, lf-SWCNTs exhibit significant promise for application in advanced protein detection/recognition devices based on NIR PL.

DOI： 10.1039/d2nr01440h

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：AMER CHEMICAL SOC  

Protein palmitoylation, a post-translational modification, is universally observed in eukaryotic cells. The localization of palmitoylated proteins to highly dynamic, sphingolipid- and cholesterol-rich microdomains (called lipid rafts) on the plasma membrane has been shown to play an important role in signal transduction in cells. However, this complex biological system is not yet completely understood. Here, we used a combined approach where an artificial lipidated protein was applied to biomimetic model membranes and plasma membranes in cells to illuminate chemical and physiological properties of the rafts. Using cell-sized giant unilamellar vesicles, we demonstrated the selective partitioning of enhanced green fluorescent protein modified with a C-terminal palmitoyl moiety (EGFP-Pal) into the liquid-ordered phase consisting of saturated phospholipids and cholesterol. Using Jurkat T cells treated with an immunostimulant (concanavalin A), we observed the vesicular transport of EGFP-Pal. Further cellular studies with the treatment of methyl beta-cyclodextrin revealed the cholesterol-dependent internalization of EGFP-Pal, which can be explained by a raft-dependent, caveolae-mediated endocytic pathway. The present synthetic approach using artificial and natural membrane systems can be further extended to explore the potential utility of artificially lipidated proteins at biological and artificial interfaces.

DOI： 10.1021/acs.langmuir.2c01205

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACS Applied Bio Materials  

Transdermal drug delivery systems (TDDSs) may be useful for preventing various diseases including cancer. However, the stratum corneum (SC) inhibits the permeation of foreign particles into the skin. To obtain an effective TDDS, we developed a protein-containing nanocarrier (PCNC) comprising an antigenic protein (ovalbumin/OVA) stabilized by a combination of surfactants, i.e., a lipid-based surface-active ionic liquid and Tween-80. The PCNC was lyophilized to remove water and cyclohexane and then dispersed in isopropyl myristate. It is biocompatible both in vitro and in vivo, and is suitable for use in a therapeutic TDDS. The skin permeability of the PCNC was significantly (p < 0.0001) enhanced, and the transdermal distribution and transdermal flux of the OVA delivery system were 25 and 28 times greater, respectively, than those of its aqueous formulation. The PCNC disrupted the order of lipid orientation in the skin's SC and increased intercellular protein delivery. It demonstrated effective antitumor activity, drastically (p < 0.001) suppressed tumor growth, increased mouse survival rates, and significantly (p < 0.001) stimulated the OVA-specific tumor immune response. The PCNC also increased the number of cytotoxic T cells expressing CD8 antibodies on their surfaces (CD8 + T-cells) in the tumor microenvironment. These findings suggest that PCNCs may be promising biocompatible carriers for transdermal antigenic protein delivery in tumor immunotherapy.

DOI： 10.1021/acsabm.2c00061

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Biomaterials  

The biomaterial-based immunoengineering has become one of the most attractive research fields in the last decade. In the present study, a solid-in-oil-in-water (S/O/W) emulsion encapsulating antigen in the oil phase of an oil-in-water (O/W) emulsion was prepared as a novel vaccine carrier consisting of similar materials to the emulsion adjuvant of which the safety, immunogenicity and vaccination efficacy have been already confirmed in human. Direct observation by high-resolution confocal laser scanning microscopy and small angle X-ray scattering analysis showed that the antigens were dispersed inside of the oil phase of the S/O/W emulsion as solid-state particles. The S/O/W emulsion robustly produced antigen-specific antibodies and enhanced the antitumor effects in a therapeutic cancer vaccination compared with free antigens or the O/W emulsion in vivo. This result is in good agreement with the activation effect of antigen-specific cytotoxic T lymphocytes and antigen presentation by the S/O/W emulsion, indicating that the S/O/W emulsion consisting of already approved materials is a promising vaccine carrier to produce both humoral and cellular immunity.

DOI： 10.1016/j.biomaterials.2022.121385

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Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Acta Biomaterialia  

Transcutaneous drug delivery is a promising method in terms of drug repositioning and reformulation because of its non-invasive and easy-to-use features. To overcome the skin barrier, which is the biggest challenge in transcutaneous drug delivery, a number of techniques, such as microemulsion, solid-in-oil dispersions and liposomes, have been studied extensively. However, the low viscosity of these formulations limits drug retention on the skin and reduces patient acceptability. Although viscosity can be increased by adding a thickening reagent, such an addition often alters formulation nanostructures and drug solubility, and importantly, decreases skin permeability. In this study, a gel-like lyotropic liquid crystal (LLC) was used as a tool to enhance skin permeability. In particular, we prepared 1-monolinolein (ML)-based LLCs with different water contents. All LLCs significantly enhanced skin permeation of a peptide drug, an epitope peptide of melanoma, despite their high viscoelasticity. Fourier transform infra-red spectroscopic analysis of the skin surface treated with the LLCs revealed that the gyroid geometry more strongly interacted with the lamellar structure inside the stratum corneum (SC) than the diamond geometry. Finally, as the result of the in vivo tumor challenge experiment using B16F10 melanoma-bearing mice, the LLC with the gyroid geometry showed stronger vaccine effect against tumor than a subcutaneous injection. Collectively, ML-based LLCs, especially with the gyroid geometry, are a promising strategy to deliver biomacromolecules into skin. Statement of significance: Transcutaneous drug delivery is a promising method for drug repositioning and reformulation because of its non-invasive and easy-to-use features. To overcome the skin barrier, which is the biggest challenge in transcutaneous drug delivery, we used a gel-like lyotropic liquid crystal (LLC) as a novel tool to enhance skin permeability. In this paper, we demonstrated that an LLC with a specific liquid crystalline structure has the highest skin permeation enhancement effect for a peptide antigen as a model drug. Moreover, the peptide antigen-loaded LLC showed a vaccine effect that was comparable to a subcutaneous injection in vivo. This study provides a basis for designing a transcutaneous delivery system of peptide drugs with LLC.

DOI： 10.1016/j.actbio.2021.11.008

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Lipidic cubic phase (LCP) is a self-assembled system composed of lipids with interpenetrated aqueous channels, and its potential in drug delivery systems has been investigated. Although LCP was shown to improve transcutaneous penetration of hydrophilic molecules of up to 1203 Da so far, the transcutaneous delivery of larger molecules such as proteins has not been achieved. This is likely because proteins are usually larger than the aqueous channels of LCP (∼37.2 Å in diameter), which limits the molecular diffusion in LCP. In this report, we overcome this issue by adding N-octyl-β-d-glucopyranoside to glyceryl monooleate-water-based LCP to give swollen LCP (SLCP), which has larger aqueous channel diameters (∼65.6 Å). First, we systemically evaluated the effect of swelling on drug diffusion in LCP/SLCP. The release kinetics of various peptides and proteins whose sizes ranged from 9.14 to 55.28 Å in diameter were evaluated, and the diffusion coefficients (D) were calculated by the Fickian diffusion model. As expected, all peptides and proteins diffused faster in SLCP than in LCP. A more detailed analysis revealed a negative linear relationship between log D and the ratio of the radius of gyration of the proteins to the aqueous channel radius, indicating that swelling of a cubic nanostructure is an effective strategy to enhance D. Next, the skin penetration of proteins encapsulated in LCP and SLCP was evaluated. The skin penetration of ovalbumin (42.9 kDa), for example, was enhanced by SLCP but not by LCP, and a positive correlation between D and the amount of skin penetration was found. Collectively, this study provides an effective measure for designing LCP systems that enhance transcutaneous penetration of biomacromolecules.

