Lactose-Appended Hydroxypropyl-β-Cyclodextrin Lowers Cholesterol Accumulation and Alleviates Motor Dysfunction in Niemann–Pick Type C Disease Model Mice

Nishida, Takumi; Yokoyama, Ryoma; Kubohira, Yuto; Maeda, Yuki; Tanaka, Takeo; Nakagata, Naomi; Takagi, Hiroki; Ishikura, Kandai; Yanagihara, K.; Misumi, Shogo; Ishitsuka, Yoichi; Kondo, Yuki; Irie, Tetsumi; Soga, Minami; Era, Takumi; Onodera, Risako; Higashi, Taishi; Motoyama, Keiichi

doi:10.1021/acsabm.2c00233

Cited by 6 publications

(3 citation statements)

References 48 publications

(92 reference statements)

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“…We further reported the safety advantages and favourable physicochemical properties of chemically pure, mono‐branched CD derivatives with α‐1,6‐linked maltosyl derivatives over HP‐β‐CD in NPC experimental models 21–23 . In another approach, we synthesized several drug delivery system‐based derivatives targeting affected organs to improve the bioavailability of highly excretable CDs 24,25 . Over the past two decades, clinical outcome data of HP‐β‐CD therapy for NPC and preclinical evidence for the therapeutic potential of alternative CD derivatives have been accumulating.…”

Section: Introductionmentioning

confidence: 99%

“… 21 , 22 , 23 In another approach, we synthesized several drug delivery system‐based derivatives targeting affected organs to improve the bioavailability of highly excretable CDs. 24 , 25 Over the past two decades, clinical outcome data of HP‐β‐CD therapy for NPC and preclinical evidence for the therapeutic potential of alternative CD derivatives have been accumulating. However, clinical translation has been hindered by the limited knowledge of the biophysical properties of CDs that affect their functions.…”

Section: Introductionmentioning

confidence: 99%

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Different solubilizing ability of cyclodextrin derivatives for cholesterol in Niemann–Pick disease type C treatment

Yamada,

Fukaura‐Nishizawa,

Nishiyama

et al. 2023

Clinical & Translational Med

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BackgroundNiemann–Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. Cyclodextrins (CDs), the most promising therapeutic candidates for NPC, but with concerns about ototoxicity, are cyclic oligosaccharides with dual functions of unesterified cholesterol (UC) shuttle and sink that catalytically enhance the bidirectional flux and net efflux of UC, respectively, between the cell membrane and the extracellular acceptors. However, the properties of CDs that regulate these functions and how they could be used to improve treatments for NPC are unclear.MethodsWe estimated CD–UC complexation for nine CD derivatives derived from native α‐, β‐, and γ‐CD with different cavity sizes, using solubility and molecular docking analyses. The stoichiometry and complexation ability of the resulting complexes were investigated in relation to the therapeutic effectiveness and toxicity of each CD derivative in NPC experimental models.FindingsWe found that shuttle and sink activities of CDs are dependent on cavity size‐dependent stoichiometry and substituent‐associated stability of CD–UC complexation. The ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking serving as shuttle and with their cytotoxicity associated with cellular UC efflux acting as sink, respectively, in NPC model cells. Notably, the ability of CD derivatives to form an inclusion complex with UC was responsible for not only efficacy but ototoxicity, while a representative derivative without this ability negligibly affected auditory function, underscoring its preventability.ConclusionsOur findings highlight the importance of strategies for optimizing the molecular structure of CDs to overcome this functional dilemma in the treatment of NPC.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Different solubilizing ability of cyclodextrin derivatives for cholesterol in Niemann–Pick disease type C treatment

