Synthesis of the anionic hydroxypropyl-β-cyclodextrin:poly(decamethylenephosphate) polyrotaxane and evaluation of its cholesterol efflux potential in Niemann–Pick C1 cells

Egele, Kerstin; Samaddar, Shayak; Schneider, Nina; Thompson, David H.; Wenz, Gerhard

doi:10.1039/c8tb02950d

Cited by 11 publications

(7 citation statements)

References 71 publications

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“…Actually, fundamental research is also focusing on cyclodextrin-based nanoparticles/nanomaterials for pharmaceutical and biomedical applications and nanomedicine, e.g., molecular diagnosis, medical imaging, antifungal treatment, antimicrobial therapy, gene therapy or tissue engineering, and on self-association of cyclodextrins for applications not only for formulation and drug delivery, and medicine, but also for materials science, supramolecular chemistry and asymmetric catalysis (Hirakawa and Tomita 2013;Morohoshi et al 2013;Zhang and Ma 2013;Chilajwar et al 2014;Melotti et al 2014;Simoes et al 2014;Dong et al 2015;Macaev and Boldescu 2015;Mavridis and Yannakopoulou 2015;Miller et al 2015;Perez-Anes et al 2015;Wu et al 2015;Brackman et al 2016;Junthip et al 2016;Okano et al 2016;Oliveri and Vecchio 2016;Ryzhakov et al 2016;Sharma and Baldi 2016;Silva et al 2016;Yuan and Zhang 2016;Saokham and Loftsson 2017;Egele et al 2019;Fenyvesi et al 2019;Hammoud et al 2019;Kumar and Rao 2019;Neva et al 2019;Pawar and Shende 2019;Topuz and Uyar 2019;Zhang et al 2019a).…”

Section: Cyclodextrins: Trends and Outlookmentioning

confidence: 99%

130 years of cyclodextrin discovery for health, food, agriculture, and the industry: a review

et al. 2021

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Cyclodextrins are a group of cyclic oligosaccharides obtained by enzymatic degradation of starch. They are remarkable macrocyclic molecules that have led major theoretical and practical advances in chemistry, biology, biochemistry, health science, and agriculture. Their molecular structure is composed of a hydrophobic cavity that can encapsulate other compounds to form inclusion complexes through host-guest interactions. This unique feature is at the origin of many applications. Cyclodextrins and their derivatives have a wide variety of practical applications in almost all sectors of the industry, including pharmacy, medicine, foods, cosmetics, chromatography, catalysis, biotechnology, and the textile industry. Villiers published the first reference to cyclodextrins in 1891, and since then, these molecules have continued to fascinate academia and industry. Currently, more than 2000 publications on cyclodextrins are published each year. On the occasion of the 130th anniversary of their discovery, in this review, we present an historical overview of the development and applications of cyclodextrins. First, we present the discovery and first chemical studies on cyclodextrins. Then, the main results obtained during the 1911-1970 exploration period are discussed. A third part presents the historical landmarks in the development of cyclodextrins from 1970 to the present day.

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Section: Cyclodextrins: Trends and Outlookmentioning

confidence: 99%

130 years of cyclodextrin discovery for health, food, agriculture, and the industry: a review

et al. 2021

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“…The absence of these stoppers results in a pseudopolyrotaxane (PPR), in which the macrocycles can enter and exit the polymeric chain, according to the chemical laws of equilibrium and kinetics [ 2 , 3 ]. These supramolecular constructs are gaining interest in different fields, mainly in drug delivery, since they can act as reservoirs of macrocycles that can be released either on-demand (by chemical or photochemical triggering) or during the slow degradation of the superstructure [ 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

“…On the contrary, β- and γ-CD form more stable complexes with PPG than with PEG [ 2 , 9 , 11 , 13 , 21 ]. The threading mechanisms of CDs with different polymers to produce PPRs and PRs have been widely described in the literature [ 3 , 4 , 12 , 22 ], as well as their synthesis, characterization and applications [ 5 , 6 , 23 , 24 , 25 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

“…While the vast majority of studies on these supramolecular structures deal with their synthesis in solution [ 1 , 2 , 3 , 4 , 7 , 9 , 10 , 11 , 12 , 13 , 14 , 20 , 21 , 22 , 24 ], the number of investigations in solid-state is much more limited [ 19 , 27 , 28 , 29 , 30 , 31 , 32 ]. Some studies have focused on the optimization of the synthesis and the characterization of the structures formed.…”

Section: Introductionmentioning

confidence: 99%

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Solvent-Free Formation of Cyclodextrin-Based Pseudopolyrotaxanes of Polyethylene Glycol: Kinetic and Structural Aspects