DOI： 10.1021/acsami.1c16659

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Oral delivery of the sparingly soluble drug methotrexate (MTX) is challenging owing to its poor bioavailability and low solubility. To address this challenge, the present study reports the conversion of MTX into a series of five ionic liquids (ILs) comprising a cationic component—i.e., cholinium (Cho), tetramethylammonium (TMA), tetrabutylphosphonium (TBP), or an amino acid ester—and an anionic component—i.e., MTX. The biocompatibility, pharmacokinetics, tissue distribution, and antitumor efficacy of each MTX-based IL were investigated to determine its usefulness as a pharmaceutical. Oral administration to mice revealed that proline ethyl ester MTX (IL[ProEt][MTX]) had 4.6-fold higher oral bioavailability than MTX sodium, followed by aspartic diethyl ester MTX, IL[TBP][MTX], IL[Cho][MTX], and IL[TMA][MTX]. The peak plasma concentration, elimination half-life, area under the plasma concentration, mean absorption time, and body clearance of IL[ProEt][MTX] were significantly (p < 0.0001) higher by 1.7-, 6.2-, 4.6-, 2.5-, and 3.6-fold, respectively, than those of MTX sodium. MTX accumulation in the lungs, spleen, kidney, and gastrointestinal tract was also reduced by 5.6-, 1.8-, 1.5-, and 1.4-fold, respectively, indicating the IL formulations had lower systemic toxicity than free MTX. Mechanistic studies revealed that the IL[ProEt][MTX] solution formed spherical structures with an average size of 190 nm. This was probably responsible for its improved oral absorption performance in vivo. In vivo antitumor studies also demonstrated that IL[ProEt][MTX] suppressed tumor growth more than MTX sodium. These results suggest that MTX-based ILs provide a simple scalable approach to improving the oral bioavailability of poorly soluble MTX.

DOI： 10.1016/j.ijpharm.2021.121129

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Since injection administration for diabetes is invasive, it is important to develop an effective transdermal method for insulin. However, transdermal delivery remains challenging owing to the strong barrier function of the stratum corneum (SC) of the skin. Here, we developed ionic liquid (IL)-in-oil microemulsion formulations (MEFs) for transdermal insulin delivery using choline-fatty acids ([Chl][FAs])—comprising three different FAs (C18:0, C18:1, and C18:2)—as biocompatible surface-active ILs (SAILs). The MEFs were successfully developed using [Chl][FAs] as surfactants, sorbitan monolaurate (Span-20) as a cosurfactant, choline propionate IL as an internal polar phase, and isopropyl myristate as a continuous oil phase. Ternary phase behavior, dynamic light scattering, and transmission electron microscopy studies revealed that MEFs were thermodynamically stable with nanoparticle size. The MEFs significantly enhanced the transdermal permeation of insulin via the intercellular route by compromising the tight lamellar structure of SC lipids through a fluidity-enhancing mechanism. In vivo transdermal administration of low insulin doses (50 IU/kg) to diabetic mice showed that MEFs reduced blood glucose levels (BGLs) significantly compared with a commercial surfactant-based formulation by increasing the bioavailability of insulin in the systemic circulation and sustained the insulin level for a much longer period (half-life > 24 h) than subcutaneous injection (half-life 1.32 h). When [Chl][C18:2] SAIL-based MEF was transdermally administered, it reduced the BGL by 56% of its initial value. The MEFs were biocompatible and nontoxic (cell viability > 90%). They remained stable at room temperature for 3 months and their biological activity was retained for 4 months at 4 °C. We believe SAIL-based MEFs will alter current approaches to insulin therapy and may be a potential transdermal nanocarrier for protein and peptide delivery.

DOI： 10.1021/acsami.1c11533

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Coronavirus disease 2019 (COVID-19) has spread across the world, and no specific antiviral drugs have yet been approved to combat this disease. Favipiravir (FAV) is an antiviral drug that is currently in clinical trials for use against COVID-19. However, the delivery of FAV is challenging because of its limited solubility, and its formulation is difficult with common organic solvents and water. To address these issues, four FAV ionic liquids (FAV-ILs) were synthesized as potent antiviral prodrugs and were fully characterized by nuclear magnetic resonance (NMR) spectroscopy, Fourier-transform infrared (FT-IR) spectrometry, powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), derivative thermogravimetry (DTG), and differential scanning calorimetry (DSC). The aqueous solubility and in vivo pharmacokinetic properties of the FAV-ILs were also evaluated. The FAV-ILs exhibited improved aqueous solubility by 78 to 125 orders of magnitude when compared with that of free FAV. Upon oral dosing in mice, the absolute bioavailability of the β-alanine ethyl ester FAV formulation was increased 1.9-fold compared with that of the control FAV formulation. The peak blood concentration, elimination half-life, and mean absorption time of FAV were also increased by 1.5-, 2.0-, and 1.5-fold, respectively, compared with the control. Furthermore, the FAV in the FAV-ILs exhibited significantly different biodistribution compared with the control FAV formulation. Interestingly, drug accumulation in the lungs and liver was improved 1.5-fold and 1.3-fold, respectively, compared with the control FAV formulation. These results indicate that the use of ILs exhibits potential as a simple, scalable strategy to improve the solubility and oral absorption of hydrophobic drugs, such as FAV.

