Chemical and Pharmaceutical Bulletin
Online ISSN : 1347-5223
Print ISSN : 0009-2363
ISSN-L : 0009-2363
Current issue
Displaying 1-16 of 16 articles from this issue
Current Topics - New Modalities and Strategies in Drug Delivery and Discovery
  • Tatsuhiro Ishida, Kentaro Kogure, Masanori Tachikawa, Kazuhiko Baba
    2022 Volume 70 Issue 5 Pages 309
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Editor's pick

    The authors had held a symposium, “New modalities and strategies in drug delivery and discovery”, in the 36th Annual Meeting of the Academy of Pharmaceutical Science and Technology, Japan (APSTJ) in Tokushima (online), Japan, 2021. In the symposium, the active young researchers from the Graduate School of Biomedical Sciences of Tokushima University presented various topics on their own researches. This Current Topics accumulated the review articles from the invited speakers of the symposium. These reviews will provide a wide range of intimate information regarding new modalities and strategies in drug delivery and discovery.

Current Topics: Reviews
  • Noriko Saito-Tarashima, Akiho Murai, Noriaki Minakawa
    2022 Volume 70 Issue 5 Pages 310-315
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    DNA and RNA are ubiquitous molecules responsible for storage and transmission of genetic information and together comprise the central dogma of molecular biology. However, the recent emergence of synthetic genetic polymers is providing an opportunity to challenge the fundamental principles of life. Herein, we describe the ongoing attempts to rewrite the central dogma with 4′-thioDNA and 4′-thioRNA, which feature a sulfur instead of an oxygen atom in the furanose ring moiety. Using reconstituted Escherichia coli gene expression machinery, studies have shown that the genetic information conserved in 4′-thioDNA can be transcribed to 4′-thioRNA and eventually translated into protein, mirroring the processes that occur in nature. Such studies underscore the feasibility of controlling life by substances other than DNA and RNA.

  • Masaya Denda, Akira Otaka
    2022 Volume 70 Issue 5 Pages 316-323
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    The growing interest in artificial proteins modified by synthetic functional units has fueled the demand for their facile preparation. Native chemical ligation (NCL) enables the chemoselective condensation of peptide thioesters with a cysteine-installed synthetic partner and has enjoyed great success in the production of artificial proteins with up to 100–150 residues. A practical method for converting expressed proteins to the corresponding thioesters should lead to significant progress in the NCL-mediated technology. This account describes our recent contributions to the conversion of naturally occurring peptides to the corresponding thioesters by chemical or chemoenzymatic protocols aiming at their future prevalent use in the preparation of sophisticated protein biologics.

  • Mai Inagaki, Masanori Tachikawa
    2022 Volume 70 Issue 5 Pages 324-329
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    The placenta, a unique organ that helps maintain a healthy pregnancy, plays a pivotal role in maternal adaptation to pregnancy and releases extracellular vesicles (EVs), autacoids, and hormones. EVs are membranous vesicles released by all types of cells, including placental trophoblasts, which are involved in intracellular communication by delivering their cargo, such as proteins, nucleic acids, and lipids, to the targeted cells in a neighboring or distant location. Recently, an increasing number of publications have reported that EVs secreted from the placenta into maternal circulation deliver their cargo to maternal organs and mediate placenta-to-maternal communication during pregnancy. This review provides an overview of the transport mechanism of placenta-derived EVs to maternal organs.

  • Yu Ishima, Toru Maruyama, Masaki Otagiri, Victor T. G. Chuang, Tatsuhi ...
    2022 Volume 70 Issue 5 Pages 330-333
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Albumin, the most abundant protein in human serum, is applied to various diseases as a drug delivery carrier because of its superior blood retention, high biocompatibility, and a wide variety of drug binding abilities. Albumin is known to distribute widely in the blood and various interstitial fluids and organs. Different albumin receptors skillfully regulate the distribution characteristics of albumin in the body. Albumin receptors are a group of diverse proteins, such as FcRn, gp60, gp18, megalin, cubilin, SPARC, and CD36. Their tissue distributions in vivo are unique, with different albumin’s recognition sites. Therefore, the distribution of albumin in vivo is ingeniously controlled by these multiple albumin receptors. Reevaluation of these albumin receptors opens up new possibilities for applying albumin as a drug delivery carrier. If the tissue distributions of albumin receptors were known and the albumin recognition site of the receptor was identified, organ-specific active targeting would be possible. In this review, we would like to scrutinize what is currently known and share information to develop next-generation albumin carriers that focus on interactions with albumin receptors.

