Papers - Seki Tomohiro
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Sugar-sensitive supramolecular structures based on phenylboronic acid-modified cyclodextrins Reviewed International journal
Kiminobu Nakamura, Tomohiro Seki, Yuya Egawa, Ryotaro Miki, Yoshiki Oda, Takashi Yamanoi, Toshinobu Seki
Chemical and Pharmaceutical Bulletin 61 ( 11 ) 1188 - 1191 2013
Language：English Publishing type：Research paper (scientific journal) Publisher：J-Stage
Supramolecular structures were developed from phenylboronic acid-modified cyclodextrins (PBA-CyDs). The intermolecular interaction between the PBA moiety and the CyD cavity was proved using 2D NMR and powder X-ray diffraction techniques. PBA-α-CyD formed a head-to-tail supramolecular polymer, whereas PBA-β-CyD formed a head-to-head dimer. The supramolecular structures were disintegrated in the presence of sugars owing to the resulting boronate sugar interactions.
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Sugar-responsive pseudopolyrotaxanes and their application in sugar-induced release of PEGylated insulin Reviewed
Tomohiro Seki, Keigo Abe, Kiminobu Nakamura, Yuya Egawa, Ryotaro Miki, Kazuhiko Juni, Toshinobu Seki
Journal of Inclusion Phenomena and Macrocyclic Chemistry 82 ( 3-4 ) 417 - 424 2015
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
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Sugar-Responsive Pseudopolyrotaxane Composed of Phenylboronic Acid-Modified Polyethylene Glycol and γ-Cyclodextrin Reviewed
Tomohiro Seki, Misato Namiki, Yuya Egawa, Ryotaro Miki, Kazuhiko Juni and Toshinobu Seki
Materials 8 ( 3 ) 1341 - 1349 2015
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
We have designed a sugar-responsive pseudopolyrotaxane (PPRX) by combining phenylboronic acid-modified polyethylene glycol (PBA-PEG) and γ-cyclodextrin. Phenylboronic acid (PBA) was used as a sugar-recognition motif in the PPRX because PBA reacts with a diol portion of the sugar molecule and forms a cyclic ester. When D-fructose or D-glucose was added to a suspension of PPRX, PPRX disintegrated, depending on the concentration of the sugars. Interestingly, catechol does not show a response although catechol has a high affinity for PBA. We analyzed the response mechanism of PPRX by considering equilibria.
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A Pseudopolyrotaxane for Glucose-Responsive Insulin Release: The Effect of Binding Ability and Spatial Arrangement of Phenylboronic Acid Group Reviewed
Tomohiro Seki, Keigo Abe, Yuya Egawa, Ryotaro Miki, Kazuhiko Juni, and Toshinobu Seki
Molecular Pharmaceutics 13 ( 11 ) 3807 - 3815 2016
Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)
A pseudopolyrotaxane (PPRX) comprising 3-carboxy-5-nitrophenylboronic acid modified γ-cyclodextrin (NPBA-γ-CyD) and naphthalene modified polyethylene glycol (Naph-PEG) as a sugar-responsive supramolecular structure is prepared. The binding of sugar by the NPBA group induced disintegration of the Naph-PEG/NPBA-γ-CyD PPRX, allowing the components to be dissolved. The Naph-PEG/NPBA-γ-CyD PPRX exhibited better sensitivity compared to that of a PPRX based on 4-carboxyphenylboronic acid modified γ-cyclodextrin (PBA-γ-CyD). We have previously reported the unique structure of Naph-PEG/PBA-γ-CyD PPRX, which formed an inclusion complex with a single-stranded PEG chain being threaded through the γ-CyD rings, with the remaining internal space being occupied by the sugar-sensing PBA moiety from a neighboring ring, thus shielding it from sugar molecules and reducing the sugar sensitivity of the PPRX. In contrast, structural analyses in this study revealed that the sugar-sensing NPBA moiety in the Naph-PEG/NPBA-γ-CyD PPRX is not included in the neighboring NPBA-γ-CyD. This spatial arrangement and the high affinity of NPBA for sugar contributed to the improved sugar responsivity. The enhanced NPBA-γ-CyD was then applied to a PPRX containing Naph-PEG-appended insulin (Naph-PEG-Ins) that showed an improved response for glucose-induced insulin release.
