Liposomal quercetin efficiently suppresses growth of solid tumors in murine models
Liposomal quercetin efficiently suppresses growth of solid tumors in murine models
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DOI：
10.1158/1078-0432.ccr-05-2365
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发表时间：
2006-05-15
影响因子：
11.5
通讯作者：
Wei, Yu-Quan
中科院分区：
文献类型：
--
作者：
Yuan, Zhi-ping;Chen, Li-juan;Wei, Yu-Quan
目的：槲皮素是一种有效的化疗药物。临床试验探索不同时间表的管理槲皮素已经阻碍了其极端的水不溶性。为了克服这一局限性，本研究旨在开发槲皮素脂质体，并研究其在体内的分布和体内外的抗肿瘤功效。实验设计：槲皮素包被聚乙二醇4000脂质体。采用高效液相色谱法检测槲皮素脂质体50 mg/kg在荷瘤小鼠体内的分布。研究槲皮素脂质体体外诱导细胞凋亡的作用。脂质体槲皮素对LL/2 Lewis肺癌C57BL/6N小鼠和CT26结肠癌、H22肝癌BALB/c小鼠的抗肿瘤活性进行了评价。观察肿瘤体积和生存时间。通过检测肿瘤组织微血管密度、细胞凋亡和热休克蛋白70的表达，探讨槲皮素抗肿瘤作用的体内机制。结果：槲皮素脂质体在静脉注射中能溶解，并在肿瘤组织中有效蓄积。槲皮素脂质体在血浆中的半衰期为2小时。槲皮素脂质体在体外诱导细胞凋亡，在体内显著抑制肿瘤生长，并呈剂量依赖性。槲皮素脂质体的最佳剂量导致40天存活率为40%。实时荧光定量PCR结果显示，槲皮素脂质体下调肿瘤组织中热休克蛋白70的表达。免疫组化分析显示，脂质体槲皮素抑制肿瘤血管生成，诱导肿瘤细胞凋亡。结论：聚乙二醇化槲皮素脂质体可显著提高槲皮素的溶解度和生物利用度，在肿瘤治疗中具有潜在的应用前景。
Purpose: Quercetin is a potent chemotherapeutic drug. Clinical trials exploring different schedules of administration of quercetin have been hampered by its extreme water insolubility. To overcome this limitation, this study is aimed to develop liposomal quercetin and investigate its distribution in vivo and antitumor efficacy in vivo and in vitro.Experimental Design: Quercetin was encapsulated in polyethylene glycol 4000 liposomes. Biodistribution of liposomal quercetin i.v. at 50 mg/kg in tumor-bearing mice was detected by high-performance liquid chromatography. Induction of apoptosis by liposomal quercetin in vitro was tested. The antitumor activity of liposomal quercetin was evaluated in the immunocompetent C57BL/6N mice bearing LL/2 Lewis lung cancer and in BALB/c mice bearing CT26 colon adenocarcinoma and H22 hepatoma. Tumor volume and survival time were observed. The mechanisms underlying the antitumor effect of quercetin in vivo was investigated by detecting the microvessel density, apoptosis, and heat shock protein 70 expression in tumor tissues.Results: Liposomal quercetin could be dissolved in i.v. injection and effectively accumulate in tumor tissues. The half-time of liposomal quercetin was 2 hours in plasma. The liposomal quercetin induced apoptosis in vitro and significantly inhibited tumor growth in vivo in a dose-dependent manner. The optimal dose of liposomal quercetin resulted in a 40-day survival rate of 40%. Quantitative real-time PCR showed that liposomal quercetin down-regulated the expression of heat shock protein 70 in tumor tissues. Immunohistochemistry analysis showed that liposomal quercetin inhibited tumor angiogenesis as assessed by CD31 and induced tumor cell apoptosis.Conclusions: Our data indicated that pegylated liposomal quercetin can significantly improve the solubility and bioavailability of quercetin and can be a potential application in the treatment of tumor.