  • Tatsuya Fukuta, Kentaro Kogure
    2022 Volume 70 Issue 5 Pages 334-340
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Targeted drug delivery using nanoparticles has been applied for the treatment of diverse diseases, including cancer and inflammatory diseases. Nanoparticle-mediated delivery of therapeutic agents via the enhanced permeability and retention effect generally augments their therapeutic efficiency; however, limitations with passive entry of nanoparticles into diseased sites, due to the presence of biological barriers represented by the endothelial layer, remain to be addressed. To this end, development of nanoparticles with intrinsic characteristics similar to circulatory cells (e.g., leukocytes, platelets) for use as biomimetic drug delivery systems (DDS) has been focused as a means to overcome the issues of conventional DDS. In particular, synthetic biomimetic nanoparticles coated with cellular membranes were recently prepared and shown to actively overcome the inflamed vessels and tumor microenvironment as a result of the functionality of membrane proteins, which allowed secure drug delivery into diseased sites. We recently developed liposomes modified with leukocyte membrane proteins via intermembrane protein transfer, a simple method to reconstitute cellular membrane proteins onto lipid bilayers. The resultant liposomes demonstrated the ability to cross the inflamed endothelial layer and permeate into tumor tissue by mimicking the properties of leukocytes. Thus, biomimetic DDS offer promise as new therapeutic approaches for various diseases by overcoming biological barriers that typically inhibit drug delivery. Herein, we review recent approaches to develop biomimetic DDS using the cell membrane coating method, and highlight our recent findings on leukocyte-mimetic liposomes prepared via intermembrane protein transfer.

  • Taro Shimizu, Yoshino Kawaguchi, Hidenori Ando, Yu Ishima, Tatsuhiro I ...
    2022 Volume 70 Issue 5 Pages 341-350
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Vaccines have contributed to the prevention of infectious diseases for a long time. Pathogen-derived antigens and adjuvants in vaccine formulations stimulate immune cells to elicit humoral and cellular immune responses against pathogens. Achieving highly immune responses with decreased adverse effects requires the development of a system that can deliver antigens to specific immune cells. Dendritic cells (DCs) are well-known professional antigen presenting cells (APCs) that initiate acquired immune responses by presenting antigens to T cells. Accordingly, DC-targeted vaccines have been investigated and applied in clinical trials for the treatment of infectious diseases and for chronic diseases such as cancers. In addition to DCs, B lymphocytes are regarded as professional APCs despite their primary role in humoral immunity. Therefore, B cell-targeted vaccines are also expected to elicit both humoral and cellular immune responses. In this review we summarize the basic functions of DCs and B cells as APCs. We also provide information on DC and B cell targeted vaccines in preclinical and clinical settings. Finally, we introduce our novel antigen delivery system that targets splenic marginal zone B cells and the ability of this system to act as a novel vaccine that elicits both humoral and cellular immune responses.

  • Nana Cristina Amorim Matsuo, Hidenori Ando, Yusuke Doi, Taro Shimizu, ...
    2022 Volume 70 Issue 5 Pages 351-358
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Oxaliplatin (l-OHP) is a third-generation platinum (Pt) agent approved for the treatment of patients with advanced colorectal cancer. Despite the fact that l-OHP has shown clinical therapeutic efficacy and better tolerability compared with other Pt agents, the use of l-OHP has been limited to clinical settings because of dose-limiting side effects such as cumulative neurotoxicity and acute dysesthesias, which can be severe. In preclinical and clinical studies, our group and several others have attempted the delivery of l-OHP to solid tumors via encapsulation in PEGylated liposomes. Herein, we review these attempts.

