目的 制备D-α-维生素E聚乙二醇1000琥珀酸酯（TPGS）表面修饰的柚皮素纳米结构脂质载体（TPGS-Nar-NLCs），探究其体内药动学特征及对急性肺损伤大鼠的治疗作用。方法 以包封率、载药量及粒径为评价指标，采用单因素实验联合Box-Behnken设计-响应面法优化TPGS-Nar-NLCs处方工艺；通过透射电镜（TEM）观测微观形貌，利用X射线粉末衍射法（XRPD）与差示扫描量热法（DSC）分析柚皮素（Nar）在载体中的存在形态；采用透析袋法考察载体体外释药性能。以游离Nar为对照，对比分析TPGS-Nar-NLCs的体内药动学差异，计算其相对口服生物利用度。构建急性肺损伤大鼠模型，设置对照组、模型组、地塞米松（阳性药，5 mg·kg^-1）组、Nar（100 mg·kg^-1）组及TPGS-Nar-NLCs低、高剂量（50、100 mg·kg^-1）组。检测各组大鼠肺脏指数、肺组织湿质量/干质量值；采用ELISA法测定大鼠血浆中肿瘤坏死因子（TNF）-α、白细胞介素（IL）-6、IL-1β炎症因子水平；通过苏木素-伊红（HE）染色观察肺组织病理损伤程度，Masson染色评估肺纤维化病变情况。结果 TPGS-Nar-NLCs最优处方工艺参数： TPGS质量分数2.05%、脂药比15.20∶ 1.00、固液脂质比5.90∶ 1.00。优化制备的TPGS-Nar-NLCs平均包封率、载药量、粒径及Zeta电位分别为（81.90± 0.84）%、（5.03± 0.07）%、（174.28± 4.29） nm、（-28.16± 1.04） mV。体外释药结果显示，TPGS-Nar-NLCs可将Nar 12 h累积释放率由28.87%提升至82.90%。体内药动学结果表明，与游离Nar相比，TPGS-Nar-NLCs达峰时间（t_max）显著延后（P＜0.05），半衰期（t_1/2）显著延长（P＜0.05），峰值血药浓度（C_max）极显著升高（P＜0.01），相对口服生物利用度提升至5.42倍。药效学结果显示，同等剂量（100 mg·kg^-1）下，TPGS-Nar-NLCs组大鼠肺脏指数、肺组织湿质量/干质量值及TNF-α、IL-6、IL-1β炎症因子水平均较游离Nar组极显著降低（P＜0.01），可有效改善肺组织病理损伤、抑制炎症反应与肺纤维化进展，整体治疗效果显著优于游离Nar。结论 TPGSNar-NLCs可显著提升Nar的口服吸收生物利用度，有效增强其对急性肺损伤的治疗作用，为Nar肺部靶向制剂的开发及急性肺损伤靶向治疗提供实验参考。

Objective To prepare D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) surface-modified naringin nanostructured lipid carriers (TPGS-Nar-NLCs) and investigate their pharmacokinetic characteristics and therapeutic efficacy in rats with acute lung injury. Methods The formulation of TPGS-Nar-NLCs was optimized using single-factor experiments combined with Box-Behnken response surface methodology, based on encapsulation efficiency, drug loading, and particle size as evaluation parameters. Transmission electron microscopy (TEM) was used to observe the microstructure, while X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) were employed to analyze the physical state of Nar within the carrier. Drug release behavior was evaluated in vitro using dialysis bag method. Free Nar was used as a control to compare the pharmacokinetics of TPGSNar-NLCs and calculate relative oral bioavailability. An acute lung injury rat model was established, and animals were divided into control group, model group, dexamethasone group (positive control, 5 mg·kg^-1), free Nar group (100 mg·kg^-1), and low- and high-dose TPGS-Nar-NLCs groups (50, 100 mg·kg^-1). Pulmonary index and wet/dry weight ratio of lung tissues were measured. Serum levels of inflammatory cytokines TNF-α, IL-6, and IL-1β were determined by ELISA. Lung tissue histopathological changes were assessed via hematoxylin-eosin (HE) staining, and pulmonary fibrosis was evaluated using Masson’s trichrome staining. Results The optimal formulation parameters for TPGS-Nar-NLCs were: TPGS concentration of 2.05%, lipid-to-drug ratio of 15.20∶ 1.00, and solid-toliquid lipid ratio of 5.90∶ 1.00. The optimized TPGS-Nar-NLCs exhibited an average encapsulation efficiency of (81.90 ± 0.84)%, drug loading of (5.03 ± 0.07)%, particle size of (174.28 ± 4.29) nm, and zeta potential of (-28.16 ± 1.04) mV. In vitro release studies showed that TPGS-Nar-NLCs significantly increased the cumulative release of Nar from 28.87% to 82.90% over 12 h. Pharmacokinetic analysis revealed that compared with free Nar, TPGS-Nar-NLCs significantly delayed the time to peak concentration (t_max, P<0.05), prolonged the half-life (t_1/2, P<0.05), and markedly increased the maximum plasma concentration (C_max, P<0.01), resulting in a relative oral bioavailability enhancement of 5.42 fold. Pharmacodynamic results indicated that at the same dose (100 mg·kg^-1), the pulmonary index, wet/dry weight ratio, and serum levels of TNF-α, IL-6, and IL-1β were significantly lower in the TPGS-Nar-NLCs group than in the free Nar group (P<0.01). TPGS-Nar-NLCs effectively alleviated lung tissue damage, suppressed inflammatory responses, and inhibited pulmonary fibrosis progression, demonstrating superior overall therapeutic effects compared to free Nar. Conclusion TPGS-Nar-NLCs significantly enhance the oral absorption and bioavailability of Nar, thereby improving its therapeutic efficacy against acute lung injury, providing experimental support for the development of Nar-based targeted pulmonary formulations and targeted therapy for acute lung injury.

R285.5;283.6

河南省科技攻关项目（242102320119）；河南省科技攻关项目（232102310384）；河南省教育厅高等教育教学改革研究与实践项目（2021SJGLX793）；郑州市社会科学调研课题（ZSLX20250281）