DOI： 10.1021/acs.molpharmaceut.1c00324

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Lipid-based biocompatible ionic liquids (LBILs) have attracted attention as carriers in transdermal drug delivery systems (TDDSs) because of their lipophilic character. In this study, we report the formulation of a peptide-LBIL complex microencapsulated in an oil phase as a potential carrier for the transdermal delivery of leuprolide acetate as a model hydrophilic peptide. The peptide-LBIL complexes were prepared via a water-in-oil emulsion composed of 1,2-dimyristoyl-sn-glycerol-3-ethyl-phosphatidylcholine (EDMPC), a fatty acid (stearic, oleic, and linoleic acid)-based LBIL, and cyclohexane followed by freeze-drying to remove the water and cyclohexane. Then, the peptide-LBIL complexes were nanodispersed and stabilized in isopropyl myristate (IPM) using sorbitol laurate (Span-20). Ionic-liquid-in-oil nanodispersions (IL/O-NDs) were prepared with varying weight ratios of LBILs and Span-20 as the surfactant and the cosurfactant, respectively. Keeping the overall surfactant constant at 10 wt % in IPM, a 5:5 wt % ratio of surfactant (IL) and cosurfactant (Span-20) in the IL/O-NDs significantly (p < 0.0001) increased the physiochemical stability, drug-loading capacity, and drug encapsulation efficiency. The in vitro and in vivo peptide delivery across the skin was increased significantly (p < 0.0001) using IL/O-NDs, compared with non-IL-treated groups. Of all of the LBIL-based formulations, [EDMPC][Linoleate]/O-ND was considered the most preferable for a TDDS based on the pharmacokinetic parameters. The transdermal delivery flux with [EDMPC][Linoleate]/O-ND was increased 65-fold compared with the aqueous delivery vehicle. The IL/O-NDs were able to deform the lipid and protein arrangements of the skin layers to enhance the transdermal permeation of the peptide. In vitro and in vivo cytotoxicity studies of the IL/O-NDs revealed the biocompatibility of the LBIL-based formulations. These results indicated that IL/O-NDs are promising biocompatible carriers for lipid-peptide TDDSs.

DOI： 10.1021/acsabm.1c00563

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DOI： 10.1016/j.ijpharm.2021.120582

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DOI： 10.1021/acsami.1c03111

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DOI： 10.1021/acs.bioconjchem.1c00027

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The objective of this study was to prepare a co-amorphous formulation of piroxicam (PIR), a non-steroidal anti-inflammatory drug, and citric acid (CA), and evaluate its skin permeation ability. A spray-drying method was employed to prepare the co-amorphous formulation and its physical properties were characterized. X-ray powder diffraction and thermal analysis confirmed a homogeneous amorphous state, and the infrared spectra revealed intermolecular interactions between PIR and CA, suggesting formation of a co-amorphous formulation of PIR and CA. The PIR-CA co-amorphous formulation exhibited no crystallization for 60 days at 4/25/40°C with silica gel. The PIR-CA co-amorphous formulation increased the solubility of PIR in polyethylene glycol 400 compared with that of the pure drug, and physical mixture (PM) of PIR and CA, confirming a supersaturated state in the formulation. The PIR-CA co-amorphous formulation demonstrated higher skin permeation than PIR alone or PM of PIR and CA, and the flux value was consistent with the degree of saturation. Thus, the increase in the skin permeation of PIR from the PIR-CA co-amorphous formulation directly depended on the increased thermodynamic activity by supersaturation in the absence of interactions between the drug and co-former in the vehicle.

DOI： 10.1016/j.ejps.2020.105667

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In this report, a strategy for constructing three-dimensional (3D) cellular architectures comprising viable cells is presented. The strategy uses a redox-responsive hydrogel that degrades under mild reductive conditions, and a confluent monolayer of cells (i.e., cell sheet) cultured on the hydrogel surface peels off and self-folds to wrap other cells. As a proof-of-concept, the self-folding of fibroblast cell sheet was triggered by immersion in aqueous cysteine, and this folding process was controlled by the cysteine concentration. Such folding enabled the wrapping of human hepatocellular carcinoma (HepG2) spheroids, human umbilical vein endothelial cells and collagen beads, and this process improved cell viability, the secretion of metabolites and the proliferation rate of the HepG2 cells when compared with a two-dimensional culture under the same conditions. A key concept of this study is the ability to interact with other neighbouring cells, providing a new, simple and fast method to generate higher-order cellular aggregates wherein different types of cellular components are added. We designated the method of using a cell sheet to wrap another cellular aggregate the ‘cellular Furoshiki’. The simple self-wrapping Furoshiki technique provides an alternative approach to co-culture cells by microplate-based systems, especially for constructing heterogeneous 3D cellular microstructures.

DOI： 10.1038/s41598-020-63362-4

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DOI： 10.1016/j.molliq.2020.114424

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DOI： 10.1021/acsabm.0c00940

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DOI： 10.1039/D0CC04491A

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Liquid marbles (LMs) have recently shown a great promise as microbioreactors to construct self-supported aqueous compartments for chemical and biological reactions. However, the evaporation of the inner aqueous liquid core has limited their application, especially in studying cellular functions. Hydrogels are promising scaffolds that provide a spatial environment suitable for three-dimensional cell culture. Here, we describe the fabrication of redox-responsive hydrogel marbles (HMs) as a three-dimensional cell culture platform. The HMs are prepared by introducing an aqueous mixture of a tetra-thiolated polyethylene glycol (PEG) derivative, thiolated gelatin (Gela-SH), horseradish peroxidase, a small phenolic compound, and human hepatocellular carcinoma cells (HepG2) to the inner aqueous phase of LMs. Eventually, HepG2 cells are encapsulated in the HMs then immersed in culture media, where they proliferate and form cellular spheroids. Experimental results show that the Gela-SH concentration strongly influences the physicochemical and microstructure properties of the HMs. After 6 days in culture, the spheroids were recovered from the HMs by degrading the scaffold, and examination showed that they had reached up to about 180 μm in diameter depending on the Gela-SH concentration, compared with 60 μm in conventional HMs without Gela-SH. After long-term culture (over 12 days), the liver-specific functions (secretion of albumin and urea) and DNA contents of the spheroids cultured in the HMs were elevated compared with those cultured in LMs. These results suggest that the developed HMs can be useful in designing a variety of microbioreactors for tissue engineering applications.

DOI： 10.1016/j.jbiosc.2020.05.010

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The skin loses its moisture with advancing age, causing cosmetic issues such as wrinkles. In addition, the loss of moisture leads to hypersensitivity to external stimuli such as UV light. Transcutaneous supplementation with hyaluronic acid (HA) is an effective and safe method of recovering the moisturizing function and elasticity of the skin. However, the transcutaneous delivery of HA remains challenging owing to the barrier function of the stratum corneum (SC) layer. To penetrate the SC barrier, we used a reverse micelle formulation that does not require high energy consumption processes for preparation. We aimed to enhance the skin permeability of HA by incorporating glyceryl monooleate-a skin permeation enhancer-into the formulation. A fluorescently-labeled HA-loaded reverse micelle formulation showed significantly enhanced permeation across Yucatan micro pig skin. Fourier transform infra-red spectroscopy of the surface of the skin treated with the reverse micelle formulation showed blue shifts of the CH₂ symmetric/asymmetric stretching peaks, indicating a reduction in the barrier function of the SC. Further study revealed that HA was released from the reverse micelles at the hydrophobic/hydrophilic interface between the SC and the living epidermis. The results demonstrated that our reverse micellar system is an easy-to-prepare formulation for the effective transcutaneous delivery of HA.

