Publications by authors named "Nobuhiro Nishiyama"

250 Publications

Differential Effect of Azetidine Substitution in Firefly Luciferin Analogues.

Chembiochem 2021 Aug 16. Epub 2021 Aug 16.

Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa, 223-8522, Japan.

Replacing an N,N-dimethylamino group in a classical fluorophore with a four membered azetidine ring provides an improved luminescence quantum yield. Herein, we extended this strategy to bioluminescent firefly luciferin analogues and evaluated its general validity. For this purpose, four types of luciferin cores were employed, and a total of eight analogues were evaluated. Among these analogues, unexpectedly, only the benzothiazole core analogue benefited from an azetidine substitution and showed enhanced bioluminescence. In addition, fluorescence measurements revealed that an azetidine substitution improved the fluorescence quantum yield by 2.3-times compared to a N,N-dimethylamino group. These findings clarify the differential effects of azetidine substituents in luciferins and present one possible strategy for enhancing photon output in benzothiazole type luciferins through a synthetic approach.
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http://dx.doi.org/10.1002/cbic.202100310DOI Listing
August 2021

Nanoprobe-Based Magnetic Resonance Imaging of Hypoxia Predicts Responses to Radiotherapy, Immunotherapy, and Sensitizing Treatments in Pancreatic Tumors.

ACS Nano 2021 Aug 6. Epub 2021 Aug 6.

Department of Radiology, Center for Medical Imaging, and State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, No. 17, South Renmin Road, Chengdu 610041, China.

Accurate diagnosis of tumors and predicting the therapeutic responses are highly demanded in the clinic to improve the treatment efficacy and survival rates. Since hypoxia develops in the progression of tumors and inversely correlates with prognosis and promotes resistance to radiotherapies and immunotherapies, it is a potential marker for therapeutic prediction. Therefore, effective discrimination of tumor hypoxia for predicting therapeutic outcomes is critical. Here, a magnetic resonance imaging (MRI)-based diagnosis strategy using contrast-amplifying nanoprobes that sense tumor acidosis and real-time observation of hypoxic conditions in tumors has been developed, aiming at accurate detection of pancreatic tumors and prediction of therapeutic effects. Our approach selectively probed xenograft, allograft, and transgenic spontaneous models of intractable pancreatic cancer, which lacks standardized predictive markers to identify patients who benefit most from treatments, and effectively discriminated the intratumoral hypoxia levels. By stratification of pancreatic tumors based on quantitative MR imaging of hypoxia, it enabled prediction of the responses to radiotherapy and immune checkpoint inhibitors. Moreover, the nanoprobe-based MRI could monitor hypoxia reduction by tumor normalization treatments, which permits visualizing pancreatic tumors that will respond to immune checkpoint blockade therapy, enhancing the response rate. The results demonstrate the potential of our strategy for accurate tumor diagnosis, patient stratification, and effective therapy.
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http://dx.doi.org/10.1021/acsnano.1c04263DOI Listing
August 2021

Synthesis of near-infrared absorbing triangular Au nanoplates using biomineralisation peptides.

Acta Biomater 2021 09 15;131:519-531. Epub 2021 Jun 15.

Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1-S1-24, O-okayama, Meguro-ku, Tokyo 152-8552, Japan. Electronic address:

Triangular Au nanoplates (TrAuNPls) possessing strong plasmonic properties can be used as photothermal agents in cancer therapy. However, the controlled preparation of such morphologies typically requires harsh synthetic conditions. Biomolecules offer an alternative route to developing biocompatible synthetic protocols. In particular, peptides offer a novel route for inorganic synthesis under ambient conditions. Herein, using the previously isolated peptide, ASHQWAWKWE, for Au nanoparticle (AuNP) synthesis, the conditions for preparing TrAuNPls via a one-pot synthetic process of mixing HAuCl and peptides at room temperature were investigated to effectively obtain particles possessing near-infrared absorbance for non-invasive optical diagnosis and phototherapy. By adjusting the peptide concentration, the size and property of TrAuNPls were controlled under neutral pH conditions. The synthesised particles showed potential as photothermal therapeutic agents in vitro. In addition, peptide characterisation using B3 derivatives revealed the importance of the third amino acid histidine in morphological regulation and potential circular Au nanoplates (AuNPl) synthesis with ASEQWAWKWE and ASAQWAWKWE peptides. These findings provide not only an easy and green synthetic method for TrAuNPls and circular AuNPls, but also some insight to help elucidate the regulation of peptide-based nanoparticle synthesis for use in cancer therapy. STATEMENT OF SIGNIFICANCE: Biological molecules have received increasing attention as a vehicle to synthesise inorganic materials with specific properties under ambient conditions; particularly, short peptides have the potential to control the synthesis of nanoscale materials with tailored functions. Here, the application of a previously isolated peptide was assessed in synthesising Au nanoparticles containing decahedral and triangular nanoplates with near-infrared absorbance. The size and absorbance peaks of the triangular nanoplates observed were peptide concentration-dependent. In addition, these fine-tuned triangular nanoplates exhibited potential as a phototherapeutic agent. Moreover, the peptide derivatives indicated the possibility of synthesising circular nanoplates. These findings may offer insight into development of new techniques for synthesising functional nanoparticles having biological applications using non-toxic molecules under mild conditions stituted in the original B3 peptide is underlined.
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http://dx.doi.org/10.1016/j.actbio.2021.06.010DOI Listing
September 2021

