Cyclodextrin‐Based Macromolecular Systems as Cholesterol‐Mopping Therapeutic Agents in Niemann–Pick Disease Type C

Puglisi, Antonino; Yaǧcı, Yusuf

doi:10.1002/marc.201800557

Cited by 26 publications

(20 citation statements)

References 97 publications

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“…Such pH‐responsive polymers based on Schiff base linkage have been reported to be promising materials for biomedical applications. [ 38,39 ] PDMS is a biocompatible and nontoxic polymer [ 40 ] while PEG is an FDA‐approved and one of the most commonly investigated biocompatible polymers. [ 41,42 ] The complete synthetic scheme for the triblock copolymer is represented in Scheme 1.…”

Section: Resultsmentioning

confidence: 99%

pH‐Responsive Micelle‐Forming Amphiphilic Triblock Copolymers

Bener

Puglisi

Yaǧcı

2020

Macro Chemistry & Physics

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A novel pH‐responsive micellar nanoparticle based on poly(ethylene glycol)–polydimethylsiloxane–poly(ethylene glycol) triblock copolymer with benzoic imine linkage is reported. A new synthetic approach to produce the pH‐cleavable polymer that can self‐assemble into stable micellar nanoparticle is presented. Such nanoparticles are stable at physiological pH, but degrade at slightly acidic pH, making this system potentially suitable to exploit pH gradients in biological compartments. The precursors, intermediates, final polymers, and micellar nanoparticles are characterized in detail by various spectroscopic techniques, gel permeation chromatography, and particle size measurements.

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Section: Resultsmentioning

confidence: 99%

pH‐Responsive Micelle‐Forming Amphiphilic Triblock Copolymers

Bener

Puglisi

Yaǧcı

2020

Macro Chemistry & Physics

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“…Knockout or silencing the OSBPL2 gene inhibited AMPK activity and increased intracellular cholesterol and cholesterol ester synthesis ( Wang et al, 2019a ; Zhang et al, 2019 ). Imbalanced cholesterol homeostasis is implicated in the pathogenesis of multiple disorders, including cardiovascular, cerebrovascular, and central nervous system diseases ( Chistiakov et al, 2016 ; Xue-Shan et al, 2016 ; Puglisi and Yagci, 2019 ). Altered levels of cholesterol and certain oxysterols have been reported in the hippocampus of rats following kainic acid-induced epilepsy ( Ong et al, 2003 ; Heverin et al, 2012 ).…”

Section: Discussionmentioning

confidence: 99%

Proteomics for Studying the Effects of Ketogenic Diet Against Lithium Chloride/Pilocarpine Induced Epilepsy in Rats

et al. 2020

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The ketogenic diet (KD) demonstrates antiepileptogenic and neuroprotective efficacy, but the precise mechanisms are unclear. Here we explored the mechanism through systematic proteomics analysis of the lithium chloride-pilocarpine rat model. Sprague-Dawley rats (postnatal day 21, P21) were randomly divided into control (Ctr), seizure (SE), and KD treatment after seizure (SE + KD) groups. Tandem mass tag (TMT) labeling and liquid chromatography-tandem mass spectroscopy (LC-MS/MS) were utilized to assess changes in protein abundance in the hippocampus. A total of 5,564 proteins were identified, of which 110 showed a significant change in abundance between the SE and Ctr groups (18 upregulated and 92 downregulated), 278 between SE + KD and SE groups (218 upregulated and 60 downregulated), and 180 between Ctr and SE + KD groups (121 upregulated and 59 downregulated) (all p < 0.05). Seventy-nine proteins showing a significant change in abundance between SE and Ctr groups were reciprocally regulated in the SD + KD group compared to the SE group (i.e., the seizure-induced change was reversed by KD). Of these, five (dystrobrevin, centromere protein V, oxysterol-binding protein, tetraspanin-2, and progesterone receptor membrane component 2) were verified by parallel reaction monitoring. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis indicated that proteins of the synaptic vesicle cycle pathway were enriched both among proteins differing in abundance between SE and Ctr groups as well as between SE + KD and SE groups. This comprehensive proteomics analyze of KD-treated epilepsy by quantitative proteomics revealed novel molecular mechanisms of KD antiepileptogenic efficacy and potential treatment targets.

