目的 制备荷载甘草查耳酮A(licochalcone A,LA)柔性脂质体(elastic liposomes,LA-EL),并评价其体外透皮效果、变形性和抗炎活性。方法 采用薄膜分散法制备LA-EL,首先通过粒径、多分散指数(polydispersity index,PDI)、包封率及透皮性能优化膜软化剂配方,然后采用透射电子显微镜(transmission electron microscopy,TEM)和微孔挤压法表征LA-EL的形貌与变形能力,并考察LA-EL的低温贮存稳定性和体外释放特性,通过制备香豆素6(coumarin 6,C6)标记的柔性脂质体C6-EL,观察其在皮肤内的分布。最后通过RAW264.7巨噬细胞实验,分析LA-EL的细胞摄取、毒性及对脂多糖(lipopolysaccharide,LPS)诱导的NO、白细胞介素-1β(interleukin-1β,IL-1β)和肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)等炎症因子的抑制作用,评价其抗炎活性。结果 采用10 mg肉豆蔻酸异丙酯(isopropyl myristate,IPM)和5 mg聚氧乙烯蓖麻油(polyoxyethylene castor oil,PCO)共修饰制备的LA-EL,具有最优的LA透皮效果和脂质体理化特性,且能显著提高LA的水溶性。LA-EL的粒径呈现单峰分布特征,在TEM下显示类球形的微观形态。在4 ℃贮存14 d内,LA-EL稳定性良好,而无IPM/PCO共修饰普通脂质体(LA-L)的粒径、PDI和包封率均发生显著变化。LA-EL的变形指数高达0.874±0.125,是LA-L的6.83倍。与LA相比,LA-EL缓释特性显著,且释药行为与LA-L基本一致。IPM/PCO共修饰脂质体不仅能够将C6有效递送至皮肤深层,还显著提高了细胞摄取效率,并且增强了LA对LPS诱导的NO和TNF-α分泌的抑制作用。结论 LA-EL具有良好的低温贮存稳定性、变形性以及优异的透皮性能,能够显著促进细胞对药物的摄取,从而有效增强LA在细胞水平上的抗炎活性。

Objective To prepare licochalcone A (LA)-loaded elastic liposomes (LA-EL) and evaluate their transdermal efficacy, deformability, and anti-inflammatory activity. Methods LA-EL were prepared using the thin-film hydration method. The formulation of membrane softeners was optimized based on particle size, polydispersity index (PDI), encapsulation efficiency, and transdermal parameters. The morphology and deformability of LA-EL were characterized by transmission electron microscopy (TEM) and extrusion through microporous membranes, respectively. Additionally, the storage stability (at 4 ℃ for 14 d) and in vitro release profile were evaluated. Coumarin 6 (C6)-labeled elastic liposomes (C6-EL) were prepared to observe their skin distribution. Finally, RAW264.7 macrophages were used to assess cellular uptake, cytotoxicity, and the inhibitory effects of LA-EL on lipopolysaccharide (LPS)-induced secretion of inflammatory mediators (NO, IL-1β, and TNF-α). Results LA-EL co-modified with 10 mg isopropyl myristate (IPM) and 5 mg polyoxyl castor oil (PCO) exhibited optimal transdermal delivery of LA and optimal physicochemical properties of liposomes, while significantly improving the water solubility of LA. The particle size distribution of LA-EL was monodisperse, and TEM revealed uniform spherical morphology. After 14 d of storage at 4 ℃, LA-EL maintained excellent stability, whereas conventional liposomes (LA-L) without IPM/PCO modification showed significant changes in particle size, PDI, and EE. The deformability index of LA-EL reached 0.874 ± 0.125, which was 6.83-fold higher than that of LA-L. Compared with free LA, LA-EL demonstrated sustained release behavior, with a drug release profile similar to that of LA-L. Importantly, IPM/PCO co-modified liposomes not only effectively delivered C6 into deeper skin layers but also significantly enhanced cellular uptake and suppressed LPS-induced NO and TNF-α production. Conclusion LA-EL exhibits good stability, deformability, and excellent transdermal performance, which can significantly promote cellular uptake of the drug, thereby effectively enhancing the anti-inflammatory activity of LA at the cellular level.

R283.6

湖北省技术创新计划项目（2024BCA002）；湖北省高等学校优秀中青年科技创新团队计划项目（T2023014）；湖北中医药大学校级科技创新项目（2024KJCX003）