Communication to the Editor
  • Yusuke Kuroda
    2022 Volume 70 Issue 5 Pages 359-361
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Supplementary material

    Despite the long history of the ene reaction between 1,2,4-triazoline-3,5-diones (TADs) and alkenes, its efficiency has always been hampered by competing side reactions, including the overreaction of ene adducts. In this communication, we demonstrate that this inherent limitation can be overcome by using 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as the solvent. HFIP uniquely facilitates the desired azo–ene process between alkene with TADs presumably through hydrogen-bonding interactions. In addition to TADs, diethyl azodicarboxylate is a competent azo compound that undergoes a sluggish ene reaction with terminal alkenes.

Regular Articles
  • Shingo Yamaguchi, Shouichi Hosaka, Kayo Sugaya, Yuji Tokunaga, Shouji ...
    2022 Volume 70 Issue 5 Pages 362-368
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    We prepared two kinds of fine particles by treating lactose monohydrate (Lac) with the same formulation in a fluidized-bed granulator, which differed in the spraying air pressure. Raman intensities of treated Lac during processing were measured using a handheld-type Raman spectrometer and plotted against particle size. As particle size increased, Raman intensity decreased in both operating conditions. A linear relationship between them was observed, and regression lines were obtained with good correlation coefficients as calibration curves in both operating conditions. We also prepared two other types of fine particles by treating Lac with the same formulation in a fluidized-bed granulator, which differed in the scale or processing mechanism. The particle size could be successfully predicted using the calibration curve obtained taking powder porosity into consideration. Based on this study, we present a new at-line approach in process analytical technology to monitor and predict particle size using a handheld-type Raman spectrometer.

    Editor's pick

    Particle size-monitoring method using a handheld-type Raman spectrometer is proposed in this study. Two types of fine particles with the same formulation under different operating conditions were prepared for calibration purposes. There was a relationship between particle size and Raman intensity during processing and calibration curves could be obtained in both operating conditions. Two other types of fine particles with the same formulation, but on different scales or using different processing mechanisms were also prepared for verification purposes. The particle size could be successfully predicted using the calibration curve obtained taking powder porosity into consideration.

  • Yang Li, LingLing Li, Wenjie Yang, Zengli Yu
    2022 Volume 70 Issue 5 Pages 369-374
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
    Advance online publication: February 26, 2022
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    As an essential metal, zinc is central to insulin biosynthesis and energy metabolism. Zinc can not only maintain the activity of insulin, but also has insulin-like effect. When zinc is sufficient, the body needs less insulin. Zinc can correct abnormal glucose tolerance and even replace insulin to improve glucose metabolism disorder in diabetic rats. However, the effect of paternal zinc deficiency on glucose metabolism of offspring is still unclear. In the present study, sixteen 8-week-old male mice were randomly allocated into low-zinc group and control group (8 mice in each group), which were fed with low zinc and standard diet for 6 weeks, respectively. The mice were mated with female mice fed with standard diet to get the first generation of mice (F1) to explore the effect zinc deficiency on the glucose metabolism of offspring. Glucose tolerance, insulin sensitivity and insulin secretion in mice were determined by oral glucose tolerance test (OGTT), insulin tolerance test (ITT) and glucose stimulated insulin secretion test (GSIS), respectively. Compared with the control group, the fasting blood glucose levels of F1 generation male mice in the low zinc group increased at 15 and 30 min after glucose injection. The blood glucose of F1 generation male mice in the low zinc group of mice decreased at 60, 90, 120, 180, 240 min after insulin injection. Compared with the control group, serum insulin of F1 generation male mice in the low zinc group decreased at 15 min after glucose injection (all p values <0.05). However F1 female mice in the low zinc group did not show abnormal glucose metabolism. Marginal zinc deficiency in male mice can cause abnormal glucose homeostasis in male offspring, but not in female offspring.