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A polyrotaxane gel using boronic acid-appended γ-cyclodextrin as a hybrid cross-linker Reviewed
Wataru Uchida, Maiki Yoshikawa, Tomohiro Seki, Ryotaro Miki, Toshinobu Seki, Takashi Fujihara, Yoshihiro Ishimaru, Yuya Egawa
Journal of Inclusion Phenomena and Macrocyclic Chemistry 89 ( 3-4 ) 281 - 288 2017
Language：English Publishing type：Research paper (scientific journal)
A boronic acid-appended γ-cyclodextrin (BA-CyD) was synthesized as a hybrid cross-linker of polyvinyl alcohol (PVA) to form a new type of hydrogel. The CyD moiety of BA-CyD forms an inclusion complex with the PVA chain to produce a mechanically interlocking structure. At the same time, the BA moiety of BA-CyD forms covalent bonds with the 1,3-diol moieties of PVA. On the basis of these two modes of interaction, the hybrid cross-linker connects two PVA chains, thus resulting in the formation of a hydrogel. To investigate the possibility of this hydrogel becoming the basis for an intelligent material for drug delivery, sugar-responsive drug release from the hydrogel was demonstrated.
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Polyol-responsive pseudopolyrotaxanes based on phenylboronic acid-modified polyethylene glycol and cyclodextrins Reviewed
Yu Kojima, Tomoyuki Okano, Tomohiro Seki, Misato Namiki, Yuya Egawa, Ryotaro Miki, Kazuhiko Juni, Toshinobu Seki
Journal of Inclusion Phenomena and Macrocyclic Chemistry 87 ( 3-4 ) 295 - 303 2017
Language：English Publishing type：Research paper (scientific journal)
Phenylboronic acid (PBA), which reacts with polyols to form cyclic esters, was attached to the amino terminal of polyethylene glycol (PEG) via amide bonds. PBA-PEG was used to prepare pseudopolyrotaxanes (pPRXs) by combining it with cyclodextrins (CyDs). In the case of α-CyD, a single stranded pPRX formed that disintegrated in the presence of catechol (CA), d-fructose (Fru), and d-glucose (Glc). The order of response was CA > Fru > Glc, which corresponds with the affinities between the PBA moiety and the polyols. In contrast, a pPRX using γ-CyD, which has a double-stranded structure, showed sugar-induced disintegration but did not show a response to CA. We explained these apparently curious responses of the pPRXs using a mechanism based on the penetrability of the polyol-bound PBA toward the cavities of the CyDs. The pPRXs, which are a class of molecular machine, show two selectivities; one is derived from polyol selectivity, and the other is based on the penetrability for CyDs.
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Sugar-Responsive Layer-by-Layer Film Composed of Phenylboronic Acid-Appended Insulin and Poly(vinyl alcohol) Reviewed
Chemical and Pharmaceutical Bulletin 66 ( 4 ) 368 - 374 2018
Language：English Publishing type：Research paper (scientific journal)
Previous studies have shown that reversible chemical bond formation between phenylboronic acid (PBA) and 1,3-diol can be utilized as the driving force for the preparation of layer-by-layer (LbL) films. The LbL films composed of a PBA-appended polymer and poly(vinyl alcohol) (PVA) disintegrated in the presence of sugar. This type of LbL films has been recognized as a promising approach for sugar-responsive drug release systems, but an issue preventing the practical application of LbL films is combining them with insulin. In this report, we have proposed a solution for this issue by using PBA-appended insulin as a component of the LbL film. We prepared two kinds of PBA-appended insulin derivatives and confirmed that they retained their hypoglycemic activity. The LbL films composed of PBA-appended insulin and PVA were successfully prepared through reversible chemical bond formation between the boronic acid moiety and the 1,3-diol of PVA. The LbL film disintegrated upon treatment with sugars. Based on the results presented herein, we discuss the suitability of the PBA moiety with respect to hypoglycemic activity, binding ability, and selectivity for D-glucose.