DOI： 10.3390/COSMETICS7030052

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Ionic liquids (ILs) attract significant attention as novel solvents for drug delivery systems because of their ability to solubilize poorly soluble drugs and tune the physiological properties of active pharmaceutical ingredients. For the next generation of IL-based drug delivery systems, biocompatibility is a high priority. In the current study, choline-fatty acids ([Cho][FA]) were used as a biocompatible IL to mediate the dissolution of a water-soluble antigen peptide in an oil-based skin penetration enhancer. Among the candidate fatty acids (C8, C10, C12, C14, C16, C18:0, and C18:1), C18:1 was selected because of its low cytotoxicity and mediation of skin permeability for an antigen peptide. Using IL[Cho][C18:1] and an oil-based penetration enhancer, the flux of transdermal delivery of the peptide increased 28-fold compared with delivery using an aqueous vehicle. Furthermore, the IL-mediated transcutaneous vaccination succeeded in suppressing tumor growth in vivo compared to injection. The skin irritation produced by this formulation was tested using an in vitro 3D constructed skin tissue model and an in vivo histological study, which concluded that the formulation did not cause skin irritation. The results suggest that biocompatible IL-mediated dissolution in an oil-based skin penetration enhancer is a promising strategy for transdermal drug delivery.

DOI： 10.1021/acs.molpharmaceut.0c00598

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DOI： 10.1021/acssuschemeng.0c03419

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Assembling proteins in close vicinity to each other provides an opportunity to gain unique function because collaborative and even synergistic functionalities can be expected in an assembled form. There have been a variety of strategies to synthesize functional protein assemblies but site-specific covalent assembly of monomeric protein units without impairing their intrinsic function remains challenging. Herein we report a powerful strategy to design protein assemblies by using microbial transglutaminase (MTG). A serendipitous discovery of self-crosslinking of enhanced green fluorescent protein (EGFP) fused with StrepTag I at the C-terminus revealed that EGFP was assembled through the crosslinking of the Lys (K) residue in the C-terminus of EGFP and the Gln (Q) residue in StrepTag I (AWRHPQFGG). Site-directed mutagenesis of the residues next to the K and Q yielded EGFP assemblies with higher molecular weights. An optimized peptide tag comprised of both K and Q residues (HKRWRHYQRGG) enabled the assembly of different types of proteins of interest (POI) when it was fused to either the N- or C-terminus. The peptide tag that enabled the self-polymerization of the functional POI without a scaffold was designated as a ‘PolyTag’.

DOI： 10.1016/j.ab.2020.113700

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Transdermal delivery of drugs is more challenging for drugs that are insoluble or sparingly soluble in water and most organic solvents. To overcome this problem, ionic liquid (IL)-mediated ternary systems have been suggested as potential drug carriers. Here, we report potent ternary (IL–EtOH–IPM) systems consisting of biocompatible ILs, ethanol (EtOH), and isopropyl myristate (IPM) that can dissolve a significant amount of the sparingly soluble drug acyclovir (ACV). The ternary systems were optically transparent and thermodynamically stable with a wide range of IL pertinence. An in vitro drug permeation study showed that the ILs in the ternary systems dramatically enhanced ACV permeation into and across the skin. Fourier Transform Infrared spectroscopy of the stratum corneum (sc) after treatment with ternary systems showed that the skin barrier function was reduced by disturbance of the regularly ordered arrangement of corneocytes and modification of the surface properties of the sc during permeation. Histological analysis, and skin irritation studies using a reconstructed human epidermis model showed the safety profile of the ternary system, and there were no significant changes in the structures of the sc, epidermis, and dermis. Therefore, ternary systems containing biocompatible ILs are promising for transdermal delivery of insoluble or sparingly soluble drugs.

DOI： 10.1016/j.ijpharm.2020.119335

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DOI： 10.1021/acssuschemeng.9b07773

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

The transdermal delivery of sparingly soluble drugs is challenging due to of the need for a drug carrier. In the past few decades, ionic liquid (IL)-in-oil microemulsions (IL/O MEs) have been developed as potential carriers. By focusing on biocompatibility, we report on an IL/O ME that is designed to enhance the solubility and transdermal delivery of the sparingly soluble drug, acyclovir. The prepared MEs were composed of a hydrophilic IL (choline formate, choline lactate, or choline propionate) as the non-aqueous polar phase and a surface-active IL (choline oleate) as the surfactant in combination with sorbitan laurate in a continuous oil phase. The selected ILs were all biologically active ions. Optimized pseudo ternary phase diagrams indicated the MEs formed thermodynamically stable, spherically shaped, and nano-sized (<100 nm) droplets. An in vitro drug permeation study, using pig skin, showed the significantly enhanced permeation of acyclovir using the ME. A Fourier transform infrared spectroscopy study showed a reduction of the skin barrier function with the ME. Finally, a skin irritation study showed a high cell survival rate (>90%) with the ME compared with Dulbecco’s phosphate-buffered saline, indicates the biocompatibility of the ME. Therefore, we conclude that IL/O ME may be a promising nano-carrier for the transdermal delivery of sparingly soluble drugs.

DOI： 10.3390/pharmaceutics12040392

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

The aim of this study was to prepare binary supercooled liquid (SCL) by intermolecular interaction and apply this formulation to transdermal drug delivery. Ketoprofen (KET) and ethenzamide (ETH) were selected as binary SCL component. Thermal analysis of physical mixtures of KET and ETH showed decreases in melting points and glass transition below room temperature, thereby indicating formation of KET–ETH SCL. Intermolecular interactions between KET and ETH in the SCL were evaluated from Fourier transform (FT)-IR spectra. KET–ETH SCL maintained SCL state at 25°C with silica gel over 31d and at 40°C/89% relative humidity (RH) over 7d. KET SCL and KET–ETH SCL showed similar permeability of KET for hairless mice skin, which was two-fold higher than that of KET aqueous suspension. Our findings suggest that the SCL state could enhance the skin permeation of drugs and the binary SCL formed by intermolecular interaction could also improve the stability of the SCL. The binary SCL system could become a new drug form for transdermal drug delivery.

DOI： 10.1248/bpb.b19-00642

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

The structure of a protein complex needs to be controlled appropriately to maximize its functions. Herein, we report the linear polymerization of bacterial alkaline phosphatase (BAP) through the site-specific cross-linking reaction catalyzed by Trametes sp. laccase (TL). We introduced a peptide loop containing a tyrosine (Y-Loop) to BAP, and the Y-Looped BAP was treated with TL. The Y-Looped BAP formed linear polymers, whereas BAP fused with a C-terminal peptide containing a tyrosine (Y-tag) showed an irregular shape after TL treatment. The sterically confined structure of the Y-Loop could be responsible for the formation of linear BAP polymers. TL-catalyzed copolymerization of Y-Looped BAP and a Y-tagged chimeric antibody-binding protein, pG₂pA-Y, resulted in the formation of linear bifunctional protein copolymers that could be employed as protein probes in an enzyme-linked immunosorbent assay (ELISA). Copolymers comprising Y-Looped BAP and pG₂pA-Y at a molar ratio of 100:1 exhibited the highest signal in the ELISA with 26- and 20-fold higher than a genetically fused chimeric protein, BAP-pG₂pA-Y, and its polymeric form, respectively. This result revealed that the morphology of the copolymers was the most critical feature to improve the functionality of the protein polymers as detection probes, not only for immunoassays but also for other diagnostic applications.

