The influence of natural deep eutectic solvents on bioactive natural products: studying interactions between a hydrogel model and Schisandra chinensis metabolites
Graphical abstract
Introduction
NAtural Deep Eutectic Solvent (NADES) species were first recognized in 2011 as botanical liquid media [1]. Since then, additional NADES species have attracted attention due to their solubilizing ability for lipophilic molecules, inspiring applications as extraction and dissolution media [2]. The NADES components are usually hydrophilic molecules [1]. Combined with the power to solubilize lipophilic components, NADES species exhibit a solvent duality (lipophilicity and hydrophilicity), suggesting that they may serve a unique function in lipophilic molecule delivery [3].
Water plays an important role as a NADES component because it can regulate the solubilizing ability of NADES species. For example, when increasing the water content of glucose-choline chloride-water (GCWat), the corresponding rutin solubilities decreased significantly [4]. This may be because the water content in NADES affects the entropy of the matrix and, thus, alters its solute-carrying phase shape or size. In addition, water involvement may cause the matrix to disassemble and form NADES component solution, associated with the release of dissolved molecules from the matrix (Fig. 1). This dynamic structure of water has been proposed as self-organizing liquid crystals [1].
The collective experience of research on bioactive natural products over the past decades has repeatedly led to the observation that lipophilic components within a crude extract have significantly higher apparent water solubility than the purified individual components. This indicates that a unique mechanism may exist that impacts the practice of traditional medicine and botanical dietary supplements. The present study aims to demonstrate a possible pathway by which NADES species introduce bioactive lipophilic metabolites into biopolymer matrices. Such a natural drug delivery mechanism mediated by NADES species has the potential to support the use of botanical materials and crude extracts beyond the reductionist administration of purified putative bioactive substances.
Section snippets
Materials
Choline chloride, chitosan, dimethylurea, d-(+)-fructose, d-(+)-glucose, d-(+)-mannose, maleic acid, sodium alginate, urea, curcuminoid (from Curcuma longa (turmeric), powder; CAS: 458-37-7), HPLC grade solvents, and DMSO-d6 (99.9 atom % D) were purchased from Sigma-Aldrich Inc. (St. Louis, MO, USA). Acetic acid and anhydrous calcium chloride were obtained from Fisher Scientific (Hampton, NH, USA). The fruits of S. chinensis were purchased in a local grocery store in the Chinatown neighborhood
Establishment and evaluation of the hydrogel model
The hydrogel system underlying this study and can be summarized in the following three points (Fig. 1): (a) NADES species are capable of dissolving relatively large amounts of hydrophobic molecules, such as shown for curcumin solubilized in MDWat (Fig. 2). (b) The NADES solution was mixed with an alginate solution, and the mixture was introduced dropwise into the chitosan solution. Once the hydrogel network was formed, the NADES solution is trapped in the micro-environment; (c) Free water can
Conclusions
The present study demonstrates that NADES such as mannose-dimethylurea-water (MDWat, 2:5:5, mole/mole) can behave as “shuttle vectors” which deliver lipophilic molecules dissolved in the NADES into hydrogel beads, and leave some of the lipophilic molecules in the hydrogel beads, then spontaneously diffuse from the polymer carrier during the preparation procedure. The investigated lipophilic therapeutics, CTE/”curcumin” and Schisandra lignans, exhibited a significant incorporation into the
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgements
This work was supported by grants P50 AT000155 and U41 AT008706 from ODS and NCCIH of the National Institutes of Health. This investigation was conducted, in part, in a facility constructed with support from the National Institutes of Health National Center for Research Resources (C06 RR15482). Yang Liu is grateful for a USP Global Fellowship from the U.S. Pharmacopeial Convention. Mary Choules acknowledges funding through grant T32 AT007533 from NCCIH/NIH. Furthermore, support from the NMR
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These authors contributed equally to this work.