目的 制备转铁蛋白修饰的青藤碱脂质体（Tf-Sin-Lips），考察其体内组织分布特征及抗肝癌活性。方法 以包封率、载药量和粒径为指标，通过单因素实验结合Box-Behnken设计-响应面法优化Tf-Sin-Lips处方工艺；采用透射电镜观察Tf-Sin-Lips形貌，并验证其混悬液的丁达尔效应。采用透析法比较青藤碱原料药和Tf-Sin-Lips在pH 7.4磷酸盐缓冲液中的体外释药行为。通过Hep3B细胞种植法构建荷瘤小鼠模型，尾iv给予青藤碱和Tf-Sin-Lips，考察体内组织分布情况；以青藤碱注射液的组织药物浓度为参考，计算Tf-Sin-Lips在肿瘤组织中相对摄取率（RUE）和峰浓度比值（Ce）。将30只荷瘤小鼠随机分为模型（0.9%氯化钠溶液）组、环磷酰胺（阳性药，20 mg·kg^-1）组、青藤碱组（100 mg·kg^-1）及Tf-Sin-Lips低、高剂量（50、100 mg·kg^-1）组，比较各组小鼠的体内肿瘤生长情况。采用试剂盒法测定小鼠血清丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、尿素氮（BUN）和肌酐（Scr）水平，并对小鼠主要脏器进行苏木素-伊红（HE）染色病理分析，评价Tf-Sin-Lips体内用药安全性。结果 优化得到Tf-Sin-Lips最佳处方为青藤碱投药量20 mg，载药用量比13.85∶1.00，磷脂与胆固醇用量比6.33∶ 1.00，水合时间2 h。Tf-Sin-Lips平均包封率、载药量、粒径Zeta电位分别为（83.26±1.17）%、（5.39± 0.09）%、（196.96± 5.19） nm和（-22.06± 1.20） mV。Tf-Sin-Lips呈囊泡结构，混悬液具有明显的丁达尔效应，体外释药具有明显的缓释特征。体内分布实验结果显示，Tf-Sin-Lips可有效改变青藤碱的体内组织分布特征，其肿瘤组织RUE与Ce分别提升至3.25倍、3.57倍。体内药效结果表明，Tf-Sin-Lips高剂量组可显著抑制荷瘤小鼠肿瘤生长，抑瘤率达65.42%。安全性检测显示，青藤碱组、Tf-Sin-Lips组可明显逆转模型小鼠血清ALT、AST、BUN、Scr的升高（P＜0.05、0.01），小鼠主要脏器无显著病理性改变。结论 Tf-Sin-Lips显著增强了青藤碱的肿瘤组织靶向性和体内抗肿瘤作用，安全性良好，具备良好的临床应用潜力。

Objective To prepare transferrin-modified sinomenine liposomes (Tf-Sin-Lips) and investigate their tissue distribution characteristics and anti-hepatocellular carcinoma activity in vivo. Methods The formulation process of Tf-Sin-Lips was optimized by single-factor experiments combined with Box-Behnken design-response surface methodology, using encapsulation rate, drug loading amount and particle size as indicators. The morphology of Tf-Sin-Lips was observed by transmission electron microscopy, and the Tyndall effect of the suspension was verified. The in vitro drug release behavior of sinomenine raw material and Tf-Sin-Lips in pH 7.4 phosphate buffer solution was compared by dialysis. A tumor-bearing mouse model was constructed by implanting Hep3B cells, and sinomenine and Tf-Sin-Lips were administered intravenously via tail vein to investigate the in vivo tissue distribution. The relative uptake rate (RUE) and peak concentration ratio (Ce) of Tf-Sin-Lips in tumor tissues were calculated based on the in vivo drug concentration of Sinomenine Injection. Thirty tumor-bearing mice were randomly divided into model (0.9% sodium chloride solution) group, cyclophosphamide (positive drug, 20 mg·kg^-1) group, sinomenine group (100 mg·kg^-1), and low and high dose groups of TfSin-Lips (50, 100 mg·kg^-1). The tumor growth in vivo among different groups of mice were compared. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatinine (Scr) in mice were determined by kits, and the main organs of mice were stained with hematoxylin-eosin (HE) for pathological analysis to evaluate the safety of Tf-Sin-Lips in vivo. Results The optimized Tf-Sin-Lips formulation was determined to be 20 mg of sinomenine dosage, 13.85∶ 1.00 drug loading ratio, 6.33∶ 1.00 phospholipid to cholesterol ratio, and 2 h of hydration time. The average encapsulation rate, drug loading amount, particle size and Zeta potential of Tf-Sin-Lips were (83.26 ± 1.17)%, (5.39 ± 0.09)%, (196.96 ± 5.19) nm and (-22.06 ± 1.20) mV, respectively. Tf-Sin-Lips presented a vesicular structure, and the suspension had a significant Tyndall effect. The in vitro drug release exhibited obvious sustained-release characteristics. The in vivo distribution experiments showed that Tf-SinLips could effectively change the in vivo tissue distribution characteristics of sinomenine, and the relative uptake rate and peak concentration ratio in tumor tissues were increased by 3.25 times and 3.57 times, respectively. The in vivo efficacy results indicated that the high-dose group of Tf-Sin-Lips could significantly inhibit tumor growth in tumor-bearing mice, with an inhibition rate of 65.42%. Safety tests showed that compared with the model group, the serum ALT, AST, BUN and SCR levels of mice in the sinomenine group and Tf-Sin-Lips group were significantly decreased (P<0.05, 0.01), and no obvious pathological damage was observed in the main organs of mice. Conclusion Tf-Sin-Lips significantly enhanced the tumor tissue targeting ability and in vivo anti-tumor effect of sinomenine, with good safety and potential for clinical application.

R285.5

河南省科技攻关项目（242102310571）；河南省科技攻关项目（252102310080）