DOI： 10.1021/acsomega.9b04163

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

The development of non-toxic ionic liquid-based active pharmaceutical ingredients (IL-APIs) for effective topical drug delivery is still challenging. The properties of IL-APIs can be boosted up by selecting potential biocompatible cations. Here, we introduced N-methyl-2-pyrrolidone (NMP) as a potent biocompatible counter ion to prepare ionic liquefied drugs for topical drug delivery. The cytotoxicity of NMP cation was investigated using mammalian cell lines (HepG2, NIH3T3 and L929 cells) and compared with conventional IL-forming cations. The synthesized NMP cation has lower toxicity than that of conventional IL-forming cations. The NMP cation showed at least 3.6, 15.2 and 58.9 times lower toxicity than that of conventional imidazolium, ammonium and phosphonium cations, respectively. The synthesized NMP-based ionic liquid (NMP-IL) was characterized using ¹H & ¹³C NMR, FT-IR, DSC and TGA. NMP-IL showed better physico-thermal stability, enhanced skin penetration, and enriched drug accumulation 2.6 times higher than that of IL [Cho][Ibu] in the target tissue. These results suggested that NMP cation based API-IL can be an effective biocompatible formulation for topical drug delivery by accumulating active drugs in the skin.

DOI： 10.1016/j.molliq.2019.112166

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

Skin dendritic cells (DCs) such as Langerhans cells and dermal dendritic cells have a pivotal role in inducing antigen-specific immunity; therefore, transcutaneous cancer vaccines are a promising strategy to prophylactically prevent the onset of a variety of diseases, including cancers. The largest obstacle to delivering antigen to these skin DC subsets is the barrier function of the stratum corneum. Although reverse micellar carriers are commonly used to enhance skin permeability to hydrophilic drugs, the transcutaneous delivery of antigen, proteins, or peptides has not been achieved to date because of the large molecular weight of drugs. To achieve effective antigen delivery to skin DCs, we developed a novel strategy using a surfactant as a skin permeation enhancer in a reverse micellar carrier. In this study, glyceryl monooleate (MO) was chosen as a skin permeation enhancer, and the MO-based reverse micellar carrier enabled the successful delivery of antigen to Langerhans cells and dermal dendritic cells. Moreover, transcutaneous vaccination with the MO-based reverse micellar carrier significantly inhibited tumor growth, indicating that it is a promising vaccine platform against tumors.

DOI： 10.1021/acs.molpharmaceut.9b01104

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

En masse vaccination is a promising strategy for combatting infectious diseases. Intranasal vaccination is a viable route of mass vaccination, and it could be performed easily via needle-free administration. However, it is not widely used because it tends not to evoke sufficient immunity. The aim of the present study was to improve the performance of intranasal vaccination by extending the amount of time that administered antigens remain in the nasal cavity, and enhancing immune responses via a nanocarrier-based adjuvant. A simple and safe solid-in-oil (S/O) system was investigated as a nanocarrier in intranasal vaccination. S/O nanodispersions are oil-based dispersions of antigens coated with surfactants. Because of the mucoadhesive capacities of surfactant and oil they have high potential to extend the amount of time that administered antigens remain in the nasal cavity, and can induce strong immune responses due to a nanocarrier-based adjuvant effect. In nasal absorption experiments antigens administered intranasally via S/O nanodispersions remained in the nasal cavity longer and induced strong mucosal and systemic immune responses. Histopathology analysis indicated that S/O nanodispersions did not modify the nasal epithelium or cilia, suggesting non-toxicity of the carrier. These results indicate the potential of intranasal vaccination using S/O nanodispersions for future vaccination.

DOI： 10.1016/j.ijpharm.2019.118777

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

Japanese cedar pollinosis is a type I allergic disease and has already become a major public health problem in Japan. Conventional subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) cannot meet patients’ needs owing to the side effects caused by both the use of conventional whole antigen molecules in the pollen extract and the administration routes. To address these issues, a surface-modified antigen and transcutaneous administration route are introduced in this research. First, the pollen extract (PE) was conjugated to galactomannan (PE-GM) to mask immunoglobulin E (IgE)-binding epitopes in the PE to avoid side effects. Second, as a safer alternative to SCIT and SLIT, transcutaneous immunotherapy (TCIT) with a solid-in-oil (S/O) nanodispersion system carrying PE-GM was proposed. Hydrophilic PE-GM was efficiently delivered through mouse skin using S/O nanodispersions, reducing the antibody secretion and modifying the type 1 T helper (Th1)/ type 2 T helper (Th2) balance in the mouse model, thereby demonstrating the potential to alleviate Japanese cedar pollinosis.

DOI： 10.3390/pharmaceutics11110563

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

DOI： 10.1016/j.jcis.2019.04.095

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

We developed a new oil-based delivery system for transdermal protein delivery, a gel-in-oil (G/O) nanosuspension, where gelatin-based hydrogel was coated with hydrophobic surfactants. The high entrapment efficiency of a model protein, phycocyanin (PC), into nano-sized gelatin hydrogel particles was achieved. Spectroscopic evaluation of PC suggested that the G/O nanosuspension could retain the functional form of PC in isopropyl myristate. In vitro skin permeation studies showed that the G/O nanosuspension facilitated the delivery of PC through the stratum corneum of Yucatan micropig skin.

DOI： 10.1016/j.ijpharm.2019.118495

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

DOI： 10.1016/j.ijpharm.2019.05.020

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

Biologically active artificial scaffolds for cell seeding are developed by mimicking extracellular matrices using synthetic materials. Here, we propose a feasible approach employing biocatalysis to integrate natural components, that is, gelatin and heparin, into a synthetic scaffold, namely a polyethylene glycol (PEG)-based hydrogel. Initiation of horseradish peroxidase-mediated redox reaction enabled both hydrogel formation of tetra-thiolated PEG via disulfide linkage and incorporation of chemically thiolated gelatin (Gela-SH) and heparin (Hepa-SH) into the polymeric network. We found that the compatibility of the type of gelatin with heparin was crucial for the hydrogelation process. Alkaline-treated gelatin exhibited superior performance over acid-treated gelatin to generate dual functionality in the resultant hydrogel originating from the two natural biopolymers. The Gela-SH/Hepa-SH dual functionalized PEG-based hydrogel supported both cellular attachment and binding of basic fibroblast growth factor (bFGF) under cell culture conditions, which increased the proliferation and phenotype transformation of NIH3T3 cells cultured on the hydrogel. Inclusion of bFGF and a commercial growth factor cocktail in hydrogel matrices effectively enhanced cell spreading and confluency of both NIH3T3 cells and HUVECs, respectively, suggesting a potential method to design artificial scaffolds containing active growth factors.

