Licorice is not only a widely used food, but also a classic tonic Chinese medicine, which mainly contains glycyrrhiza polysaccharides (GP) and flavonoids with excellent anti-inflammatory and antioxidant pharmacological activities. In this study, a neutral homogeneous polysaccharide (GP1–2) was isolated from Glycyrrhiza uralensis Fisch. However, its gelation behavior and properties have yet to be comprehensively studied. In this study, a Ca2+ cross-linked physical hydrogel based on neutral GP1–2 (GP1–2-Ca2+) is fabricated. The ability of metal ions to cross-linked gelation with GP1–2 is explored with respect to the polysaccharide concentrations, ion species, and pH environments. The pH range of Ca2+ cross-linked with GP1–2 to form hydrogel is 8 to 10, and the gelation concentration ranges from 20.0 % to 50.0 % w/v. Subsequently, the properties of the GP1–2-Ca2+ hydrogels are investigated using rheological measurements, scanning electron microscopy, free radical scavenging, MTT assays, healing capability, and enzyme-linked immunosorbent assays. The results reveal that the structure of GP1–2 presents an irregular porous structure, however, the physical gel formed after cross-linking with Ca2+ microscopically showed a globular porous structure with uniform distribution, suggesting that this structure characteristic may be used as a carrier material for drug delivery. Meanwhile, the GP1–2-Ca2+ hydrogel also possessed extraordinary viscoelasticity, cytocompatibility, antioxidant properties, anti-inflammatory activity, and ability to promote wound healing. Furthermore, the potential of GP1–2-Ca2+ hydrogels as drug delivery materials was validated by using rhein as a model drug for encapsulation, it is demonstrated that its cumulative release behavior of GP1–2-Ca2+ is pH-dependent. All in all, this study reveals the potential application of natural polysaccharides in drug delivery, highlighting its dual roles as carrier materials and bioactive ingredients.
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