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

J Control Release 2021 04 24;332:184-193. Epub 2021 Feb 24.

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

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

Cochlear implantation in a patient with a mutation.

Clin Case Rep 2021 Jan 11;9(1):298-303. Epub 2020 Nov 11.

Department of Otolaryngology, Head and Neck Surgery Tokyo Medical University Shinjuku-ku Japan.

Cochlear implants (CIs) are generally considered useful in the treatment of hereditary hearing loss with progressive deafness. Early CI can be beneficial for maintaining social activities in mutation patients.
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http://dx.doi.org/10.1002/ccr3.3520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7813023PMC
January 2021

Electrical Isolation of the Marshall Bundle by Radiofrequency Catheter Ablation: In Patients With Atrial Fibrillation.

JACC Clin Electrophysiol 2020 12 16;6(13):1647-1657. Epub 2020 Sep 16.

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. Electronic address:

Objectives: This study sought to isolate arrhythmogenic Marshall bundles (MBs) by radiofrequency (RF) catheter ablation.

Background: The vein of Marshall (VOM) is surrounded by a muscular bundle called the MB. The MB is 1 of the arrhythmogenic sources of atrial fibrillation (AF) and electrically connects to either the left atrial (LA) myocardium or coronary sinus (CS) musculature. By eliminating such electric connections using RF catheter ablation, the MB might be electrically isolated.

Methods: This retrospective study included 20 patients (64 ± 10 years old, 5 women) who underwent an MB isolation for nonparoxysmal AF. After pulmonary vein isolation, we performed venography of the VOM and inserted a 2-F electrode catheter into the VOM. RF applications were delivered to eliminate the MB electrograms from both the LA and CS when the MB was considered arrhythmogenic.

Results: MB isolation was achieved in 14 patients (70%). Of them, complete or partial MB isolation was accomplished in 7 patients (35%) each. The average number of RF applications in the LA (35 W, 30 s) and CS (25 W, 30 s) was 15 ± 14 and 4 ± 3, respectively. No severe adverse events were observed. During a follow-up of 23 ± 11 months, 18 patients (90%) maintained sinus rhythm.

Conclusions: RF applications targeting recordings from an electrode catheter in the VOM were feasible, and the MB could be electrically isolated. Elimination of the MB potentials would be a clear endpoint for patients with an arrhythmogenic MB.
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http://dx.doi.org/10.1016/j.jacep.2020.06.025DOI Listing
December 2020

Photodynamic therapy using LCST polymers exerting pH-responsive isothermal phase transition.

J Control Release 2020 12 22;328:608-616. Epub 2020 Sep 22.

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

In photodynamic therapy (PDT), the inherent physicochemical properties of a photosensitizer (PS) critically affect its biodistribution and therapeutic outcome as well as side effect. Here, we developed a PS-polymer conjugate displaying isothermal hydrophilic-to-hydrophobic phase transition in response to tumorous acidic pH. The polymer backbone was poly(N-isopropylacrylamide (NIPAAm)/2-aminoisoprpylacrylamide (AIPAAm)) (P(NIPAAm/AIPAAm)), which shows lower critical solution temperature (LCST) of 30 °C. The amine groups in its side chains were converted to hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amides, forming poly(NIPAAm/AIPAAm-PMM). The conjugation of PMM moieties drastically increased the LCST of the polymer to 40 °C and displayed hydrophilic character to minimalize unspecific interaction of PS-P(NIPAAm/AIPAAm-PMM) in bloodstream, diminishing potential photosensitivity. The detachment of PMM at tumorous pH lowered the LCST to that of original P(NIPAAm/AIPAAm), permitting hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C). This pH-responsive isothermal phase transition facilitated interaction with the cultured cancer cells, accomplishing 8.1 times-enhanced cellular uptake and strong phototoxicity in a tumorous pH-selective manner. Even in subcutaneous tumor models, our polymer conjugates exhibited efficient tumor accumulation and significantly augmented PDT effect without inducing unfavorable photochemical toxicity to the skin. This study offers a novel concept of PS delivery systems targeting tumorous pH by the use of isothermal phase transition.
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http://dx.doi.org/10.1016/j.jconrel.2020.09.036DOI Listing
December 2020

Potential urinary monitoring of the enhanced permeability and retention effect using MMP-2-responsive poly(ethylene glycol) derivatives.