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Sugar-responsive smart materials based on phenylboronic acid and cyclodextrin Invited Reviewed
Yuya Egawa, Tomohiro Seki, Ryotaro Miki, Toshinobu Seki
Journal of Inclusion Phenomena and Macrocyclic Chemistry 94 ( 1-2 ) 1 - 10 2019
Language：English Publishing type：Research paper (scientific journal)
This review focuses on sugar-responsive materials based on phenylboronic acid (PBA) as a sugar-sensing motif and cyclodextrins (CyDs) as a basic skeleton of smart materials. PBA modified α-CyD (PBA-α-CyD) forms a supramolecular polymer through intermolecular interactions between PBA part and CyD cavity. Similarly, PBA-β-CyD forms a head-to-head dimer. Meanwhile, combining PBA-γ-CyD and polyethylene glycol (PEG) produces a molecular necklace. Additionally, combining PBA-modified PEG and native α-CyD or γ-CyD results in another type of molecular necklace. These supramolecular structures are obtained as powders, and their solubility increases in the presence of sugar. Besides the powder type, a unique gel is formed through crosslinking polyvinyl alcohol with PBA-triazole-γ-CyD (PBA-Tri-γ-CyD). This gel can contain model drug, and it shows sugar-responsive drug release. The sugar response of all of these smart materials can be explained by the concept of equilibrium. The smart materials are constructed with CyD-guest interactions. The CyD-guest equilibrium moves by a reaction between sugar and PBA moiety attached to the smart material. In these smart materials, sugar induces a dissociation in the CyD-guest interaction, and this dissociation results in sugar-induced disintegration of CyD-guest supramolecular structures.
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Cell Adhesive Character of Phenylboronic Acid-Modified Insulin and Its Potential as Long-Acting Insulin Reviewed
Yui Ohno, Momoko Kawakami, Tomohiro Seki, Ryotaro Miki, Toshinobu Seki and Yuya Egawa
Pharmaceuticals 12 ( 3 ) 121 2019
Language：English Publishing type：Research paper (scientific journal)
Phenylboronic acid (PBA) derivatives have attracted substantial attention owing to their unique character of forming dynamic covalent bonds with polyol compounds. Recent studies have shown interactions between PBA and sugar chains on the cell surface; they have interesting applications for sensors and drug delivery systems. In this study, we prepared phenylboronic acid-modified insulin (PBA-Ins) to evaluate its glucose-lowering activity and cell adhesiveness. In the case of intravenous injection, PBA-Ins showed longer glucose-lowering activity than native insulin. We hypothesized that this prolonged effect was the result of the interaction between the PBA moiety and sugar chains on the cell surface. Red blood cells (RBCs) were used as a cell model, and we confirmed PBA-Ins’s affinity for RBCs, which induced RBC agglutination. Interestingly, using an alternative PBA-Ins administration route markedly changed its glucose-lowering activity. Unlike the intravenous injection of PBA-Ins, the subcutaneous injection showed a small effect on glucose level, which indicated that a small amount of PBA-Ins was absorbed into the bloodstream. This suggested the importance of investigating the interaction between the PBA moiety and many types of cells, such as adipocytes, in subcutaneous tissues.