DOI： 10.1021/acsabm.9b00275

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

DOI： 10.1016/j.molliq.2019.01.063

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

DOI： 10.1021/acs.langmuir.8b02809

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

We report a one-step emulsification and rapid freeze-drying process to develop a curcumin-ionic liquid (CCM-IL) complex that could be readily dispersed in water with a significantly enhanced solubility of ∼8 mg mL^-1 and half-life (t_1/2) of ∼260 min compared with free CCM (solubility ∼30 nM and t_1/2 ∼ 20 min). This process using an IL consisting of a long chain carbon backbone as a surfactant, may provide an alternative way of enhancing the solubility of poorly water-soluble drugs.

DOI： 10.1039/c9cc02812a

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

DOI： 10.1002/chem.201900370

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

DOI： 10.1252/jcej.18we060

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

DOI： 10.1016/j.jphotochem.2018.10.006

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

DOI： 10.1002/biot.201800085

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

Lipid modification of proteins plays a significant role in regulating the cellular environment. Mimicking natural lipidated proteins is a key technique for assessing the function of proteins modified with lipids and also to render self-assembly of lipids to a target protein. Herein, we report a facile method of conjugating proteins with lipid-fused peptides under homogeneous physiological conditions by using the microbial transglutaminase (MTG) reaction. MTG catalyzes the cross-linking reaction between a specific glutamine (Q) in a protein and a lysine (K) in newly designed lipid-fused peptides. The water-soluble peptide substrates for lipid modification, C₁₄-X-MRHKGS, were newly synthesized, where C₁₄, X, and MRHKGS represent myristic acid, linker peptides composed of G, P, or S, and MTG-reactive K surrounded with basic amino acids, respectively. The MTG-mediated cross-linking reaction between a protein fused with LLQG at the C-terminus and C₁₄-X-MRHKGS (5 molar eq) dissolved in a phosphate saline solution resulted in lipid-protein conjugates with yields of 70 to 100%. The anchoring ability of the obtained lipid-protein conjugates to cell membranes was dependent on the number of G residues in the G_nS linker, suggesting that self-assembly and hydrophobicity of the G_nS motif serves to enhance membrane anchoring of lipid-protein conjugates.

DOI： 10.1021/acsabm.8b00271

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

DOI： 10.1016/j.ijpharm.2018.05.021

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

Block copolymer of poly(ethylene glycol)-block-poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PEG-P[Asp(DET)]) has been originally introduced as a promising gene carrier by forming a nanomicelle with plasmid DNA. In this study, the polyplex micelle of PEG-SS-P[Asp(DET)], which disulfide linkage (SS) between PEG and cationic polymer can detach the surrounding PEG chains upon intracellular reduction, was firstly evaluated with respect to in vivo transduction efficiency and toxicity in comparison to that of PEG-P[Asp(DET)] in peritoneally disseminated cancer model. Intraperitoneal (i.p.) administration of PEG-SS-P[Asp(DET)] polyplex micelles showed a higher (P<0.05) transgene expression compared with PEG-P[Asp(DET)] in tumors. In contrast, the delivered distribution of the micelles was not different between the two polyplex micelles. PEG-SS-P[Asp(DET)] micelle encapsulating human tumor necrosis factor alpha (hTNF-alpha) gene exhibits a higher antitumor efficacy against disseminated cancer compared with PEG-P[Asp(DET)] or saline control. No hepatic and renal toxicities were observed by the administration of polyplex micelles. In conclusion, PEG-detachable polyplex micelles may represent an advantage in gene transduction in vivo over PEG-undetachable polyplex micelles after i.p. administration for peritoneal dissemination of cancer. (C) 2012 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.jconrel.2012.03.021

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

Aims: This study is to elucidate whether cyclic adenosine monophosphate (cAMP)-mediated signal is involved in lower regenerative potential of cirrhotic liver.

DOI： 10.1111/j.1872-034X.2011.00868.x

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

Paclitaxel, one of key drugs to treat a wide range of malignancies, exhibits relative low sensitivity for colorectal cancer. The present study was to examine whether and how phosphatidylinositol 3'-kinase (PI3K) signals affect the sensitivity of colorectal cancer to paclitaxel. Four colorectal cancer cell lines were exposed to paclitaxel in the presence of PI3K signal inhibitors, such as LY294002, siRNA for Akt, or rapamycicn, with or without MAPK inhibitor, PD98059. Cell viability and apoptosis were determined by MTT assay, cell cycle analysis in flow cytometer and Hoechst nuclear staining. To analyze the PI3K activity, the expression in phosphorylated Akt and downstream effectors of p70S6 kinase (S6K) were evaluated by Western blot analysis. Paclitaxel alone (5-10 nM) did not induce the apoptosis in all four cell lines. Although LY294002 alone did not affect the cell viability, it suppressed the Akt and S6K activities and induced the sub-G1 arrest/apoptosis when paclitaxel was co-administered, as well as the Akt siRNA and rapamycin did. Simultaneous blockade of PI3K and MAPK pathways more suppressed the S6K activity and further increased the apoptosis. In conclusion, PI3K is involved in low susceptibility of colorectal cancer to paclitaxel and dual PI3K/MAPK targeting agents may evolve a new paclitaxel-based chemotherapy for colorectal cancer. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2011.02.042

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

We report a new supramolecular rotor (1), in which a lanthanum( III) bis(porphyrinate)s double-decker (LaDD) bears two porphyrinatorhodium(III)-based rotors whose planes are situated orthogonally to one another. In [D-2]dichloromethane, H-1 NMR spectral results indicated that rotational information was transmitted from the LaDD rotor to two porphyrinatorhodium( III)-based rotors through mechanical interaction of the teeth of the rotors. Mechanical interaction was achieved among the multiple rotors in 1 even after switching the rotational activity of the LaDD rotor by using [D-5]pyridine. The spatial arrangement of the two porphyr inatorhodium(III)-based rotors is a critical factor in maintaining mechanical interaction between multiple molecular rotors when changing the dynamic properties of one rotor.

DOI： 10.1002/ejoc.201001656

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

DOI： 10.1021/ja063040x

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京理科大学   Country：Japan  

Event date： 2023.3

Language：English   Presentation type：Oral presentation (general)  

Venue：東京農工大学   Country：Japan  

Event date： 2022.11

Language：English   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2022.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京大学   Country：Japan  

Event date： 2022.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2022.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京工業大学   Country：Japan  

Event date： 2022.10

Language：English  

Venue：Bali, Indonesia/Online   Country：Indonesia  

Event date： 2022.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名古屋大学   Country：Japan  

Event date： 2022.8

Language：English   Presentation type：Oral presentation (general)  

Venue：Kuala Lumpur Convention Centre/Hybrid (Online)   Country：Malaysia  

Event date： 2022.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：鳥取大学/オンライン   Country：Japan  

Event date： 2022.7

Language：English   Presentation type：Oral presentation (general)  

Venue：IPB University/online hybrid   Country：Indonesia  

Event date： 2022.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：崇城大学   Country：Japan  

Event date： 2022.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2022.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2022.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.5

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2021.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2019.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2019.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2019.9

Language：English  

Venue：Sapporo convention center   Country：Japan  

Event date： 2019.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2019.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東北大学   Country：Japan  

