纳米脂质体槲皮素对肝癌腹水抑制效应实验研究

Nanoliposomal Quercetin Inhibits Formation of Malignant Ascites of Hepatocellular Carcinoma

背景与目的:槲皮素是一种具有多种生物活性、潜在的化疗药物,但由于不溶于水限制了其临床运用。本研究探讨用纳米脂质体包裹的槲皮素在小鼠体内分布及对肝细胞癌腹水生成的影响。方法:用旋转蒸发法制备纳米脂质体槲皮素,于BALB/c小鼠右前腋下接种肝癌细胞H2212天后,每只小鼠静脉给纳米脂质体槲皮素1.5mg,采用高压液相色谱法(highpressureliquidchromatography,HPLC)测定不同时间点血浆、正常组织和肿瘤组织中槲皮素含量。观察不同浓度的纳米脂质体槲皮素对腹水生成的抑制作用。100mg/kg纳米脂质体槲皮素处理肝癌腹水小鼠模型,观察小鼠存活期、体重及腹腔渗透性变化,流式细胞仪分析腹水中凋亡细胞比例。结果:纳米脂质体槲皮素粒径为(130±20)nm,含药量为25%(重量比)。纳米脂质体槲皮素能有效聚集在肿瘤组织,在BALB/c小鼠体内半衰期为4h。纳米脂质体槲皮素在体内抑制腹水形成与药物浓度有关。100mg/kg的纳米脂质体槲皮素可延长肝癌小鼠的存活时间,减少腹膜的通透性,增加腹水内凋亡细胞比例。结论:纳米脂质体槲皮素能有效积聚在肿瘤组织中并抑制癌性腹水生成,是一种有希望的抗肿瘤药物,值得进一步研究。

BACKGROUND ＆ OBJECTIVE： Quercetin is a potential chemotherapeutic drug with many biological activities. However, the insolubility of quercetin seriously limits its clinical use. This study was to investigate the biodistribution of quercetin encapsulated by pegylated nanoliposomes and its therapeutic efficacy on the formation of carcinomatous ascites of hepatocellular carcinoma in mice. METHODS： Nanoliposomal quercetin was prepared with conventional rotary evaporation method. BALB/c mice inoculated with hepatocellular carcinoma cells （H22） at the anterior right subaxilla for twelve days were given intravascular injection with nanoliposomal quercetin at 1.5 mg/body （based on quercetin） at different time points. Then the levels of quercetin in the plasma, tumor tissues and normal organs were tested by high pressure liquid chromatography （HPLC）. Various dosages of nanoliposomal quercetin were peritoneally given to tumor-bearing mice to determine the optimal dose. The tumor-bearing mice were treated intraperitoneally with 100 mg/kg nanoliposomal quercetin once a day for 14 days. The formation of malignant ascites, increase of body weight, survival time and peritoneal capillary permeability were assessed. Apoptotic cells in ascites were detected by flow cytometry. RESULTS. Nanoliposomal quercetin was a spherical particle with 25% drug content （W/W） and 130±20 nm in diameter. Nanoliposomal quercetin effectively aggregated in tumor tissues and its halflife period was 4 h. Nanoliposome quercetin inhibited the formation of malignant ascites of hepatocellular carcinoma model in a dose-dependent manner. Moreover, 100 mg/kg nanoliposomal quercetin significantly enhanced the apoptosis of cancer cells in ascites, inhibited the increase of body weight, reduced peritoneal capillary permeability and prolonged the survival time of tumor-bearing mice compared with PBS control. CONCLUSION： Nanoliposomal quercetin can effectively accumulate in tumor tissues and inhibit the formation of malignant ascites, thus it might be used as a potential antitumor drug which deserves future study.