J Control Release 2021 01 8;329:513-523. Epub 2020 Sep 8.

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

The enhanced permeability and retention (EPR) effect is fundamental to tumor-targeted drug delivery using nanoparticles. However, recent studies reported heterogeneity of the EPR effect, and companion diagnostics are considered to be key to predicting and optimizing the benefits of the EPR effect. Here, as a new material to simply endow the function of companion diagnostics to nanoparticles, we designed a poly(ethylene glycol) (PEG) derivative conjugated with low molecular fluorescent dye through synthetic substrate linker that can be cleaved in response to MMP-2, which is overexpressed in tumor extracellular matrix. Upon tumor accumulation, the low molecular fluorescent dye is released from the PEG and quickly excreted to urine, thereby reporting its tumor accumulation level as a fluorescent signal in the urine. In this study, this urinary reporter was conjugated with albumin, and the functionalized albumin exhibited efficient accumulation in various tumors. Importantly, the functionalized albumin exhibited significantly higher excretion of the fluorescent dye in the urine in mice with tumors compared with those without tumors. The PEG derivatives proposed in this study may be a promising tool to predict the EPR effect in individual cancer patients.
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http://dx.doi.org/10.1016/j.jconrel.2020.09.004DOI Listing
January 2021

Sequential Self-Assembly Using Tannic Acid and Phenylboronic Acid-Modified Copolymers for Potential Protein Delivery.

Biomacromolecules 2020 09 10;21(9):3826-3835. Epub 2020 Aug 10.

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

Tannic acid (TA) can form stable complexes with proteins, attracting significant attention as protein delivery systems. However, its systemic application has been limited due to nonspecific interaction. Here, we report a simple technique to prepare systemically applicable protein delivery systems using sequential self-assembly of a protein, TA, and phenylboronic acid-conjugated PEG-poly(amino acid) block copolymers in aqueous solution. Mixing the protein and TA in aqueous solution led to covering of the protein with TA, and subsequent addition of the copolymer resulted in the formation of boronate esters between TA and copolymers, constructing the core-shell-type ternary complex. The ternary complex covered with PEG exhibited a small hydrodynamic diameter of ∼10-20 nm and prevented an unfavorable interaction with serum components, thereby accomplishing significantly prolonged blood circulation and enhanced tumor accumulation in a subcutaneous tumor model. The technique utilizing supramolecular self-assembly may serve as a novel approach for designing protein delivery systems.
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http://dx.doi.org/10.1021/acs.biomac.0c00903DOI Listing
September 2020

Iron chelation cancer therapy using hydrophilic block copolymers conjugated with deferoxamine.

Cancer Sci 2021 Jan 29;112(1):410-421. Epub 2020 Nov 29.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Yokohama, Japan.

Cancer cells have high iron requirements due to their rapid growth and proliferation. Iron depletion using iron chelators has a potential in cancer treatment. Previous studies have demonstrated that deferoxamine (DFO) specifically chelates Fe(III) and exhibited antitumor activity in clinical studies. However, its poor pharmacokinetics has limited the therapeutic potential and practical application. Although polymeric iron chelators have been developed to increase the blood retention, none of previous studies has demonstrated their potential in iron chelation cancer therapy. Here, we developed polymeric DFO by the covalent conjugation of DFO to poly(ethylene glycol)-poly(aspartic acid) (PEG-PAsp) block copolymers. The polymeric DFO exhibited iron-chelating ability comparable with free DFO, thereby arresting cell cycle and inducing apoptosis and antiproliferative activity. After intravenous administration, the polymeric DFO showed marked increase in blood retention and tumor accumulation in subcutaneous tumor models. Consequently, polymeric DFO showed significant suppression of the tumor growth compared with free DFO. This study reveals the first success of the design of polymeric DFO for enhancing iron chelation cancer therapy.
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http://dx.doi.org/10.1111/cas.14607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780030PMC
January 2021

Visualization of the electrophysiologically defined junction between the superior vena cava and right atrium.

J Cardiovasc Electrophysiol 2020 08 23;31(8):1964-1969. Epub 2020 Jun 23.

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.

Introduction: An electrical superior vena cava (SVC) isolation from the right atrium (RA) sometimes can be challenging. For a safe and efficient SVC isolation, we aimed to visualize the accurate position of the SVC-RA junction on a three-dimensional (3D) mapping system using the decremental conduction properties of the SVC-RA junction in patients with atrial fibrillation (AF).