Event date： 2019.7

Language：Japanese  

Venue：セミナーハウス（東京都八王子市）   Country：Japan  

Event date： 2019.7 - 2018.7

Language：English  

Venue：Fullon Hotel, Tamsui Fishermen’s Wharf, Taipei   Country：Taiwan, Province of China  

Event date： 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：甲南大学   Country：Japan  

Event date： 2018.12

Language：English   Presentation type：Oral presentation (general)  

Venue：北九州国際会議場   Country：Japan  

Event date： 2018.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京大学   Country：Japan  

Event date： 2018.11

Language：English  

Venue：National Taiwan Uninversity of Science & Technology   Country：Taiwan, Province of China  

Event date： 2018.10

Language：English   Presentation type：Oral presentation (general)  

Venue：EXCO   Country：Korea, Republic of  

Event date： 2018.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪大学   Country：Japan  

Event date： 2018.7

Language：Japanese  

Venue：ANAホリデイ・イン リゾート宮崎   Country：Japan  

Event date： 2018.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：長崎ブリックホール   Country：Japan  

Event date： 2018.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：日本大学   Country：Japan  

Event date： 2017.12

Language：English  

Venue：京都大学   Country：Japan  

Event date： 2017.10

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：志賀島休暇村   Country：Japan  

Event date： 2017.9

Language：Japanese  

Venue：東京大学   Country：Japan  

Event date： 2017.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：みやこめっせ   Country：Japan  

Event date： 2017.7

Language：Japanese  

Venue：東京国際フォーラム   Country：Japan  

Event date： 2017.5

Language：Japanese  

Venue：幕張メッセ   Country：Japan  

Language：Others  

Country：Other  

Event date： 2025.3

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Event date： 2024.9

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Event date： 2024.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：つくば  

Event date： 2024.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：日本大学船橋キャンパス  

Event date： 2024.3

Language：English   Presentation type：Oral presentation (general)  

Venue：Nihon University College of Science & Technology Funabashi Campus  

Event date： 2024.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪公立大学  

Event date： 2024.3

Language：English   Presentation type：Oral presentation (general)  

Venue：Osaka  

Event date： 2024.3

Language：English   Presentation type：Oral presentation (general)  

Venue：Nakamozu Campus, Osaka Metropolitan University, Osaka, Japan  

Event date： 2024.3

Language：English   Presentation type：Oral presentation (general)  

Venue：Nakamozu Campus, Osaka Metropolitan University  

Event date： 2024.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：大阪公立大学  

Event date： 2024.3

Language：Japanese  

Venue：大阪公立大学 中百舌鳥キャンパス  

Event date： 2024.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン  

Event date： 2024.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン  

Event date： 2024.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン  

Event date： 2023.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Graha Widya Bhakti, KST BJ. Habibie, South Tangerang, Indonesia   Country：Indonesia  

Event date： 2023.12

Language：English   Presentation type：Oral presentation (general)  

Venue：The-K Hotel Gyeongju, Gyeongju, Korea   Country：Korea, Republic of  

Event date： 2023.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Korea   Country：Korea, Republic of  

Event date： 2023.12

Language：English   Presentation type：Oral presentation (general)  

Venue：The K Hotel   Country：Korea, Republic of  

Event date： 2023.12

Language：English   Presentation type：Oral presentation (general)  

Venue：The-K Hotel Gyeongju, Gyeongju, Korea   Country：Korea, Republic of  

Event date： 2023.12

Language：English   Presentation type：Oral presentation (general)  

Venue：韓国慶州   Country：Korea, Republic of  

Event date： 2023.12

Language：English   Presentation type：Oral presentation (general)  

Venue：The-K Hotel Gyeongju, Gyeongju, Korea   Country：Korea, Republic of  

Event date： 2023.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Korea   Country：Korea, Republic of  

Event date： 2023.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Gyeongju, Korea   Country：Korea, Republic of  

Event date： 2023.12

Language：English   Presentation type：Oral presentation (general)  

Venue：プサン   Country：Korea, Republic of  

Event date： 2023.11

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Event date： 2023.11

Language：Japanese  

Venue：早稲田大学先進研究センター  

Event date： 2023.11

Language：Japanese  

Venue：早稲田大学リサーチイノベーションセンター  

Event date： 2023.11

Language：Japanese  

Venue：早稲田大学リサーチイノベーションセンター  

Event date： 2023.11

Language：Japanese  

Venue：早稲田大学リサーチイノベーションセンター（121号館）B1F  

Event date： 2023.11

Language：English  

Venue：Pusan National University   Country：Korea, Republic of  

Event date： 2023.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：熊本大学  

Event date： 2023.11

Language：English  

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Event date： 2023.10

Language：Japanese  

Venue：タワーホール船堀  

Event date： 2023.10

Language：Japanese  

Venue：タワーホール船堀  

Event date： 2023.10

Language：English  

Venue：Biotechnology Center of Ho Chi Minh City (HCMBiotech)   Country：Viet Nam  

Event date： 2023.10

Language：English  

Venue：Vietnam   Country：Viet Nam  

Event date： 2023.9

Language：Japanese  

Venue：東京大学  

Event date： 2023.9

Language：Japanese  

Venue：大阪公立大学 I-siteなんば  

Event date： 2023.9

Language：Japanese  

Venue：高野山大学  

Event date： 2023.9

Language：Japanese  

Venue：高野山大学  

Event date： 2023.9

Language：Japanese  

Venue：福岡大学  

Event date： 2023.9

Language：Japanese  

Venue：福岡大学七隈キャンパス  

Event date： 2023.9

Language：Japanese  

Venue：福岡大学 七隈キャンパス  

Event date： 2023.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：福岡大学  

Event date： 2023.9

Language：Japanese  

Venue：福岡大学 七隈キャンパス  

Event date： 2023.9

Language：Japanese  

Venue：福岡大学  

Event date： 2023.9

Language：Japanese  

Venue：東京理科大学野田キャンパス薬学部  

Event date： 2023.9

Language：Japanese  

Venue：千葉  

Event date： 2023.9

Language：Japanese  

Venue：東京理科大学野田キャンパス薬学部  

Event date： 2023.9

Language：Japanese  

Venue：東京理科大学野田キャンパス薬学部  

Event date： 2023.9

Language：Japanese  

Venue：東京理科大学  

Event date： 2023.9

Language：Japanese  

Venue：東京大学  

Event date： 2023.9

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：名古屋大学  

Event date： 2023.8

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Event date： 2023.8 - 2023.10