DOI： 10.3390/ph12030121
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Imaging of glucose metabolism by 13C-MRI distinguishes pancreatic cancer subtypes in mice Reviewed International journal
Shun Kishimoto, Jeffrey R Brender, Daniel R Crooks, Shingo Matsumoto, Tomohiro Seki, Nobu Oshima, Hellmut Merkle, Penghui Lin, Galen Reed, Albert P. Chen, Jan Henrik Ardenkjaer-Larsen, Jeeva Munasinghe, Keita Saito, Kazutoshi Yamamoto, Peter L. Choyke, James Mitchell, Andrew N. Lane, Teresa W.M. Fan, W. Marston Linehan, Murali C. Krishna
eLife 8 e46312 2019
Language：English Publishing type：Research paper (scientific journal)
Metabolic differences among and within tumors can be an important determinant in cancer treatment outcome. However, methods for determining these differences non-invasively in vivo is lacking. Using pancreatic ductal adenocarcinoma as a model, we demonstrate that tumor xenografts with a similar genetic background can be distinguished by their differing rates of the metabolism of 13C labeled glucose tracers, which can be imaged without hyperpolarization by using newly developed techniques for noise suppression. Using this method, cancer subtypes that appeared to have similar metabolic profiles based on steady state metabolic measurement can be distinguished from each other. The metabolic maps from 13C-glucose imaging localized lactate production and overall glucose metabolism to different regions of some tumors. Such tumor heterogeneity would not be not detectable in FDG-PET.
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Investigation of factors that cause insulin precipitation and/or amyloid formation in insulin formulations Reviewed International journal
Yui Ohno, Tomohiro Seki, Yu Kojima, Ryotaro Miki, Yuya Egawa, Osamu Hosoya, Keizo Kasono, Toshinobu Seki
Journal of Pharmaceutical Health Care and Sciences in press 2019
Authorship：Second author Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Nature
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Dynamic Imaging of Glucose and Lactate Metabolism by 13C-MRS without Hyperpolarization Reviewed
Brender JR, Kishimoto S, Merkle H, Reed G, Hurd RE, Chen AP, Ardenkjaer-Larsen JH, Munasinghe J, Saito K, Seki T, Oshima N, Yamamoto K, Choyke PL, Mitchell J, Krishna MC
Scientific Reorts 9 3410 2019
Language：English Publishing type：Research paper (scientific journal)
Metabolic reprogramming is one of the defining features of cancer and abnormal metabolism is associated with many other pathologies. Molecular imaging techniques capable of detecting such changes have become essential for cancer diagnosis, treatment planning, and surveillance. In particular, 18F-FDG (fluorodeoxyglucose) PET has emerged as an essential imaging modality for cancer because of its unique ability to detect a disturbed molecular pathway through measurements of glucose uptake. However, FDG-PET has limitations that restrict its usefulness in certain situations and the information gained is limited to glucose uptake only.13C magnetic resonance spectroscopy theoretically has certain advantages over FDG-PET, but its inherent low sensitivity has restricted its use mostly to single voxel measurements unless dissolution dynamic nuclear polarization (dDNP) is used to increase the signal, which brings additional complications for clinical use. We show here a new method of imaging glucose metabolism in vivo by MRI chemical shift imaging (CSI) experiments that relies on a simple, but robust and efficient, post-processing procedure by the higher dimensional analog of singular value decomposition, tensor decomposition. Using this procedure, we achieve an order of magnitude increase in signal to noise in both dDNP and non-hyperpolarized non-localized experiments without sacrificing accuracy. In CSI experiments an approximately 30-fold increase was observed, enough that the glucose to lactate conversion indicative of the Warburg effect can be imaged without hyper-polarization with a time resolution of 12s and an overall spatial resolution that compares favorably to 18F-FDG PET.
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Metabolic Reprogramming Associated with Aggressiveness Occurs in the G-CIMP-High Molecular Subtypes of IDH1mut Lower Grade Gliomas Reviewed
Ruiz-Rodado Victor, Tathiane M Malta, Tomohiro Seki, Adrian Lita, Tyrone Dowdy, Orieta Celiku, Alejandra Cavazos-Saldana, Aiguo Li, Yang Liu, Sue Han, Wei Zhang, Hua Song, Dionne Davis, Sunmin Lee, Jane B Trepel, Thais S Sabedot, Jeeva Munasinghe, Chunzhang Yang, Christel Herold-Mende, Mark R Gilbert, Murali Krishna Cherukuri, Houtan Noushmehr, Mioara Larion
Neuro-Oncology 2019.10
Language：English Publishing type：Research paper (scientific journal)
Background
Early detection of increased aggressiveness of brain tumors is a major challenge in the field of neuro-oncology because of the inability of traditional imaging to uncover it. IDH-mutant gliomas represent an ideal model system to study the molecular mechanisms associated with tumorigenicity because they appear indolent and non-glycolytic initially, but eventually a subset progresses towards secondary glioblastoma with a Warburg-like phenotype. The mechanisms and molecular features associated with this transformation are poorly understood.