Methods: This study consisted of 15 consecutive AF patients (11 males, age 59 ± 10 years). A 3D mapping catheter was positioned in the SVC-RA junction region while delivering a single extra-stimulus from the right atrial appendage (RAA), to discriminate the RA and SVC potentials. The electrophysiological SVC-RA junction was defined as the most proximal points where the SVC potentials were recorded, which were tagged on the 3D mapping system around the SVC-RA junction, where radiofrequency energy applications were applied.

Results: Around the SVC-RA junction, 9 ± 2 points were tagged on the 3D mapping system. The highest and lowest SVC-RA junction points were located on the anterior wall and posterior wall, respectively. The difference in the level between the highest and lowest SVC-RA junction points was 16.2 ± 6.3 mm. A successful SVC isolation was obtained in all patients without any complications.

Conclusion: The plane of the electrophysiologically defined SVC-RA junction was not perpendicular to the body axis, but slanted due to the anterior side being higher. Recognizing the precise location of the SVC-RA junction would contribute to a safe and efficacious SVC isolation.
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http://dx.doi.org/10.1111/jce.14613DOI Listing
August 2020

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

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

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

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

Polymeric modification of gemcitabine via cyclic acetal linkage for enhanced anticancer potency with negligible side effects.

Biomaterials 2020 03 22;235:119804. Epub 2020 Jan 22.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259, Nagatsuta, Midori-Ku, Yokohama, Kanagawa, 226-8503, Japan. Electronic address:

Gemcitabine (GEM) is a powerful anticancer drug for various cancers. However, the anticancer efficacy and the side effects should be addressed for effective therapeutics. To this end, we created a GEM-conjugated polymer (P-GEM) based on cyclic acetal linkage as a delivery carrier of GEM. The obtained P-GEM stably conjugated GEM at physiological pH (i.e., bloodstream), but released GEM in response to acidic environments such as endosome/lysosome. After systemic administration of P-GEM for mice bearing subcutaneous tumors, it achieved prolonged blood circulation and enhanced tumor accumulation relative to free GEM system. In addition, the polymer-drug conjugate structure of P-GEM realized effective distribution in the tumor tissues toward the induction of apoptosis in most areas of the tumor sites. Of note, the molecular design of P-GEM achieved minimal accumulation in normal tissues, resulting in negligible GEM-derived adverse effects (e.g., gastrointestinal toxicity and hematotoxicity). Ultimately, even four times smaller dose of P-GEM on a GEM basis realized comparable/higher tumor growth suppression effect for two distinct pancreatic tumor models, compared to free GEM system. The obtained results suggest the huge potential of the present design of GEM-conjugated polymer for anticancer therapeutics.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119804DOI Listing
March 2020

Ring-Fused Firefly Luciferins: Expanded Palette of Near-Infrared Emitting Bioluminescent Substrates.

Anal Chem 2020 03 4;92(6):4235-4243. Epub 2020 Feb 4.

Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.

Firefly bioluminescence is broadly applied as a noninvasive imaging modality in the biomedical research field. One limitation in firefly bioluminescence imaging is the limited variety of luciferins emitting in the near-infrared (NIR) region (650-900 nm), where tissue penetration is high. Herein, we describe a series of structure-inherent NIR emitting firefly luciferin analogues, , designed through a ring fusion strategy. This strategy resulted in pH-independent structure-inherent NIR emission with a native firefly luciferase, which was theoretically supported by quantum chemical calculations of the oxidized form of each luciferin. When applied to cells, displayed dose-independent improved NIR emission even at low concentrations where the native d-luciferin substrate does not emit. Additionally, excellent blood retention and brighter photon flux (7-fold overall, 16-fold in the NIR spectral range) than in the case of d-luciferin have been observed with one of the in mice bearing subcutaneous tumors. We believe that these synthetic luciferins provide a solution to the longstanding limitation in the variety of NIR emitting luciferins and pave the way to the further development of NIR bioluminescence imaging platforms.
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http://dx.doi.org/10.1021/acs.analchem.9b04562DOI Listing
March 2020

Comprehensive analysis of syndromic hearing loss patients in Japan.

Sci Rep 2019 08 19;9(1):11976. Epub 2019 Aug 19.

Department of Otorhinolaryngology - Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.
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http://dx.doi.org/10.1038/s41598-019-47141-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6700179PMC
August 2019

The Durability of Atrial Fibrillation Ablation Using an Oesophageal Temperature Cut-Off of 38°C.

Heart Lung Circ 2019 Jul 14;28(7):1050-1058. Epub 2018 Jun 14.

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.

Background: A lower cut-off of the oesophageal temperature (ET) during catheter ablation of atrial fibrillation (AF) should be safer, but its durability may become in question. We evaluated an ET cut-off of 38°C with an output of 25W on the posterior wall.