Language：Japanese  

Venue：東京理科大学野田キャンパス薬学部  

Event date： 2023.7

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：幕張メッセ　国際会議場  

Event date： 2023.7

Language：Japanese  

Venue：幕張メッセ国際会議場  

Event date： 2023.7

Language：Japanese  

Venue：幕張メッセ　国際会議場  

Event date： 2023.7

Language：Japanese  

Venue：あいち健康の森プラザホテル  

Event date： 2023.7

Language：Japanese  

Venue：あいち健康の森プラザホテル  

Event date： 2023.7

Language：Japanese  

Venue：あいち健康の森プラザホテル  

Event date： 2023.7

Language：Japanese  

Venue：鹿児島大学  

Event date： 2023.7

Language：Japanese  

Venue：鹿児島大学  

Event date： 2023.7

Language：English  

Venue：台湾   Country：Taiwan, Province of China  

Event date： 2023.7

Language：English  

Venue：National Cheng Kung University   Country：Taiwan, Province of China  

Event date： 2023.7

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Event date： 2023.7

Language：Japanese  

Venue：北九州  

Event date： 2023.7

Language：Japanese  

Venue：北九州国際会議場  

Event date： 2023.6

Language：Japanese  

Venue：砺波青少年自然の家  

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京理科大学   Country：Japan  

Event date： 2023.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京理科大学   Country：Japan  

Event date： 2023.3

Language：English  

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Event date： 2022.12

Language：English  

Venue：Online   Country：Indonesia  

Event date： 2022.11

Language：English  

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Event date： 2022.11

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Event date： 2022.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：鹿児島大学   Country：Japan  

Event date： 2022.11

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：鹿児島大学   Country：Japan  

Event date： 2022.10

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Event date： 2022.10

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Event date： 2022.10

Language：English   Presentation type：Oral presentation (general)  

Venue：Bali, Indonesia/Online   Country：Indonesia  

Event date： 2022.9

Language：Japanese  

Venue：信州大学   Country：Japan  

Event date： 2022.9

Language：Japanese  

Venue：名古屋大学   Country：Japan  

Event date： 2022.9

Language：Japanese  

Venue：名古屋大学   Country：Japan  

Event date： 2022.9

Language：Japanese  

Venue：名古屋大学   Country：Japan  

Event date： 2022.8

Language：English   Presentation type：Oral presentation (general)  

Venue：Kuala Lumpur Convention Centre/Hybrid (Online)   Country：Malaysia  

Event date： 2022.8

Language：English   Presentation type：Oral presentation (general)  

Venue：Kyushu University   Country：Japan  

Event date： 2022.8

Language：English   Presentation type：Oral presentation (general)  

Venue：Kyushu University   Country：Japan  

Event date： 2022.7

Language：Japanese   Presentation type：Oral presentation (invited, special)  

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Event date： 2022.7

Language：Japanese  

Venue：福岡大学   Country：Japan  

Event date： 2022.7

Language：English   Presentation type：Oral presentation (keynote)  

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Event date： 2022.7

Language：Japanese   Presentation type：Oral presentation (invited, special)  

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Event date： 2022.7

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2022.6

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2022.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2022.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2022.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2022.3

Language：English   Presentation type：Oral presentation (invited, special)  

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Event date： 2022.3

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2022.3

Language：Japanese   Presentation type：Oral presentation (invited, special)  

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Event date： 2022.3

Language：Japanese   Presentation type：Oral presentation (invited, special)  

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Event date： 2022.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.12

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2021.12

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2021.12

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2021.11

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2021.9

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2021.9

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2021.7

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2021.7

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2021.7

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2021.6

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：幕張メッセ国際会議場   Country：Japan  

Event date： 2021.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2021.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2020.3 - 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京理科大学   Country：Japan  

Event date： 2020.3 - 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京理科大学   Country：Japan  

Event date： 2020.3 - 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：東京理科大学   Country：Japan  

Event date： 2020.3 - 2019.3

Language：Japanese  

Venue：関西大学   Country：Japan  

Event date： 2020.3 - 2019.3

Language：Japanese  

Venue：岡山大学   Country：Japan  

Event date： 2019.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Chungnam National University, Daejeon   Country：Korea, Republic of  

Event date： 2019.12

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：オンライン   Country：Japan  

Event date： 2019.11

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2019.11

Language：English  

Venue：万国津梁館 沖縄県名護市   Country：Japan  

Event date： 2019.9

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2019.9

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2019.9

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2019.9

Language：Japanese  

Venue：オンライン   Country：Japan  

Event date： 2019.9

Language：Japanese  

Venue：東北大学   Country：Japan  

Event date： 2019.9

Language：Japanese  

Venue：東北大学   Country：Japan  

Event date： 2019.7

Language：Japanese  

Venue：琵琶湖国定公園白浜荘   Country：Japan  

Event date： 2019.7

Language：Japanese  

Venue：セミナーハウス（東京都八王子市）   Country：Japan  

Event date： 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：甲南大学   Country：Japan  

Event date： 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：甲南大学   Country：Japan  

Event date： 2018.12

Language：Japanese  

Venue：北九州国際会議場   Country：Japan  

Event date： 2018.12

Language：English  

Venue：Chiang Mai University   Country：Thailand  

Event date： 2018.12

Language：English   Presentation type：Oral presentation (general)  

Venue：Chiang Mai University   Country：Thailand  

Event date： 2018.3 - 2019.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：京都大学   Country：Japan  

Event date： 2018.3

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：広島大学   Country：Japan  

Event date： 2017.12

Language：English  

Venue：KAIST   Country：Korea, Republic of  

Event date： 2017.9

Language：Japanese  

Venue：東京大学   Country：Japan  

Event date： 2017.8

Language：English   Presentation type：Oral presentation (general)  

Venue：Hong Kong   Country：China  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：Japanese   Publisher：日本DDS学会  

Language：English  

Japanese cedar pollinosis (JCP) is a common affliction caused by an allergic reaction to cedar pollen and is considered a disease of national importance in Japan. Antigen-specific immunotherapy (AIT) is the only available curative treatment for JCP. However, low compliance and persistence have been reported among patients subcutaneously or sublingually administered AIT comprising a conventional antigen derived from a pollen extract. To address these issues, many research studies have focused on developing a safer, simpler, and more effective AIT for JCP. Here, we review the novel antigens that have been developed for JCP AIT, discuss their different administration routes, and present the effects of anti-allergy treatment. Then, we describe a new form of AIT called transcutaneous immunotherapy (TCIT) and its solid-in-oil (S/O) nanodispersion formulation, which is a promising antigen delivery system. Finally, we discuss the applications of S/O nanodispersions for JCP TCIT. In this context, we predict that TCIT delivery by using a S/O nanodispersion loaded with novel antigens may offer an easier, safer, and more effective treatment option for JCP patients.

DOI： 10.3390/pharmaceutics12030240

Language：Japanese  

共役系高分子を自在に並べる

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：14

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：15

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：8

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：13

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：10

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Number of participants：135

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：8

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Type：Peer review 

Number of peer-reviewed articles in foreign language journals：3

Number of peer-reviewed articles in Japanese journals：0

Proceedings of International Conference Number of peer-reviewed papers：0

Proceedings of domestic conference Number of peer-reviewed papers：0

Type：Competition, symposium, etc. 

Type：Competition, symposium, etc. 

Number of participants：450

Type：Competition, symposium, etc. 

Number of participants：106