  • Seiya Ohki, Miyu Kunimatsu, Shingo Ogawa, Hiroki Takano, Tomomi Furiha ...
    2022 Volume 70 Issue 5 Pages 375-382
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Supplementary material

    Evaluation of endogenous melatonin (MEL) secretion using its urinary metabolites is useful for the treatment of circadian rhythm sleep disorders. The primary melatonin metabolites excreted in the urine are 6-hydroxymelatonin (6-O-MEL) sulfate (S-O-MEL) and 6-O-MEL glucuronate, which result from sequential MEL metabolism by phases I and II drug metabolizing enzymes. To determine the accurate MEL secretion level, these urinary metabolites should be enzymatically deconjugated and converted into MEL. Furthermore, the use of LC–tandem mass spectrometry (LC–MS/MS) is preferable for the precision of this determination. Therefore, as part of our ongoing efforts to ultimately determine the level of MEL secretion, we herein aimed to develop an LC–MS/MS-based quantification method for 6-O-MEL and optimize deconjugation conditions. We determined the LC–MS/MS conditions of 6-O-MEL measurement and optimized the conditions of enzymatic reactions. The most efficient S-O-MEL deconjugation (102.1%) was achieved with Roche Glucuronidase/Arylsulfatase (from Helix pomatia) at 37 °C, pH-4.0 reaction buffer, and 60 min of reaction time. For human urine samples, the minimum amount of the enzyme required was 5944 units. Under these conditions, the accuracy and precision values of the 6-O-MEL determination (relative errors and standard deviation) were −3.60–−0.47% and <6.80%, respectively. Finally, we analyzed the total amount of MEL metabolites excreted in 24-h urine samples; it was 6.70–11.28 µg in three subjects, which is comparable with the values reported till date. Thus, we have established a new method of measuring the total 6-O-MEL in human urine samples using an LC–MS/MS coupled with the prerequisite deconjugation reaction.

  • Kazuki Ohshima, Shuji Ohsaki, Hideya Nakamura, Satoru Watano
    2022 Volume 70 Issue 5 Pages 383-390
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Numerous efforts have been devoted to improving the solubility of poorly water-soluble drugs. Recently, it was reported that the use of metal-organic frameworks (MOFs), which are a new class of porous materials consisting of metal ions and organic ligands, is effective in improving the solubility of poorly water-soluble drugs. Our previous study demonstrated an improvement in the solubility of indomethacin (IDM) triggered by the zeolitic imidazolate framework-8 (ZIF-8). The present study aimed to elucidate the solubilization mechanism using the ZIF series, namely, ZIF-8, ZIF-67, and ZIF-L. It was confirmed that the solubility of ZIF-trapped IDM and ibuprofen (IBU) was enhanced compared to the raw drugs, regardless of the ZIF type. This study focused on 2-methylimidazole (2-MIM), which is commonly used as a ZIF organic ligand. Both IDM and IBU were easily dissolved by the addition of 2-MIM, suggesting that the presence of 2-MIM enhanced the solubility of the drugs. Inductively coupled plasma measurements also confirmed the presence of metal ions of ZIFs in the supernatant solution after the drug release tests, indicating the decomposition of ZIFs during drug release. The findings of this study demonstrated the solubilization mechanism of poorly water-soluble drugs using ZIF particles. We observed that the drugs loaded on the ZIFs were released simultaneously with the decomposition of some of the ZIFs. The 2-MIM molecules were also released concurrently. The presence of 2-MIM improved the solubility of poorly water-soluble drugs.

    Editor's pick

    The authors elucidated the mechanism of solubilization of poorly water-soluble drugs using zeolitic imidazolate frameworks (ZIFs), a member of metal-organic frameworks. The solubility of ZIF-trapped drugs was enhanced compared to the raw drugs. The authors focused on 2-methylimidazole (2-MIM), used as an organic ligand in ZIFs. Drugs were easily dissolved by the addition of 2-MIM, suggesting that the presence of 2-MIM enhanced the drug solubility. The findings of this study demonstrated the solubilization mechanism of poorly water-soluble drugs using ZIFs. ZIFs are expected to be used as drug carriers to maximize the bioavailability of poorly water-soluble drugs.