Methods: In 636 consecutive patients (age: 60±10years, male: 542, paroxysmal AF: 405, CHADS score: 0.7±0.9), an ET probe was utilised in 303 patients (259 pulmonary vein isolations [PVIs] and 44 simultaneous isolations of the posterior wall and all PVs box isolations [BOXIs]). When the ET increased to >38°C, the radiofrequency delivery was switched off and the ablation point was tagged as an "EsoTag" by the CARTO™ system (Biosense Webster, Irvine, CA, USA). We analysed the characteristics of the ablation lesions at the EsoTags with respect to the dormant conduction, gaps in the redo-session, and ablation outcome.

Results: EsoTags were identified in 94.6% of the left PVIs and all BOXIs, and dormant conduction at the EsoTags was identified in 12.0% and 6.8%, respectively. In 10,796 ablation points, the ablation at the EsoTags that were associated with dormant conduction had a significantly shorter duration, smaller force-time integral, and smaller Δimpedance. The duration of an ET of >38°C was significantly and positively correlated with the body mass index and negatively with the left atrial appendage flow velocity. During the redo-sessions in a 10.5±6.0months of follow-up (PVI: 14.7%, BOXI: 11.4%), reconnections at the EsoTags with dormant conduction were observed only in two patients after the PVI. The AF survival rate did not significantly differ in the presence of dormant conduction at the EsoTags (83.1% vs. 75.0%, p=0.696). There were no patients hospitalised for gastroparesis.

Conclusions: Atrial fibrillation ablation utilising an oesophageal temperature cut-off of 38°C might be safe and durable.
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http://dx.doi.org/10.1016/j.hlc.2018.05.197DOI Listing
July 2019

Sonodynamic Therapy With Anticancer Micelles and High-Intensity Focused Ultrasound in Treatment of Canine Cancer.

Front Pharmacol 2019 21;10:545. Epub 2019 May 21.

Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.

Sonodynamic therapy (SDT) is a minimally invasive anticancer therapy involving a chemical sonosensitizer and high-intensity focused ultrasound (HIFU). SDT enables the reduction of drug dose and HIFU irradiation power compared to those of conventional monotherapies. In our previous study, mouse models of colon and pancreatic cancer were used to confirm the effectiveness of SDT vs. drug-only or HIFU-only therapy. To validate its usefulness, we performed a clinical trial of SDT using an anticancer micelle (NC-6300) and our HIFU system in four pet dogs with spontaneous tumors, including chondrosarcoma, osteosarcoma, hepatocellular cancer, and prostate cancer. The fact that no adverse events were observed, suggests the usefulness of SDT.
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http://dx.doi.org/10.3389/fphar.2019.00545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536587PMC
May 2019

Pyruvate Responsiveness Based on α-Oxohydrazone Formation for Intracellular siRNA Release from Polyion Complex-Based Carriers.

Biomacromolecules 2019 06 23;20(6):2305-2314. Epub 2019 May 23.

Laboratory for Chemistry and Life Science, Institute of Innovative Research , Tokyo Institute of Technology , R1-11, 4259, Nagatsuta , Midori-Ku, Yokohama , Kanagawa 226-8503 , Japan.

Selective release of small interfering RNA (siRNA) payloads in response to intracellular substances is a prerequisite for the smart design of siRNA carriers. In this context, we developed a molecular program that allows reactivity with pyruvate for siRNA release in the cell on the basis of polyionic-complex- (PIC-) based siRNA carriers. Hydrazide can react with the α-keto acid structure of anionic pyruvate to form α-oxohydrazone, resulting in the reduction of the cationic net charge of the cationic polymer bearing a hydrazide moiety, which in turn leads to an inefficient electrostatic interaction with anionic siRNA and the consequent destabilization of the PIC (i.e., PGlu [DET/hydrazide]) in pyruvate-enriched environments, such as the cytoplasm, thus achieving effective siRNA release from the PIC and its associated gene-silencing activity. The present study provides the rationale for an α-oxohydrazone-formation-based smart design of pyruvate-responsive materials in the cell.
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http://dx.doi.org/10.1021/acs.biomac.9b00261DOI Listing
June 2019

In vivo rendezvous of small nucleic acid drugs with charge-matched block catiomers to target cancers.

Nat Commun 2019 04 24;10(1):1894. Epub 2019 Apr 24.

Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, 3-25-14 Tonomachi, Kawasaki-ku, Kawasaki, 210-0821, Japan.