Methods
We employed model systems for IDH1 mutant gliomas with different growth and proliferation rates in vivo and in vitro. We described the metabolome, transcriptome and epigenome of these models in order to understand the link between their metabolism and the tumor biology. To verify whether this metabolic reprogramming occurs in the clinic we analyzed TCGA data.
Results
We reveal that the aggressive glioma models have lost DNA methylation in the promoters of glycolytic enzymes, especially LDHA, and have increased mRNA and metabolite levels compared to the indolent model. We find that the acquisition of the high glycolytic phenotype occurs at the G-CIMP-high molecular subtype in patients and is associated with the worst outcome.
Conclusion
We propose very early monitoring of lactate levels as a biomarker of metabolic reprogramming and tumor aggressiveness. -
Molecular Imaging of the Tumor Microenvironment reveals the Relationship between Tumor Oxygenation, Glucose Uptake and Glycolysis in Pancreatic Ductal Adenocarcinoma. Reviewed International journal
Kazutoshi Yamamoto, Jeffery R Brender, Tomohiro Seki, Shun Kishimoto, Nobu Oshima, Rajani Choudhuri, Stephen S Adler, Elaine Jagoda, Keita Saito, Nallathamby Devasahayam, Peter L. Choyke, James B Mitchell and Murali C. Krishna
Cancer Research 2020.04
Language：English Publishing type：Research paper (scientific journal)
Molecular imaging approaches for metabolic and physiological imaging of tumors have become important for treatment planning and response monitoring. However, the relationship between the physiological and metabolic aspects of tumors is not fully understood. Here, we developed new hyperpolarized MRI and EPR imaging procedures that allow more direct assessment of tumor glycolysis and oxygenation status quantitatively. We investigated the spatial relationship between hypoxia, glucose uptake, and glycolysis in three human pancreatic ductal adenocarcinoma tumor xenografts with differing physiological and metabolic characteristics. At the bulk tumor level, there was a strong positive correlation between 18F-FDG PET and lactate production, while pO2 was inversely related to lactate production and 18F-FDG uptake. However, metabolism was not uniform throughout the tumors, and the whole tumor results masked different localizations that became apparent while imaging. 18F-FDG uptake negatively correlated with pO2 in the center of the tumor and positively correlated with pO2 on the periphery. In contrast to pO2 and 18F-FDG uptake, lactate dehydrogenase activity was distributed relatively evenly throughout the tumor. The heterogeneity revealed by each measure suggests a multimodal molecular imaging approach can improve tumor characterization, potentially leading to better prognostics in cancer treatment.