  • Kengo Kasama, Yuya Hinami, Karin Mizuno, Satoshi Horino, Tomoya Nishio ...
    2022 Volume 70 Issue 5 Pages 391-399
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Supplementary material

    The highly enantioselective lipase-catalyzed kinetic resolution (KR) of racemic C1-symmetric biaryl compounds including heterocyclic moieties, such as carbazole and dibenzofuran, has been achieved for the first time. This enzymatic esterification was accelerated by the addition of disodium carbonate while maintaining its high enantioselectivities, and was particularly effective for biaryls having N-substituted carbazole moieties. Furthermore, mesoporous silica-supported oxovanadium-catalyzed cross-dehydrogenative coupling of 3-hydroxycarbazole and 2-naphthol was followed by the lipase-catalyzed KR in one-pot to synthesize the optically active heterocyclic biaryl compounds with high optical purity.

    Editor's pick

    The highly enantioselective lipase-catalyzed kinetic resolution (KR) of racemic C1-symmetric biaryl compounds including heterocyclic moieties, such as carbazole and dibenzofuran, has been achieved for the first time. This enzymatic esterification was accelerated by the addition of disodium carbonate while maintaining its high enantioselectivities (up to 99% ee), and was particularly effective for biaryls having N-substituted carbazole moieties. Furthermore, mesoporous silica-supported oxovanadium-catalyzed cross-dehydrogenative coupling of 3-hydroxycarbazole and 2-naphthol was followed by the lipase-catalyzed KR in one-pot to synthesize the optically active heterocyclic biaryl compounds with high optical purity.

  • Fumihiko Ogata, Noriaki Nagai, Mamiko Funaki, Ayako Tabuchi, Yuhei Kob ...
    2022 Volume 70 Issue 5 Pages 400-407
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Coal fly ash (FA) was treated by hydrothermal activation with sodium hydroxide solution at different concentrations to optimize the conversion method. Zeolite of the sodium type is prepared from coal FA by 1, 1.5, and 3 mol/L sodium hydroxide solutions (ZE1, ZE1.5, and ZE3). These adsorbents’ morphology, crystal structure, scanning electron microscopy, Fourier transform (FT)-IR spectra, cation exchange capacity (CEC), specific surface area and pore volumes, and pHpzc were determined. An adsorption experiment was performed to evaluate the effects of contact time, pH, temperature, and coexistence. From the results, the values of CEC and specific surface area of prepared samples was in the order ZE3 < ZE1.5 < ZE1. The similar trends were observed in lead ions adsorption. In addition, our obtained data elucidate that the ion exchange with sodium ions in the interlayer ZE1 is one of the adsorption mechanisms of Pb2+ from water layer. Finally, lead ions adsorbed on ZE1 could be desorbed using a hydrochloric acid solution, showing that ZE1 could be reused as a water purification agent.

Note
  • Le Thi Vien, Tran Thi Hong Hanh, Tran Hong Quang, Do Cong Thung, Nguye ...
    2022 Volume 70 Issue 5 Pages 408-412
    Published: May 01, 2022
    Released on J-STAGE: May 01, 2022
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    Supplementary material

    Three new sulfated naphthopyrone derivatives namely delicapyrons F–H (13) and two new sulfated anthraquinone derivatives namely delicaquinons A (4) and B (5), together with 6-methoxycomaparvin-5-methylether-8-O-sodium sulfate (6), 6-methoxycomaparvin-8-O-sodium sulfate (7), comaparvin-8-O-sodium sulfate (8), and 3-propyl-1,6,8-trihydroxy-9,10-anthraquinone-6-O-sodium sulfate (9) were isolated from the Vietnamese crinoid Comanthus delicata. Their chemical structures were elucidated by extensive analysis of the one dimensional (1D) and 2D-NMR, high resolution electrospray ionization quadrupole time-of-flight (HR-ESI-QTOF) mass spectra as well as calculation of optical rotation. In addition, significant cytotoxicity was observed for 6 against LNCaP (prostate cancer) cell line with IC50 value of 20.29 ± 2.43 µM, whereas moderate or weak cytotoxic effects were observed for 13 and 58 on SK-Mel-2 (melanoma) cell line and 7 and 8 against LNCaP cell line, with IC50 values ranging from 49.96 ± 1.74 to 76.92 ± 5.85 µM.

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