Stabilisation of fragile oligonucleotides, typically small interfering RNA (siRNA), is one of the most critical issues for oligonucleotide therapeutics. Many previous studies encapsulated oligonucleotides into ~100-nm nanoparticles. However, such nanoparticles inevitably accumulate in liver and spleen. Further, some intractable cancers, e.g., tumours in pancreas and brain, have inherent barrier characteristics preventing the penetration of such nanoparticles into tumour microenvironments. Herein, we report an alternative approach to cancer-targeted oligonucleotide delivery using a Y-shaped block catiomer (YBC) with precisely regulated chain length. Notably, the number of positive charges in YBC is adjusted to match that of negative charges in each oligonucleotide strand (i.e., 20). The YBC rendezvouses with a single oligonucleotide in the bloodstream to generate a dynamic ion-pair, termed unit polyion complex (uPIC). Owing to both significant longevity in the bloodstream and appreciably small size (~18 nm), the uPIC efficiently delivers oligonucleotides into pancreatic tumour and brain tumour models, exerting significant antitumour activity.
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http://dx.doi.org/10.1038/s41467-019-09856-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482185PMC
April 2019

Asymptomatic Cerebral Infarction During Catheter Ablation for Atrial Fibrillation: Comparing Uninterrupted Rivaroxaban and Warfarin (ASCERTAIN).

JACC Clin Electrophysiol 2018 12 26;4(12):1598-1609. Epub 2018 Sep 26.

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan. Electronic address:

Objectives: This randomized study compared uninterrupted rivaroxaban therapy with warfarin therapy as prophylaxis against catheter ablation (CA)-induced asymptomatic cerebral infarction (ACI) and identified the risk factors of rivaroxaban.

Background: The reported incidence of ACI during CA for atrial fibrillation (AF) remains at 10% to 30%, and periprocedural oral anticoagulation could affect this incidence.

Methods: Patients with nonvalvular AF undergoing radiofrequency CA were randomly assigned to receive either uninterrupted rivaroxaban or warfarin as periprocedural anticoagulation therapy. CA was performed after at least 1 month of adequate anticoagulation. Cerebral magnetic resonance imaging (MRI) was performed within 2 weeks before and 1 day after CA to detect ACI.

Results: A total 132 patients were enrolled; 127 (median: 60.0 years of age; 83.5% males; 64.6% incidence of paroxysmal AF) complied with the study protocol and were analyzed; 64 patients received rivaroxaban, and 63 patients received warfarin. The rates of CA-induced ACI in the rivaroxaban group (15.6% [10 of 64 patients]) were similar to those in the warfarin group (15.9% [10 of 63 patients]; p = 1.000). No thromboembolic events developed; no differences in major or nonmajor bleeding rates were observed between the 2 drug groups (3.1% vs. 1.6%, respectively, or 18.8% vs. 19.0%, respectively). Multiple regression analysis indicated that the presence of deep and subcortical white matter hyperintensity (p = 0.002; odds ratio [OR]: 5.323) and the frequency of cardioversions (p = 0.016; OR: 1.250) were associated with the incidence of ACI.

Conclusions: No notable differences were found between the incidence of CA-induced ACI in the rivaroxaban group and that in the warfarin group in this randomized study.
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http://dx.doi.org/10.1016/j.jacep.2018.08.003DOI Listing
December 2018

Poly( N-isopropylacrylamide)-Based Polymer-Inducing Isothermal Hydrophilic-to-Hydrophobic Phase Transition via Detachment of Hydrophilic Acid-Labile Moiety.

Biomacromolecules 2019 04 2;20(4):1493-1504. Epub 2019 Jan 2.

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

The polymerization of N-isopropylacrylamide (NIPAAm) with ionizable monomers results in pH-responsive lower critical solution temperature (LCST) polymer which works in an ionization-dependent manner. However, gradual ionization of the comonomer occurs at a broad pH range due to the electrostatic field generated by the polymers, limiting the extent of LCST shift in response to pH change. Furthermore, excess introduction of comonomer may dull phase transition behavior. Here, we report the development of an ionization-independent LCST polymer that exerts a sharp isothermal hydrophilic-to-hydrophobic phase transition in response to slight pH change. Our polymer has a poly(NIPAAm/2-aminoisoprpylacrylamide (AIPAAm)) (P(NIPAAm/AIPAAm)) backbone that retains the continuous structural similarity of N-alkyl groups for preserving phase transition sensitivity, and primary amine for forming hydrophilic acid-labile 2-propionic-3-methylmaleic (PMM) amide linkage. The PMM moiety improves the polymer's hydrophilicity and drastically increases the LCST. Detachment of the PMM moiety in response to mild acidic condition (pH < 6.8) lowers the LCST to that of original P(NIPAAm/AIPAAm), permitting isothermal pH-responsive phase transition. Utilizing this mechanism, P(NIPAAm/AIPAAm) modified with PMM amide linkage exhibits a sharp hydrophilic-to-hydrophobic transition at a physiological temperature (37 °C) and, strikingly, facilitates interaction with cultured cells. Most importantly, our polymer showed significantly higher accumulation within a solid tumor after systemic injection compared to conventional PNIPAAm, which may be due to its phase transition responding to slightly acidic tumor microenvironment. Thus, this study provides a novel polymer that offers delicate control of LCST and pH-responsiveness suitable for use in even fuzzy biological environments.
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http://dx.doi.org/10.1021/acs.biomac.8b01465DOI Listing
April 2019

Epirubicin-loaded polymeric micelles effectively treat axillary lymph nodes metastasis of breast cancer through selective accumulation and pH-triggered drug release.

