目的 构建半乳糖修饰的pH敏感型青蒿琥酯纳米囊泡（Gal-Art-NVs），考察其体内组织分布及抗肿瘤作用。方法 采用乙醇注入法制备Gal-Art-NVs。以包封率、载药量、粒径为指标，通过单因素实验结合Box-Behnken响应面法优化Gal-ArtNVs处方工艺，并将其制备成冻干粉。透射电镜观察Gal-Art-NVs微观形态，体外透析法考察其在pH 5.0、5.5、6.5、7.4磷酸盐缓冲液中的释药行为。建立肝癌大鼠模型，采用尾iv给药，测定不同时间点青蒿琥酯注射液和Gal-Art-NVs在各组织中的药物质量浓度，计算相对摄取率（RUE）和峰浓度比值（Ce），评价该给药系统的体内靶向性；同时计算抑瘤率以评价Gal-Art-NVs的体内抗肿瘤效果。结果 Gal-Art-NVs最佳处方为：青蒿琥酯质量浓度为0.98 mg·mL^-1，失水山梨醇单油酸酯与胆固醇琥珀酸单酯用量比为1.93∶ 1.00，囊材与青蒿琥酯用量比为20.77∶ 1.00，半乳糖硬脂酸酯用量为囊材总质量的8%。优化后Gal-ArtNVs平均包封率为（85.68± 1.07）%，载药量为（3.91± 0.14）%，粒径为（183.76± 7.60） nm，ζ电位为（-26.79±1.04） mV，呈椭圆形囊泡状。该纳米囊泡在pH 5.0、5.5磷酸盐缓冲液中可显著提高青蒿琥酯的释药速率及累积释放率，表现出明显的pH敏感性。与青蒿琥酯注射液相比，Gal-Art-NVs在肿瘤组织的RUE和Ce分别增至3.02倍和1.95倍；与模型组相比，GalArt-NVs可显著抑制荷瘤裸鼠的肿瘤生长，Gal-Art-NVs组（30 mg·kg^-1）抑瘤率达64.21%。结论 Gal-Art-NVs具有pH敏感性，能增加青蒿琥酯在肿瘤部位蓄积，从而有效提高其抗肿瘤药效。

Objective To construct galactose-modified pH-sensitive artesunate nanovesicles (Gal-Art-NVs) and investigate their in vivo tissue distribution and anti-tumor efficacy. Methods Gal-Art-NVs were prepared by the ethanol injection method. The formulation process was optimized based on the encapsulation efficiency, drug loading, and particle size through single-factor experiments combined with the Box-Behnken response surface method, and then freeze-dried. The microscopic morphology of GalArt-NVs was observed by transmission electron microscopy, and their drug release behavior in phosphate buffer solutions at pH 5.0, 5.5, 6.5, and 7.4 was investigated by in vitro dialysis. A rat model of liver cancer was established, and tail intravenous administration was used to determine the drug concentration in various tissues at different time points for artesunate injection and Gal-Art-NVs, the relative uptake rate (RUE) and peak concentration ratio (Ce) were calculated to evaluate the in vivo targeting of the drug delivery system. Meanwhile, the tumor inhibition rate was calculated to evaluate the in vivo anti-tumor effect of Gal-Art-NVs. Results The optimal formulation of Gal-Art-NVs was as follows: Artesunate concentration of 0.98 mg·mL^-1, the ratio of sorbitan monooleate 80 to cholesterol succinate was 1.93∶ 1.00, the ratio of the carrier to artesunate was 20.77∶ 1.00, and the amount of galactose stearate was 8% of the total carrier mass. After optimization, the average encapsulation efficiency of Gal-Art-NVs was (85.68 ± 1.07)%, the drug loading was (3.91 ± 0.14)%, the particle size was (183.76 ± 7.60) nm, and the ζ potential was (-26.79 ± 1.04) mV, presenting an elliptical vesicular shape. The nanovesicles significantly increased the drug release rate and cumulative release rate of artesunate in phosphate buffer solutions at pH 5.0 and 5.5, demonstrating obvious pH sensitivity. Compared with artesunate injection, the RUE and Ce of Gal-Art-NVs in tumor tissues increased by 3.02 times and 1.95 times, respectively. Compared with the model group, Gal-ArtNVs significantly inhibited tumor growth in nude mice bearing tumors, with an inhibition rate of 64.21% in the Gal-Art-NVs group (30 mg·kg^-1). Conclusion Gal-Art-NVs have pH sensitivity and can increase the accumulation of artesunate in tumor sites, thereby effectively enhancing its anti-tumor efficacy.

R283.6

2024 年河南省科技发展计划资助项目（242102310295）； 2024 年河南省医学科技攻关计划项目（LHGJ20240330）； 2025 年度校级重点科研项目（2025-XJKY-50）