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“…However, there is no consensus on its mechanism of action [45] nor on the need to cross the BBB to display efficacy [46]. Recent reports indicate that increasing the molecular weight of CDs could represent a useful approach to improve the therapeutic outcome by prolonging the circulation time of these drugs [19]. On the other hand, increasing the molecular weight can also decrease the amount of drug reaching the brain due to the BBB [47].…”

Section: Discussionmentioning

confidence: 99%

Elucidating the mechanism of cyclodextrins in the treatment of Niemann-Pick Disease Type C using crosslinked 2-hydroxypropyl-β-cyclodextrin

Carradori

Chen

Werner

et al. 2020

Preprint

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Niemann-Pick Disease Type C (NPC) is a severe neurovisceral disorder that is pathophysiologically characterized by intracellular transport abnormalities leading to cytoplasmic accumulation of lipids such as cholesterol and multiple sphingolipids, including sphingosine. The compound 2-hydroxypropyl-β-cyclodextrin (HPβCD) is a compound with high cholesterol complexation capacity and is currently under clinical investigation for the treatment of NPC. However, due to its short blood half-life, high doses are required to produce a therapeutic effect. It has been reported in mice that HPβCD’s circulation time and efficacy can be improved by increasing its size via polymerization, but the biodegradable nature of these systems did not allow the contribution of the macromolecule to the activity to be determined. In this work, stable forms of polymerized HPβCD were generated (via epichlorohydrin crosslinking) to investigate their in vitro mechanisms of action and in vivo effects. Crosslinked CDs (8-312 kDa) displayed a 10-fold greater complexation capacity towards cholesterol than monomeric HPβCD but were taken up by cells to a lower extent (in a size-dependent fashion), resulting in an overall comparable in vitro effect on intracellular cholesterol accumulation that was dependent on cholesterol complexation. When tested in vivo, the crosslinked 19.3 kDa HPβCD exhibited a longer terminal half-life than the monomeric HPβCD. However, it did not increase the life span of Npc1 mice, possibly due to reduced organ penetration and brain diffusion consequence of its large molecular weight. This could be circumvented by the application of magnetic resonance imaging-guided low intensity-pulsed focused ultrasound (MRIg-FUS), which increased the brain penetration of the CD. In conclusion, stable forms of polymerized HPβCD constitute valuable tools to elucidate CDs’ mechanism of action. Moreover, the use of MRIg-FUS to maximize CDs tissue penetration warrants further investigation, as it may be key to harnessing CDs full therapeutic potential in the treatment of NPC.Graphical abstractThe 2-hydroxypropyl-β-cyclodextrin (HPβCD) is a well-established pharmaceutical excipient that can complex cholesterol and is currently under clinical investigation to treat Niemann-Pick Disease Type C (NPC). However, high doses of the drug are needed to achieve a therapeutic effect. Using stable and long circulating crosslinked HPβCDs, this study attempts to further understand the mechanisms behind CDs’ activity.

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Cyclodextrin‐Based Macromolecular Systems as Cholesterol‐Mopping Therapeutic Agents in Niemann–Pick Disease Type C

Cited by 26 publications

References 97 publications

pH‐Responsive Micelle‐Forming Amphiphilic Triblock Copolymers

pH‐Responsive Micelle‐Forming Amphiphilic Triblock Copolymers

Proteomics for Studying the Effects of Ketogenic Diet Against Lithium Chloride/Pilocarpine Induced Epilepsy in Rats

Elucidating the mechanism of cyclodextrins in the treatment of Niemann-Pick Disease Type C using crosslinked 2-hydroxypropyl-β-cyclodextrin

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