Yamada,

Fukaura‐Nishizawa,

Nishiyama

et al. 2023

Clinical & Translational Med

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“…As hepatocytes specifically express asialoglycoprotein receptor (ASGR) at high levels, specific ligands for ASGR, such as N -acetyl- d- galactosamine (GalNAc), galactose, and lactose, have been utilized for targeted delivery to hepatocytes . Notably, the GalNAc-modified small interfering RNA (siRNA)-based drug, Givosiran, has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of hepatic porphyria. , Additionally, various GalNAc-modified siRNA drugs have been developed for the treatment of liver diseases, and clinical trials are currently ongoing. , Recently, β-CD derivatives modified with ASGR ligands (e.g., lactose) have been developed to improve cholesterol accumulation in the liver in NPC disease. − Accordingly, the modification of ASGR ligands is a promising methodology for liver-specific delivery of therapeutic molecules.…”

Section: Introductionmentioning

confidence: 99%

Exploring Receptor Binding Affinities and Hepatic Cell Association of N-Acetyl-d-Galactosamine-Modified β-Cyclodextrin-Based Polyrotaxanes for Liver-Targeted Therapies

2023

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Acid-degradable polyrotaxanes (PRXs) containing threading β-cyclodextrins (β-CDs) are promising candidates for therapeutic applications of β-CDs in metabolic diseases with cholesterol overload or imbalance. To improve cellular uptake specificity and efficiency of PRXs in hepatocytes, N-acetyl-Dgalactosamine (GalNAc)-modified PRXs were developed to facilitate asialoglycoprotein receptor (ASGR)-mediated endocytosis. Binding affinity studies revealed that the dissociation constant (K D ) values between recombinant ASGR and GalNAc-PRXs decreased with an increase in the number of modified GalNAc units. Additionally, the K D values for GalNAc-PRXs were smaller than those for GalNAc-modified β-CD and amylose, suggesting that the PRX backbone structure improves the binding affinity with ASGR. However, the intracellular uptake levels of GalNAc-PRXs in HepG2 cells increased with a decrease in the number of modified GalNAc units, which was opposite to the trend observed in the binding affinity study. We found that GalNAc-PRXs had a large number of GalNAc units localized in recycling endosomes, resulting in the low intracellular uptake. The cholesterol-reducing abilities of GalNAc-PRXs were assessed using cholesterol-overloaded HepG2 cells. GalNAc-PRXs with a small number of GalNAc units were demonstrated to show superior cholesterol-reducing effects compared to previously designed acid-degradable PRX and clinically tested β-CD derivatives. Thus, we conclude that GalNAc modification is a promising molecular design for the therapeutic application of β-CD-threaded PRXs in various metabolic diseases with cholesterol overload or imbalance in the liver.

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Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2021–2022

Harvey

2024

Mass Spectrometry Reviews

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The use of matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry for the analysis of carbohydrates and glycoconjugates is a well‐established technique and this review is the 12th update of the original article published in 1999 and brings coverage of the literature to the end of 2022. As with previous review, this review also includes a few papers that describe methods appropriate to analysis by MALDI, such as sample preparation, even though the ionization method is not MALDI. The review follows the same format as previous reviews. It is divided into three sections: (1) general aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, fragmentation, quantification and the use of computer software for structural identification. (2) Applications to various structural types such as oligo‐ and polysaccharides, glycoproteins, glycolipids, glycosides and biopharmaceuticals, and (3) other general areas such as medicine, industrial processes, natural products and glycan synthesis where MALDI is extensively used. Much of the material relating to applications is presented in tabular form. MALDI is still an ideal technique for carbohydrate analysis, particularly in its ability to produce single ions from each analyte and advancements in the technique and range of applications show little sign of diminishing.

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Lactose-Appended Hydroxypropyl-β-Cyclodextrin Lowers Cholesterol Accumulation and Alleviates Motor Dysfunction in Niemann–Pick Type C Disease Model Mice

Cited by 6 publications

References 48 publications

Different solubilizing ability of cyclodextrin derivatives for cholesterol in Niemann–Pick disease type C treatment

Different solubilizing ability of cyclodextrin derivatives for cholesterol in Niemann–Pick disease type C treatment

Exploring Receptor Binding Affinities and Hepatic Cell Association of N-Acetyl-d-Galactosamine-Modified β-Cyclodextrin-Based Polyrotaxanes for Liver-Targeted Therapies

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2021–2022

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