目的制备蛇床子素巯基化纳米胶束（Ost-SH-NMs），考察其口服药动学特征及对阿霉素诱导大鼠心肌损伤的保护作用。方法采用单因素实验结合Box-Behnken设计-响应面法优化Ost-SH-NMs处方工艺；通过透射电镜观测Ost-SHNMs微观形貌，借助X-射线粉末衍射法分析药物晶型状态；检测并对比游离蛇床子素与Ost-SH-NMs的溶解度，采用体外透析法考察二者释药行为。将游离蛇床子素与Ost-SH-NMs分别ig给药SD大鼠，测定不同时间点血药浓度，计算主要药动学参数。通过ip阿霉素构建大鼠心肌损伤模型，分组ig给予游离蛇床子素与Ost-SH-NMs，检测大鼠左心室射血分数（LVEF）、左心室短轴缩短率（LVFS）及血清肌酸激酶（CK）、乳酸脱氢酶（LDH）、肌酸激酶同工酶（CK-MB）、超氧化物歧化酶（SOD）、丙二醛（MDA）相关指标；采用苏木素-伊红（HE）染色与Masson染色观察心肌组织形态结构及纤维化病变程度。结果优化得到Ost-SH-NMs最佳制备处方：二硬脂酰基磷脂酰乙醇胺-聚乙二醇2000（DSPE-PEG2000-SH）与蛇床子素投料比10.3∶ 1.0，水相体积19.5 mL，水合时间1.9 h。优化制备的Ost-SH-NMs包封率、载药量、沉降率、粒径及Zeta电位分别为（87.60± 0.92）%、（7.83± 0.07）%、（4.17± 0.22）%、（66.95± 3.87） nm、（-22.07± 0.82） mV。微观形貌显示Ost-SH-NMs呈类球形，且蛇床子素在纳米胶束中以无定型状态存在。Ost-SH-NMs可极显著提升蛇床子素水溶性，12 h药物累积释放率可达87.19%。药动学结果表明，Ost-SH-NMs可将蛇床子素口服相对生物利用度提升至4.64倍。药效学实验显示，与同剂量（60 mg·kg^-1）游离蛇床子素组相比，Ost-SH-NMs组大鼠LVEF、LVFS及SOD水平极显著升高（P＜0.01），LDH、CK、CK-MB、MDA水平极显著降低（P＜0.01）；同时可有效改善心肌组织炎症浸润与胶原沉积，心肌保护效果显著优于游离蛇床子素。结论 Ost-SH-NMs可显著改善蛇床子素的口服吸收效率，对阿霉素诱导的大鼠心肌损伤具有显著保护作用，具备良好的开发前景。

Objective To prepare osthole thiolated nanomicelles (Ost-SH-NMs) and evaluate its oral pharmacokinetic characteristics and protective effects against doxorubicin-induced myocardial injury in rats. Methods The formulation process of Ost-SH-NMs was optimized using single-factor experiments combined with Box-Behnken design-response surface methodology. Transmission electron microscopy was used to observe the microstructure of Ost-SH-NMs, while X-ray powder diffraction was employed to analyze the crystalline state of the drug. The solubility of free osthole and Ost-SH-NMs was measured and compared, and drug release behavior was evaluated by in vitro dialysis. Free osthole and Ost-SH-NMs were ig administered to SD rats, and blood concentrations at different time points were determined to calculate key pharmacokinetic parameters. A rat model of myocardial injury was established via intraperitoneal injection of doxorubicin. Rats were divided into groups and treated orally with either free osthole or Ost-SH-NMs. Left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and serum levels of creatine kinase (CK), lactate dehydrogenase (LDH), CK-MB, superoxide dismutase (SOD), and malondialdehyde (MDA) were measured. Histopathological changes and fibrosis were assessed using hematoxylin-eosin (HE) and Masson staining. Results The optimal preparation formula for Ost-SH-NMs was obtained: A ratio of distearoylphosphatidylethanolamine-polyethylene glycol 2000-thiol (DSPE-PEG2000-SH) to osthole of 10.3∶ 1.0, an aqueous phase volume of 19.5 mL, and a hydration time of 1.9 h. The optimized Ost-SH-NMs exhibited encapsulation efficiency, drug loading, sedimentation rate, particle size, and zeta potential of (87.60 ± 0.92)%, (7.83 ± 0.07)%, (4.17 ± 0.22)%, (66.95 ± 3.87) nm, and (-22.07 ± 0.82) mV, respectively. Microscopic observation revealed that Ost-SH-NMs had a nearly spherical morphology, and osthole existed in an amorphous state within the nanomicelles. Ost-SH-NMs significantly enhanced the water solubility of osthole, achieving a cumulative drug release of up to 87.19% over 12 h. Pharmacokinetic results showed that OstSH-NMs increased the relative bioavailability of osthole after oral administration by 4.64-fold. In pharmacodynamic studies, compared with the group receiving free osthole at the same dose (60 mg·kg^-1), the Ost-SH-NMs group showed significantly higher LVEF, LVFS, and SOD levels (P < 0.01), and significantly lower LDH, CK, CK-MB, and MDA levels (P < 0.01). Moreover, Ost-SH-NMs effectively alleviated inflammatory infiltration and collagen deposition in myocardial tissue, demonstrating stronger cardioprotective effects compared to free osthole. Conclusion Ost-SH-NMs significantly improve the oral absorption efficiency of osthole and exhibit significant protective effects against doxorubicin-induced myocardial injury in rats, indicating promising potential for further development.

R285.5

河南省科技攻关项目（232102310384）