目的 为解决槲皮素水溶性差的问题，制备一种高载药量、适合静脉给药的纳米混悬剂，并探究其体内外抗肿瘤作用。方法 采用反溶剂沉淀联合高压均质法，以聚乙二醇1000维生素E琥珀酸酯（TPGS）为稳定剂制备了槲皮素纳米混悬剂（quercetin nanosuspensions，Q-NSps）。动态光散射法测定粒径，扫描电镜观察其形态，HPLC法测定其载药量和体外药物释放情况，并考察了其冻干保护、放置稳定性、溶血和静脉注射的适宜性；MTT法检测槲皮素及其纳米混悬剂对4T1、HeLa、HepG2细胞的生长抑制作用；以4T1荷瘤小鼠模型对比考察其体内抗肿瘤效果。结果 制备的Q-NSps大小均匀，呈球型，平均粒径143.9 nm，PDI为0.231，表面电位-22.6 mV；载药量（45.82±1.73）%，用1%麦芽糖为保护剂冻干复溶后粒径变化不大；Q-NSps 30 d放置稳定，不溶血，可静脉注射；体外有良好的缓释作用，144 h累积释放82.86%；对4T1、HeLa、HepG2的生长抑制均显著高于游离药物，在体内研究中，45 mg/kg的Q-NSps与阳性药紫杉醇注射液（8 mg/kg）表现出相同的抑瘤效果（56.78%vs 55.08%，P>0.05）。结论 制备的Q-NSps粒径小，稳定性好，显著提高了槲皮素体内外抗肿瘤效果，有望成为一种抗肿瘤药物用于临床。

Objective In order to solve the problem of poor water solubility of quercetin, quercetin nanosuspensions (Q-NSps) with high drug loading and suitable for intravenous administration was prepared, and study its anti-tumor effect in vitro and in vivo.Methods Quercetin was made into nanoparticles (Q-NSps) via the method of anti-solvent precipitation combined with high-pressure homogenization using polyethylene glycol 1 000 vitamin E succinate (TPGS) as stabilizer. The particle size of the resultant nanoparticles was measured by dynamic light scattering and the morphology was observed by scanning electron microscopy. The drug loading and the in vitro drug release were measured using HPLC analysis. In the meantime, the lyoprotectants were screened, the storage stability, hemolysis, and the suitability for intravenous injection were also studied; The in vitro anti-tumor activity of quercetin and its nanoparticles were assessed in contrast using MTT assay and the in vivo anti-tumor therapeutic efficacy was investigated using 4T1 tumor bearing mice.Results Q-NSps had uniform size and spherical shape, the average particle size was 143.9 nm, the polydispersity index (PDI) was 0.231, and the Zeta potential was -22.6 mV. The drug loading content was (45.82 ±1.73)%. Using 1% maltose as lyoprotectant, Q-NSps could be lyophilized and then reconstituted into nanoparticles of the similar size. Q-NSps were stable for 30 d at storage, showed no hemolysis, and were suitable to intravenous administration. The resultant nanosuspensions displayed a good sustained in vitro release, and the cumulative release reaching 82.86% at 144 h. Q-NSps showed significantly higher growth inhibition against 4T1, HeLa, and HepG2 cell lines. The in vivo study demonstrated that Q-NSps (45 mg/kg, iv) had the similar antitumor therapeutic efficacy as paclitaxel injections (56.78% vs 55.08%, P > 0.05).Conclusion The obtained Q-NSps had small particle size, good stability, and significantly improved anti-tumor effect of quercetin in vitro and in vivo, so Q-NSps are promising to be a antitumor drug for application in clinic.

国家自然科学基金-广东联合基金资助项目（U1401223）