J Control Release 2018 12 2;292:130-140. Epub 2018 Nov 2.

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

Suppression of axillary lymph node metastasis (ALNM) is an important goal in the treatment of breast cancer. While several therapies directed to ALNM have been evaluated, effective and safe treatments for ALNM in triple negative breast cancer (TNBC) have not been established yet, especially against initial/small metastases. Here, we demonstrated the therapeutic effect of an anthracycline drug, epirubicin (EPI)-loaded polymeric micelles equipped with pH-triggered drug release property (EPI/m) against ALNM of TNBC. EPI/m effectively inhibited the spread of the primary tumor and the growth of ALNM, through selective accumulation and penetration in both primary tumor and vascularized ALNM, as well as efficient drug activation triggered by the intratumoral acidic environment. Furthermore, we revealed that the improvement of the activated drug distribution of EPI/m contributed to dose-dependent enhancement of the antitumor effect through expansion of the therapeutic window. These findings highlight the utility of pH-responsive property in EPI/m for the treatment of ALNM in TNBC.
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http://dx.doi.org/10.1016/j.jconrel.2018.10.035DOI Listing
December 2018

Poly(ethylene glycol)-poly(lysine) block copolymer-ubenimex conjugate targets aminopeptidase N and exerts an antitumor effect in hepatocellular carcinoma stem cells.

Oncogene 2019 01 8;38(2):244-260. Epub 2018 Aug 8.

Departments of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan.

Previous studies highlighted that aminopeptidase N (APN)/CD13 acts as a scavenger in the survival of hepatocellular carcinoma (HCC) stem cells by reducing reactive oxygen species (ROS) levels. Hence, it has been proposed that APN/CD13 inhibition can increase cellular ROS levels and sensitize cells to chemotherapeutic agents. Although ubenimex, also known as bestatin, competitively inhibits proteases such as APN/CD13 on the cellular membrane and it is clinically used for patients with acute myeloid leukemia and lymphedema, research has demonstrated that higher concentrations of the agent induce the death of APN/CD13 HCC stem cells. In this study, we developed a poly(ethylene glycol)-poly(lysine) block copolymer-ubenimex conjugate (PEG-b-PLys(Ube)) to increase the efficacy of reagents in APN/CD13 cancer stem cells. Exposure to PEG-b-PLys(Ube) increased the intracellular ROS concentration by inhibiting APN enzyme activity, permitting the induction of apoptosis and attenuation of HCC cell proliferation. In addition, PEG-b-PLys(Ube) exhibited a relatively stronger antitumor effect in mice than PEG-b-PLys alone or phosphate-buffered saline. Moreover, an isobologram analysis revealed that combinations of fluorouracil, cisplatin, or doxorubicin with PEG-b-PLys(Ube) exhibited synergistic effects. This study demonstrated that PEG-b-PLys(Ube) does not impair the properties of ubenimex and exerts a potent antitumor effect.
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http://dx.doi.org/10.1038/s41388-018-0406-xDOI Listing
January 2019

Effect of multiple cyclic RGD peptides on tumor accumulation and intratumoral distribution of IRDye 700DX-conjugated polymers.

Sci Rep 2018 05 25;8(1):8126. Epub 2018 May 25.

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

Strategic delivery of IRDye 700DX (photosensitizer) is a key for improving its effect in photodynamic therapy. In this study, we have synthesized IRDye 700DX-conjugated polymers containing multiple cyclic RGD peptides to deliver IRDye 700DX selectively to tumor cells and tumor-associated blood vessels overexpressing αβ integrin. Our polymer has a backbone of hydrophilic poly(ethylene glycol)-poly(L-glutamic acid) block copolymer, and cyclic RGD peptides are conjugated to side chains of the poly(L-glutamic acid) while IRDye 700DX is conjugated to the terminal of poly(ethylene glycol). The polymers exhibited selective accumulation to the target sites in a subcutaneous solid tumor, and the accumulation was augmented with the increased number of cyclic RGD peptides. More importantly, the polymer containing 15 cyclic RGD peptides in one construct revealed preferential accumulation on the tumor-associated blood vessels without compromising penetration to deep portions of the tumor, thereby drastically inhibiting tumor growth upon photoirradiation, while the polymer containing 5 cyclic RGD peptides showed moderate antitumor activity despite efficient accumulation in the tumor with almost homogenous intratumoral distribution. These results suggest that controlling the intratumoral distribution of IRDye 700DX is critical for successful PDT, and our polymer containing multiple cyclic RGD peptides may be a promising carrier for this spatial control.
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http://dx.doi.org/10.1038/s41598-018-26593-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5970177PMC
May 2018

Puncture of the Closed Coronary Sinus Ostium in a Patient With Coronary Sinus Atresia.

