In Vitro and In Vivo Evaluation of 6-O-α-Maltosyl-β-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C

Yasmin, Nushrat; Ishitsuka, Yoichi; Fukaura, Madoka; Yamada, Yoshiki; Nakahara, Shuichi; Ishii, Akira; Kondo, Yuki; Tanaka, Takeo; Nakagata, Naomi; Motoyama, Keiichi; Higashi, Taishi; Okada, Yasuyo; Nishikawa, J; Ichikawa, Atsushi; Iohara, Daisuke; Hirayama, Fumitoshi; Higaki, Kazutaka; Ohno, Kousaku; Matsuo, Muneaki; Irie, Tetsumi

doi:10.3390/ijms20051152

Cited by 19 publications

(11 citation statements)

References 37 publications

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“…No other drug-related serious adverse events were observed [121]. New cyclodextrin derivatives like 6-O-α-Maltosyl-β-Cyclodextrin [122] or polyrotaxane-based delivery systems [123] are also developed to improve the efficacy of the treatment. Not just hydroxypropyl-β-cyclodextrin but also hydroxypropyl-γ-cyclodextrin can be efficient in case of cholesterol accumulation defect.…”

Section: Cyclodextrins Biological Barriers and The Significance Of Lmentioning

confidence: 99%

Cyclodextrins in Drug Delivery Systems and Their Effects on Biological Barriers

et al. 2019

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Cyclodextrins are widely used excipients, composed of glucopyranose units with a cyclic structure. One of their most important properties, is that their inner cavity is hydrophobic, while their surface is hydrophilic. This enables them for the complex formation with lipophilic molecules. They have several applications in the pharmaceutical field like solubility enhancers or the building blocks of larger drug delivery systems. On the other hand, they have numerous effects on cells or biological barriers. In this review the most important properties of cyclodextrins and cyclodextrin-based drug delivery systems are summarized with special focus on their biological activity.

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Section: Cyclodextrins Biological Barriers and The Significance Of Lmentioning

confidence: 99%

Cyclodextrins in Drug Delivery Systems and Their Effects on Biological Barriers

et al. 2019

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“…Chitotriosidase and lysosphingomyelin levels have also been found to be helpful in monitoring response to therapy [19]. Recent research is also on to find new therapeutic options for NPC, and one of the studied molecules is 6- O - α -maltosyl- β -cyclodextrin (G2- β -CD) in treatment of NPC1 disease [23]. Promising results have been demonstrated in NPC1 deficient mice models.…”

Section: Discussionmentioning

confidence: 99%

Niemann-Pick Disease: An Underdiagnosed Lysosomal Storage Disorder

Panigrahi

Dhanorkar

Suthar

et al. 2019

Case Reports in Genetics

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Lysosomal storage disorders (LSDs) collectively constitute a significant public health burden in developing countries. Commoner LSDs include Gaucher, Fabry, and Niemann-Pick disease (NPD), but many cases remain undiagnosed. With the high incidence of consanguineous marriages, South East Asian countries are expected to have high prevalence of these LSDs. Here we report 4 cases of NPD type A/B in 3 families presenting with hepatosplenomegaly and cytopenias including one family with two sibs having hypertension and mitral valve prolapse. The diagnosis of NPD was proven by mutation analysis with identification of novel mutations, including a novel 4 bp insertion mutation (C>CCTGG) in exon 2 of the SMPD1 gene. We also had two cases of NPD type C, confirmed on mutation analysis.

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“…β-cyclodextrin (1134 g/mol, β-CD) and 2-hydroxypropyl-β-cyclodextrin (1319.6 g/mol, HP-β-CD) were obtained from Jiangsu Fengyuan Biochemical Technology (Jiangsu, China) and Zhiyuan Biotechnology (Shandong, China), respectively. Sulfobutyl ether-β-cyclodextrin (SBE-β-CD) with an average degree of sulfobutyl substitution of 6.6 (mean molecular weight was 2176.8 g/mol) was obtained from Zhiyuan Biotechnology (Shandong, China), while 6-O-alpha-D-maltosyl-β-cyclodextrin (G 2 -β-CD), a mono-maltose substituted derivative with an exact molecular weight of 1458.47 g/mol, was purchased from Shanghai Aladdin Biochemical Technology (Shanghai, China) (Mohtar et al., 2017 ; Yasmin et al., 2019 ). Fraxinellone (Frax, purity > 98%) was obtained from Pufei De Biotech (Chengdu, China).…”

Section: Methodsmentioning

confidence: 99%

Rational formulation engineering of fraxinellone utilizing 6-O-α-D-maltosyl-β-cyclodextrin for enhanced oral bioavailability and hepatic fibrosis therapy

Feng

Yang

et al. 2021

Drug Delivery

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Although Fraxinellone (Frax) isolated from Dictamnus albus L. possessed excellent anti-hepatic fibrosis activity, oral administration of Frax suffered from the inefficient therapeutic outcome in vivo due to negligible oral absorption. At present, the oral formulation of Frax is rarely exploited. For rational formulation design, we evaluated preabsorption risks of Frax and found that Frax was rather stable while poorly dissolved in the gastrointestinal tract (78.88 μg/mL), which predominantly limited its oral absorption. Further solubility test revealed the outstanding capacity of cyclodextrin derivatives (CDs) to solubilize Frax (6.8–12.8 mg/mL). This led us to study the inclusion complexes of Frax with a series of CDs and holistically explore their drug delivery performance. Characterization techniques involving 1 H-NMR, FT-IR, DSC, PXRD, and molecular docking confirmed the most stable binding interactions when Frax complexed with 6-O-α-D-maltosyl-β-cyclodextrin (G 2 -β-CD-Frax). Notably, G 2 -β-CD-Frax exhibited the highest solubilizing capacity, fast dissolution rate, and superior Caco-2 cell internalization with no obvious toxicity. Pharmacokinetic studies demonstrated markedly higher oral bioavailability of G 2 -β-CD-Frax (5.8-fold that of free drug) than other Frax-CDs. Further, long-term administration of G 2 -β-CD-Frax (5 mg/kg) efficiently inhibited CCl 4 -induced hepatic fibrosis in the mouse without inducing any toxicity. Our results will inspire the continued advancement of optimal oral Frax formulations for anti-fibrotic therapy.

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In Vitro and In Vivo Evaluation of 6-O-α-Maltosyl-β-Cyclodextrin as a Potential Therapeutic Agent Against Niemann-Pick Disease Type C

Cited by 19 publications

References 37 publications

Cyclodextrins in Drug Delivery Systems and Their Effects on Biological Barriers

Cyclodextrins in Drug Delivery Systems and Their Effects on Biological Barriers

Niemann-Pick Disease: An Underdiagnosed Lysosomal Storage Disorder

Rational formulation engineering of fraxinellone utilizing 6-O-α-D-maltosyl-β-cyclodextrin for enhanced oral bioavailability and hepatic fibrosis therapy

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