目的 制備荷載甘草查耳酮A(licochalcone A,LA)柔性脂質(zhì)體(elastic liposomes,LA-EL),并評(píng)價(jià)其體外透皮效果、變形性和抗炎活性。方法 采用薄膜分散法制備LA-EL,首先通過粒徑、多分散指數(shù)(polydispersity index,PDI)、包封率及透皮性能優(yōu)化膜軟化劑配方,然后采用透射電子顯微鏡(transmission electron microscopy,TEM)和微孔擠壓法表征LA-EL的形貌與變形能力,并考察LA-EL的低溫貯存穩(wěn)定性和體外釋放特性,通過制備香豆素6(coumarin 6,C6)標(biāo)記的柔性脂質(zhì)體C6-EL,觀察其在皮膚內(nèi)的分布。最后通過RAW264.7巨噬細(xì)胞實(shí)驗(yàn),分析LA-EL的細(xì)胞攝取、毒性及對(duì)脂多糖(lipopolysaccharide,LPS)誘導(dǎo)的NO、白細(xì)胞介素-1β(interleukin-1β,IL-1β)和腫瘤壞死因子-α(tumor necrosis factor-α,TNF-α)等炎癥因子的抑制作用,評(píng)價(jià)其抗炎活性。結(jié)果 采用10 mg肉豆蔻酸異丙酯(isopropyl myristate,IPM)和5 mg聚氧乙烯蓖麻油(polyoxyethylene castor oil,PCO)共修飾制備的LA-EL,具有最優(yōu)的LA透皮效果和脂質(zhì)體理化特性,且能顯著提高LA的水溶性。LA-EL的粒徑呈現(xiàn)單峰分布特征,在TEM下顯示類球形的微觀形態(tài)。在4 ℃貯存14 d內(nèi),LA-EL穩(wěn)定性良好,而無(wú)IPM/PCO共修飾普通脂質(zhì)體(LA-L)的粒徑、PDI和包封率均發(fā)生顯著變化。LA-EL的變形指數(shù)高達(dá)0.874±0.125,是LA-L的6.83倍。與LA相比,LA-EL緩釋特性顯著,且釋藥行為與LA-L基本一致。IPM/PCO共修飾脂質(zhì)體不僅能夠?qū)6有效遞送至皮膚深層,還顯著提高了細(xì)胞攝取效率,并且增強(qiáng)了LA對(duì)LPS誘導(dǎo)的NO和TNF-α分泌的抑制作用。結(jié)論 LA-EL具有良好的低溫貯存穩(wěn)定性、變形性以及優(yōu)異的透皮性能,能夠顯著促進(jìn)細(xì)胞對(duì)藥物的攝取,從而有效增強(qiáng)LA在細(xì)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

湖北省技術(shù)創(chuàng)新計(jì)劃項(xiàng)目（2024BCA002）；湖北省高等學(xué)校優(yōu)秀中青年科技創(chuàng)新團(tuán)隊(duì)計(jì)劃項(xiàng)目（T2023014）；湖北中醫(yī)藥大學(xué)校級(jí)科技創(chuàng)新項(xiàng)目（2024KJCX003）