JACC Clin Electrophysiol 2017 Jun 1;3(6):640-642. Epub 2017 Mar 1.

Department of Cardiology, Keio University School of Medicine, Shinjukuku, Tokyo, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jacep.2016.12.013DOI Listing
June 2017

Prevalence and clinical characteristics of obstructive- and central-dominant sleep apnea in candidates of catheter ablation for atrial fibrillation in Japan.

Int J Cardiol 2018 06;260:99-102

Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.

Introduction: We aimed to study the prevalence and types of sleep apnea (SA) as well as their clinical characteristics in atrial fibrillation (AF) ablation candidates in Japan.

Methods: Before catheter ablation, 197 consecutive AF patients (age: 60 ± 9 years, body mass index; 25.0 ± 3.0) were evaluated with portable polygraphy. We compared the clinical characteristics, according to the severity of SA as well as its types, as defined by the presence of obstruction and the mixed vs. central apnea indices.

Results: The mean apnea-hypopnea index (AHI) was 17.7 ± 11.9, with 135 AF patients having an AHI ≥10 (68.5%). Patients with an AHI ≥10 had a significantly higher body mass index, plasma brain natriuretic peptide (BNP) level, prevalence of hypertension, and larger left atrial size. Among patients with an AHI ≥10, the incidence of obstructive-dominant SA was 60.9% and that of central-dominant SA was 7.6%. The prevalence of hypertension was significantly higher in obstructive-dominant SA patients (obstructive vs. central: 48.3% vs. 20.0%, P = 0.038). The obstructive apnea index correlated with plasma BNP level and age, but the central and mixed apnea indices did not.

Conclusions: The prevalence of SA was common in AF ablation candidates, even without an obesity epidemic, and the SA type was predominantly obstructive. Portable polygraphy was useful for detecting undiagnosed SA patients in AF ablation candidates.
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http://dx.doi.org/10.1016/j.ijcard.2018.01.103DOI Listing
June 2018

Design of drug delivery systems for physical energy-induced chemical surgery.

Biomaterials 2018 09 22;178:583-596. Epub 2018 Mar 22.

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

Physical energy-induced chemical surgery, a technique that induces antitumor effects by delivering a drug that exerts a therapeutic effect in response to physical energy and irradiating the diseased part with the corresponding physical energy, is a useful method to treat cancers with minimal systemic side effects. Among chemical surgery, photodynamic therapy (PDT) and neutron capture therapy (NCT) require a system that selectively delivers drugs to the diseased site. Although PDT and NCT have a similar concept, drug delivery systems (DDSs) for their purpose need different functions to solve the unique problems derived from the characteristics of respective physical energy. In this review, we will describe recent chemistry-based solutions including ours to overcome these challenges.
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http://dx.doi.org/10.1016/j.biomaterials.2018.03.038DOI Listing
September 2018

An Ethylenediamine-based Switch to Render the Polyzwitterion Cationic at Tumorous pH for Effective Tumor Accumulation of Coated Nanomaterials.

Angew Chem Int Ed Engl 2018 04 23;57(18):5057-5061. Epub 2018 Mar 23.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, R1-11, 4259, Nagatsuta, Midori-ku, Yokohama, Kanagawa, 226-8503, Japan.

Polyzwitterions are employed as coating polymers for biomaterials to induce an antifouling property on the surface. Fine-tuning the betaine structure switches the antifouling property to be interactive with anionic tissue constituents in response to a tumorous pH gradient. The ethylenediamine moiety in the carboxybetaine enabled stepwise protonation and initiated the di-protonation process around tumorous pH (6.5). The net charge of the developed polyzwitterion (PGlu(DET-Car)) was thus neutral at pH 7.4 for antifouling, but was cationic at pH 6.5 for interaction with anionic constituents. Quantum dots coated with PGlu(DET-Car) exhibited comparable stealth and enhanced tumor accumulation relative to the PEG system. The present study provides a novel design of smart switchable polyzwitterion based on a precise control of the net charge.
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http://dx.doi.org/10.1002/anie.201801641DOI Listing
April 2018
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