Guembe-Michel

Durán

Sirera

et al. 2022

IJMS

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Pseudopolyrotaxanes (PPRs) are supramolecular structures consisting of macrocycles able to thread on a linear polymer chain in a reversible, non-covalent way, often referred to in the literature as “molecular necklaces”. While the synthesis and reaction mechanisms of these structures in solution have been widely described, their solvent-free production has received little attention, despite the advantages that this route may offer. We propose in this work a kinetic mechanism that describes the PPR formation in the solid phase as a process occurring in two consecutive stages. This mechanism has been used to investigate the spontaneous formation of a PPR that occurs when grinding α-Cyclodextrin (α-CD) with polyethylene glycol (PEG). In the threading stage, the inclusion of the polymer and subsequent release of the water molecules lodged in the cavity of the macrocycle cause vibrational changes that are reflected in the time-dependence of the FTIR-ATR spectra, while the further assembly of PPRs to form crystals produces characteristic reflections in the XRD patterns, due to the channel-like arrangement of CDs, that can be used to track the formation of the adduct in crystalline form. The effects that working variables have on the kinetics of the reaction, such as temperature, feed ratio, molar mass of the polymer and the introduction of an amorphous block in the polymer structure, have been investigated. The rate constants of the threading step increase with the temperature and the activation energy of the process increases at lower proportions of CD to PEG. This is attributed to the lower degree of covering of the polymer chain with CDs that reduces the hydrogen-bonding driven stabilization between adjacent macrocycles. The formation of crystalline PPR, which takes place slowly at room temperature, is markedly promoted at higher temperatures, with lower proportions of CD favoring both the formation and the growth of the crystals. The molar mass of the polymer does not modify the typical channel-like arrangement of packed PPRs but the conversion into crystalline PPR diminishes when using PEG1000 instead of PEG400. At a microscopic level, the crystals arrange into lamellar structures, in the order of hundreds of nm, embedded in an amorphous-like matrix. The introduction of a polypropylene oxide block in the structure of the polymer (Pluronic L62) renders poorer yields and a considerable loss of crystallinity of the product of the reaction. The methodology here proposed can be applied to the general case of inclusion complexes of CDs with drugs in the solid phase, or to multicomponent systems that contain polymers as excipients in pharmaceutical formulations along with CDs.

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“…We have previously reported the synthesis and cholesterol mobilization from endo-lysosomal compartments of NPC1 cells by β-cyclodextrin (β-CD)-based polyrotaxanes (PR) as potential NPC therapeutics [12][13][14][15]; findings that were subsequently corroborated using compounds of similar structure [16,17]. Polyrotaxanes are non-covalent self-assemblies derived from macrocycles that are threaded onto a polymer core followed by the attachment of a bulky molecule (or endcap) to prevent dethreading of the macrocycle.…”

Section: Introductionmentioning

confidence: 99%

Structure-function relationships of cholesterol mobilization from the endo-lysosome compartment of NPC1-deficient human cells by β-CD polyrotaxanes

et al. 2022

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Niemann-Pick Type C is a rare metabolic disorder characterized by the cellular accumulation of cholesterol within endosomal and lysosomal compartments. 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) containing polyrotaxanes represent an attractive approach for treating this disease due to their ability to circulate in the blood stream for longer periods of time as a prodrug form of HP-β-CD. Once inside the cell, the macromolecular structure is thought to break down into the Pluronic precursor and the active cyclodextrin agent that promotes cholesterol mobilization from the aberrant accumulations within NPC-deficient cells. We now report that both cholesterol and decaarginine (R10) endcapped polyrotaxanes are able to remove cholesterol from NPC1 patient fibroblasts. R10 endcapped materials enter these cells and are localized within endosomes after 16 h. The cholesterol mobilization from endo-lysosomal compartments of NPC1 cells by the polyrotaxanes was directly related to their extent of endcapping and their threading efficiency. Incorporation of 4-sulfobutylether-β-cyclodextrin (SBE-β-CD) significantly improved cholesterol mobilization due to the improved solubility of the compounds. Additionally, in our efforts to scale-up the synthesis for preclinical studies, we prepared a library of polyrotaxanes using a solid phase synthesis method. These compounds also led to significant cholesterol mobilization from the cells, however, cytotoxicity studies showed that they were substantially more toxic than those prepared by the solvent-assisted method, thus limiting the therapeutic utility of agents prepared by this expedited method. Our findings demonstrate that complete endcapping of the polyrotaxanes and improved solubility are important design features for delivering high copy numbers of therapeutic β-CD to promote enhanced sterol clearance in human NPC1-deficient cells.

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Synthesis of the anionic hydroxypropyl-β-cyclodextrin:poly(decamethylenephosphate) polyrotaxane and evaluation of its cholesterol efflux potential in Niemann–Pick C1 cells

Abstract: We describe for the first time the homogenous assembly of a water soluble polyrotaxane from HP-β-CD and an anionic posphodiester. The resulting polyrotaxane displays cholesterol normalization activity in NPC cells.

Cited by 11 publications

References 71 publications

130 years of cyclodextrin discovery for health, food, agriculture, and the industry: a review

130 years of cyclodextrin discovery for health, food, agriculture, and the industry: a review

Solvent-Free Formation of Cyclodextrin-Based Pseudopolyrotaxanes of Polyethylene Glycol: Kinetic and Structural Aspects

Structure-function relationships of cholesterol mobilization from the endo-lysosome compartment of NPC1-deficient human cells by β-CD polyrotaxanes

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