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Metabolic Landscape of a Genetically Engineered Mouse Model of IDH1 Mutant Glioma Reviewed International journal
Victor Ruiz-Rodado, Tomohiro Seki, Tyrone Dowdy, Adrian Lita, Meili Zhang, Sue Han, Chunzhang Yang, Murali K. Cherukuri, Mark R. Gilbert and Mioara Larion
Cancers 12 ( 6 ) 1633 2020.06
Language：English Publishing type：Research paper (scientific journal) Publisher：MDPI
Understanding the metabolic reprogramming of aggressive brain tumors has potential
applications for therapeutics as well as imaging biomarkers. However, little is known about the
nutrient requirements of isocitrate dehydrogenase 1 (IDH1) mutant gliomas. The IDH1 mutation
involves the acquisition of a neomorphic enzymatic activity which generates D-2-hydroxyglutarate
from α-ketoglutarate. In order to gain insight into the metabolism of these malignant brain tumors,
we conducted metabolic profiling of the orthotopic tumor and the contralateral regions for the
mouse model of IDH1 mutant glioma; as well as to examine the utilization of glucose and glutamine
in supplying major metabolic pathways such as glycolysis and tricarboxylic acid (TCA). We also
revealed that the main substrate of 2-hydroxyglutarate is glutamine in this model, and how this
re-routing impairs its utilization in the TCA. Our 13C tracing analysis, along with hyperpolarized
magnetic resonance experiments, revealed an active glycolytic pathway similar in both regions (tumor
and contralateral) of the brain. Therefore, we describe the reprogramming of the central carbon
metabolism associated with the IDH1 mutation in a genetically engineered mouse model which
reflects the tumor biology encountered in glioma patients. -
Real-Time insight into in vivo redox status utilizing hyperpolarized [1-13C] N-acetyl cysteine Reviewed
Kazutoshi Yamamoto, Ana Opina, Deepak Sail, Burchelle Blackman, Keita Saito, Jeffrey R. Brender, Ronja M. Malinowski, Tomohiro Seki, Nobu Oshima, Daniel R. Crooks, Shun Kishimoto, Yu Saida, Yasunori Otowa, Peter L. Choyke, Jan H. Ardenkjær-Larsen, James B. Mitchell, W. Marston Linehan, Rolf E. Swenson & Murali C. Krishna
Scientific Reports 11 12155 2021.06
Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Nature
Drastic sensitivity enhancement of dynamic nuclear polarization is becoming an increasingly critical methodology to monitor real-time metabolic and physiological information in chemistry, biochemistry, and biomedicine. However, the limited number of available hyperpolarized 13C probes, which can effectively interrogate crucial metabolic activities, remains one of the major bottlenecks in this growing field. Here, we demonstrate [1-13C] N-acetyl cysteine (NAC) as a novel probe for hyperpolarized 13C MRI to monitor glutathione redox chemistry, which plays a central part of metabolic chemistry and strongly influences various therapies. NAC forms a disulfide bond in the presence of reduced glutathione, which generates a spectroscopically detectable product that is separated from the main peak by a 1.5 ppm shift. In vivo hyperpolarized MRI in mice revealed that NAC was broadly distributed throughout the body including the brain. Its biochemical transformation in two human pancreatic tumor cells in vitro and as xenografts differed depending on the individual cellular biochemical profile and microenvironment in vivo. Hyperpolarized NAC can be a promising non-invasive biomarker to monitor in vivo redox status and can be potentially translatable to clinical diagnosis.
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Synthesis of [1-13C-5-12C]-alpha-ketoglutarate enables noninvasive detection of 2-hydroxyglutarate Reviewed
Natsuko Miura, Chandrasekhar Mushti, Deepak Sail, Jenna E. AbuSalim, Kazutoshi Yamamoto, Jeffrey R. Brender, Tomohiro Seki, Deyaa I. AbuSalim, Shingo Matsumoto, Kevin A. Camphausen, Murali C. Krishna, Rolf E. Swenson, Aparna H. Kesarwala
NMR in Biomedicine e4588 2021.07
Language：English Publishing type：Research paper (scientific journal) Publisher：Wiley Analytical Science
Isocitrate dehydrogenase 1 (IDH1) mutations that generate the oncometabolite 2-hydroxyglutarate (2-HG) from α-ketoglutarate (α-KG) have been identified in many types of tumors and are an important prognostic factor in gliomas. 2-HG production can be determined by hyperpolarized carbon-13 magnetic resonance spectroscopy (HP-13C-MRS) using [1-13C]-α-KG as a probe, but peak contamination from naturally occurring [5-13C]-α-KG overlaps with the [1-13C]-2-HG peak. Via a newly developed oxidative-Stetter reaction, [1-13C-5-12C]-α-KG was synthesized. α-KG metabolism was measured via HP-13C-MRS using [1-13C-5-12C]-α-KG as a probe. [1-13C-5-12C]-α-KG was synthesized in high yields, and successfully eliminated the signal from C5 of α-KG in the HP-13C-MRS spectra. In HCT116 IDH1 R132H cells, [1-13C-5-12C]-α-KG allowed for unimpeded detection of [1-13C]-2-HG. 12C-enrichment represents a novel method to circumvent spectral overlap, and [1-13C-5-12C]-α-KG shows promise as a probe to study IDH1 mutant tumors and α-KG metabolism.
