New Lipidyl-Cyclodextrins Obtained by Ring Opening of Methyl Oleate Epoxide Using Ball Milling

Oliva, E.; Mathiron, David; Rigaud, Sébastien; Monflier, Éric; Sevin, Emmanuel; Bricout, H.; Tilloy, S.; Gosselet, Fabien; Fénart, Laurence; Bonnet, Véronique; Pilard, Serge; Djedaïni‐Pilard, Florence

doi:10.3390/biom10020339

Cited by 16 publications

(17 citation statements)

References 43 publications

(67 reference statements)

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“…In a BM reaction, due to the much smaller amount of water, the hydrolysis is significantly suppressed; furthermore, the better utilization of the reagent also allows for the reduction of the molar amount of the reagent. The aqueous solubility of the epoxides used in CD derivatizations is low, so in anhydrous media, the contact area in BM is increasing [ 84 ]. This method enables the preparation of novel lipidyl CDs, which were previously much more difficult or impossible to prepare, and the reproducible preparation of polymerized CDs, too [ 85 ].…”

Section: Discussionmentioning

confidence: 99%

Toward a Greener World—Cyclodextrin Derivatization by Mechanochemistry

Jicsinszky

Cravotto

2021

Molecules

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Cyclodextrin (CD) derivatives are a challenge, mainly due to solubility problems. In many cases, the synthesis of CD derivatives requires high-boiling solvents, whereas the product isolation from the aqueous methods often requires energy-intensive processes. Complex formation faces similar challenges in that it involves interacting materials with conflicting properties. However, many authors also refer to the formation of non-covalent bonds, such as the formation of inclusion complexes or metal–organic networks, as reactions or synthesis, which makes it difficult to classify the technical papers. In many cases, the solubility of both the starting material and the product in the same solvent differs significantly. The sweetest point of mechanochemistry is the reduced demand or complete elimination of solvents from the synthesis. The lack of solvents can make syntheses more economical and greener. The limited molecular movements in solid-state allow the preparation of CD derivatives, which are difficult to produce under solvent reaction conditions. A mechanochemical reaction generally has a higher reagent utilization rate. When the reaction yields a good guest co-product, solvent-free conditions can be slower than in solution conditions. Regioselective syntheses of per-6-amino and alkylthio-CD derivatives or insoluble cyclodextrin polymers and nanosponges are good examples of what a greener technology can offer through solvent-free reaction conditions. In the case of thiolated CD derivatives, the absence of solvents results in significant suppression of the thiol group oxidation, too. The insoluble polymer synthesis is also more efficient when using the same molar ratio of the reagents as the solution reaction. Solid reactants not only reduce the chance of hydrolysis of multifunctional reactants or side reactions, but the spatial proximity of macrocycles also reduces the length of the spacing formed by the crosslinker. The structure of insoluble polymers of the mechanochemical reactions generally is more compact, with fewer and shorter hydrophilic arms than the products of the solution reactions.

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Section: Discussionmentioning

confidence: 99%

Toward a Greener World—Cyclodextrin Derivatization by Mechanochemistry

Jicsinszky

Cravotto

2021

Molecules

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“…After 6 days of co-culture, the resulting hBLECs express TJ proteins at cell-cell contacts and transporters typically observed in the brain endothelium, maintaining the properties of in vivo BBB for at least 20 days [28], a period during which we performed transport experiments. This model is now widely used to investigate BBB physiology, as well as molecules and cells passage across the BBB [80][81][82][83][84][85]. The loading of the human BBB model with GM1 or OligoGM1, followed by the measure of permeability parameters, provided evidence to consider OligoGM1 as a molecule transported by the paracellular mechanism, and importantly with a rate 20-fold higher then ganglioside GM1 (Figure 3).…”

Section: Discussionmentioning

confidence: 99%

GM1 Oligosaccharide Crosses the Human Blood–Brain Barrier In Vitro by a Paracellular Route

Biase

Lunghi

Maggioni

et al. 2020

IJMS

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Ganglioside GM1 (GM1) has been reported to functionally recover degenerated nervous system in vitro and in vivo, but the possibility to translate GM1 s potential in clinical settings is counteracted by its low ability to overcome the blood-brain barrier (BBB) due to its amphiphilic nature. Interestingly, the soluble and hydrophilic GM1-oligosaccharide (OligoGM1) is able to punctually replace GM1 neurotrophic functions alone, both in vitro and in vivo. In order to take advantage of OligoGM1 properties, which overcome GM1 s pharmacological limitations, here we characterize the OligoGM1 brain transport by using a human in vitro BBB model. OligoGM1 showed a 20-fold higher crossing rate than GM1 and time-concentration-dependent transport. Additionally, OligoGM1 crossed the barrier at 4 • C and in inverse transport experiments, allowing consideration of the passive paracellular route. This was confirmed by the exclusion of a direct interaction with the active ATP-binding cassette (ABC) transporters using the "pump out" system. Finally, after barrier crossing, OligoGM1 remained intact and able to induce Neuro2a cell neuritogenesis by activating the TrkA pathway. Importantly, these in vitro data demonstrated that OligoGM1, lacking the hydrophobic ceramide, can advantageously cross the BBB in comparison with GM1, while maintaining its neuroproperties. This study has improved the knowledge about OligoGM1 s pharmacological potential, offering a tangible therapeutic strategy.However, transferring the GM1 neuronal potential from the preclinical models to the clinic depends on its ability to reach the brain structures when administered peripherally. This last aspect is actually severely limited by GM1 s amphiphilicity, which hampers the passage across the blood-brain barrier (BBB) [2,7,8]. This barrier is located at the brain microvessel level and strongly restricts the entry of cells and xenobiotics into the CNS. The BBB anatomical support is the specialized brain endothelial cells of these vessels. These cells do not show any fenestrations and are specifically characterized by the presence of tight junctions (TJ), composed of junctional proteins and TJ-associated proteins. Additionally, these cells express several proteins belonging to the ATP-binding cassette (ABC) transporters family, which act as efflux pumps and play an important role by limiting BBB crossing of several drugs and biological molecules [9,10]. The major efflux pumps expressed at the BBB are P-glycoprotein (P-gp, aka ABCB1), breast cancer resistance protein (BCRP, aka ABCG2), and the multidrug-resistance-associated proteins (MRPs, aka ABCCs).Importantly, the fate of peripherally administered GM1 observed in the rodent models has not been determined in humans, as often the two species display different BBB permeability rates for the same molecule [7,8]. One of the possible explanations for these discrepancies is the species difference recently reported between rodents and human for the expression of several receptors and transporters expressed in the BBB, in...

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“…Cyclodextrins find various applications in pharmaceutics, from being simple solubilizers to sustained-release agents. Now, self-assembled nanoparticles formed by a new family of o-lipidyl cyclodextrins are opening the way to controlled delivery systems with high loading capacity [ 4 ]. These CDs are obtained using sustainable mechanochemical procedures and biocompatible with intestinal epithelial cells, thus promising a bright and green future in pharmaceutics.…”

Section: Unveiling More Properties and Applications Of Cyclodextrinsmentioning

confidence: 99%