目的 制备葡聚糖修饰异甘草素/玉米醇溶蛋白纳米粒（Dex-Iso/Zein-NPs），考察其在大鼠体内的口服药动学行为及对大鼠急性痛风性关节炎的改善作用。方法 采用单因素试验联合Box-Behnken响应面法优化Dex-Iso/Zein-NPs处方工艺；透射电镜（TEM）表征纳米粒微观外貌； X-射线粉末衍射（XRPD）分析异甘草素晶型状态；测定纳米粒表观溶解度与体外释药行为，考察粉末储存稳定性。SD大鼠ig给予异甘草素原料药、物理混合物及Dex-Iso/Zein-NPs，HPLC法检测血浆药物浓度，计算物理混合物与Dex-Iso/Zein-NPs的相对口服生物利用度；采用尿酸钠晶体注射法建立大鼠急性痛风性关节炎模型，对比异甘草素、物理混合物及Dex-Iso/Zein-NPs对大鼠踝关节肿胀度、肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）、环氧化酶-2（COX-2）水平的影响；苏木素-伊红（HE）染色观察滑膜组织病理改变。结果 Dex-Iso/Zein-NPs最优处方：玉米醇溶蛋白与异甘草素质量比10.90∶ 1.00，反溶剂相与溶剂相体积比3.15∶ 1.00，葡聚糖质量浓度2.4 g·L^-1；所得纳米粒包封率（83.94±0.73）%，载药量（5.69±0.09）%，粒径（181.22±6.14） nm，Zeta电位（-30.84±1.09） mV。纳米粒呈类球形，异甘草素在纳米粒中以无定形存在。Dex-Iso/Zein-NPs可将异甘草素表观溶解度提升34.17倍，18 h累积释放率达88.10%；相对于异甘草素原料药，其相对口服生物利用度提高至5.50倍。相较于原料药，Dex-Iso/Zein-NPs可显著降低大鼠踝关节肿胀度及TNF-α、IL-1β、COX-2水平（P＜0.01），作用优于物理混合物； HE染色提示纳米粒可减轻滑膜炎症细胞浸润与组织病理损伤，药效与秋水仙碱组相近。结论 Dex-Iso/Zein-NPs可显著提高异甘草素表观溶解度、体外释放度及口服生物利用度，增强其对大鼠急性痛风性关节炎的改善作用。

Objective To prepare dextran-modified isoliquiritigenin /zein nanoparticles (Dex-Iso/Zein-NPs) and evaluate their oral pharmacokinetics in rats as well as their therapeutic effects on acute gouty arthritis. Methods The formulation process of Dex-Iso/Zein-NPs was optimized using single-factor experiments combined with the Box-Behnken response surface methodology. Transmission electron microscopy (TEM) was used to characterize the morphology of the nanoparticles, while X-ray powder diffraction (XRPD) analyzed the crystalline state of isoliquiritigenin. The apparent solubility and in vitro drug release profiles of the nanoparticles were determined, along with evaluation of powder stability during storage. SD rats were orally administered with pure isoliquiritigenin, a physical mixture, or Dex-Iso/Zein-NPs; plasma drug concentrations were measured by HPLC to calculate the relative oral bioavailability of the physical mixture and Dex-Iso/Zein-NPs. An acute gouty arthritis model in rats was established via intra-articular injection of sodium urate crystals into the ankle joint. The effects of isoliquiritigenin, the physical mixture, and Dex-Iso/Zein-NPs on ankle joint swelling, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and cyclooxygenase-2 (COX-2) levels were compared. Hematoxylin-eosin (HE) staining was performed to assess histopathological changes in synovial tissues. Results The optimal formulation of Dex-Iso/Zein-NPs was achieved at a Zein-to- isoliquiritigenin mass ratio of 10.90∶ 1.00, an anti-solvent-to-solvent volume ratio of 3.15∶ 1.00, and a dextran concentration of 2.4 g·L^-1. The resulting nanoparticles exhibited an encapsulation efficiency of (83.94 ±0.73)%, drug loading of (5.69 ±0.09)%, particle size of (181.22 ±6.14) nm, and zeta potential of (-30.84 ±1.09) mV. The nanoparticles were nearly spherical, and isoliquiritigenin existed in an amorphous form within them. Dex-Iso/Zein-NPs increased the apparent solubility of isoliquiritigenin by 34.17-fold, with a cumulative release rate reaching 88.10% over 18 hours, and enhanced its relative oral bioavailability by 5.50-fold. Compared to the pure drug, Dex-Iso/Zein-NPs significantly reduced ankle joint swelling and levels of TNF-α, IL-1β, and COX-2 in rats (P < 0.01), showing superior efficacy to the physical mixture. HE staining revealed that the nanoparticles alleviated synovial tissue inflammatory cell infiltration and tissue damage, with therapeutic effects comparable to those of colchicine. Conclusion Dex-Iso/Zein-NPs significantly improved the solubility, in vitro release, and oral bioavailability of isoliquiritigenin, thereby enhancing its therapeutic effect on acute gouty arthritis in rats.

R285.5

河南省科技攻关项目（232102310384）