DOI： 10.1002/nbm.4588
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Simple Esterification of [1-13C]-Alpha-Ketoglutarate Enhances Membrane Permeability and Allows for Noninvasive Tracing of Glutamate and Glutamine Production Reviewed International journal
Jenna E. AbuSalim, Kazutoshi Yamamoto, Natsuko Miura, Burchelle Blackman, Jeffrey R. Brender, Chandrasekhar Mushti, Tomohiro Seki, Kevin A. Camphausen, Rolf E. Swenson, Murali C. Krishna, and Aparna H. Kesarwala
ACS Chemical Biology 16 ( 11 ) 2144 - 2150 2021.09
Language：English Publishing type：Research paper (scientific journal) Publisher：ACS Publications
Alpha-ketoglutarate (α-KG) is a key metabolite and signaling molecule in cancer cells, but the low permeability of α-KG limits the study of α-KG mediated effects in vivo. Recently, cell-permeable monoester and diester α-KG derivatives have been synthesized for use in vivo, but many of these derivatives are not compatible for use in hyperpolarized carbon-13 nuclear magnetic resonance spectroscopy (HP-13C-MRS). HP-13C-MRS is a powerful technique that has been used to noninvasively trace labeled metabolites in real time. Here, we show that using diethyl-[1-13C]-α-KG as a probe in HP-13C-MRS allows for noninvasive tracing of α-KG metabolism in vivo.
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Structure-based relaxation analysis reveals C-terminal [1-13C]glycine-d2 in peptides has long spin-lattice relaxation time that is applicable to in vivo hyperpolarized magnetic resonance studies International coauthorship
Yohei Kondo, Yutaro Saito, Tomohiro Seki, Yoichi Takakusagi, Jumpei Morimoto, Hiroshi Nonaka, Koichiro Miyanishi, Wataru Mizukami, Makoto Negoro, Abdelazim Elsayed Elhelaly, Fuminori Hyodo, Masayuki Matsuo, Natarajan Raju, Rolf Swenson, Murali C. Krishna, Kazutoshi Yamamoto, and Shinsuke Sando
ChemRxiv (American Chemical Society (ACS) 2022.01
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Structure-guided design enables development of a hyperpolarized molecular probe for the detection of aminopeptidase N activity in vivo Reviewed
Yutaro Saito, Hiroyuki Yatabe, Iori Tamura, Yohei Kondo, Ryo Ishida, Tomohiro Seki, Keita Hiraga, Akihiro Eguchi, Yoichi Takakusagi, Keisuke Saito, Nobu Oshima, Hiroshi Ishikita, Kazutoshi Yamamoto, Murali C. Krishna, Shinsuke Sando
Science Advances 8 ( 13 ) 2022.03
Language：English Publishing type：Research paper (scientific journal)
Dynamic nuclear polarization (DNP) is a cutting-edge technique that markedly enhances the detection sensitivity of molecules using nuclear magnetic resonance (NMR)/magnetic resonance imaging (MRI). This methodology enables real-time imaging of dynamic metabolic status in vivo using MRI. To expand the targetable metabolic reactions, there is a demand for developing exogenous, i.e., artificially designed, DNP-NMR molecular probes; however, complying with the requirements of practical DNP-NMR molecular probes is challenging because of the lack of established design guidelines. Here, we report Ala-[1-13C]Gly-d2-NMe2 as a DNP-NMR molecular probe for in vivo detection of aminopeptidase N activity. We developed this probe rationally through precise structural investigation, calculation, biochemical assessment, and advanced molecular design to achieve rapid and detectable responses to enzyme activity in vivo. With the fabricated probe, we successfully detected enzymatic activity in vivo. This report presents a comprehensive approach for the development of artificially derived, practical DNP-NMR molecular probes through structure-guided molecular design.