Improving penetration in tumors with nanoassemblies of phospholipids and doxorubicin
Improving penetration in tumors with nanoassemblies of phospholipids and doxorubicin
复制标题
利用磷脂和阿霉素纳米组合物提高肿瘤渗透性
DOI：
10.1093/jnci/djm027
复制
发表时间：
2007-07-04
影响因子：
10.3
通讯作者：
Liang, Wei
中科院分区：
文献类型：
--
作者：
Tang, Ning;Du, Gangjun;Liang, Wei
背景 药物递送和渗透到远离肿瘤血管的肿瘤细胞对于实体瘤化疗的有效性至关重要。我们假设含有阿霉素的 10 至 20 nm 磷脂纳米组装体可以提高药物的渗透、积累和抗肿瘤活性。方法通过自组装程序将阿霉素掺入聚乙二醇-磷脂酰乙醇胺 (PEG-PE) 嵌段共聚物胶束中，形成纳米组装体 阿霉素和 PEG-PE。采用甲基噻唑四唑法检测胶束包裹的阿霉素（M-Dox）对A549人非小细胞肺癌细胞的体外细胞毒性，并使用共聚焦显微镜、全内反射荧光显微镜和流式细胞术检测细胞内分布和细胞摄取机制。用 M-Dox 或游离阿霉素治疗携带皮下或肺 Lewis 肺癌 (LLC) 肿瘤的 C57B1/6 小鼠（每组 n = 10-40），并比较肿瘤生长、阿霉素药代动力学和死亡率。在无肿瘤小鼠中分析毒性。所有统计检验都是双向的。结果将阿霉素封装在PEG-PE胶束中增加了其被A549细胞内化到溶酶体中并增强了细胞毒性。药物封装的阿霉素在抑制皮下 LLC 肿瘤模型中的肿瘤生长方面更有效（用 5 mg/kg M-Dox 治疗的小鼠的平均肿瘤体积 = 1126 mm(3)，对照小鼠的平均肿瘤体积 = 3693 mm(3)，差异 = 2567 mm(3)，95% 置信区间 [CI] = 2190 至 2943 mm(3)，P
Background Drug delivery and penetration into neoplastic cells distant from tumor vessels is critical for the effectiveness of solid tumor chemotherapy. We hypothesized that 10- to 20-nm nanoassemblies of phospholipids containing doxorubicin would improve the drug's penetration, accumulation, and antitumor activity.Methods Doxorubicin was incorporated into polyethylene glycol-phosphatidylethanolamine (PEG-PE) block copolymer micelles by a self-assembly procedure to form nanoassemblies of doxorubicin and PEG-PE. In vitro cytotoxicity of micelle-encapsulated doxorubicin (M-Dox) against A549 human non-small-cell lung carcinoma cells was examined using the methylthiazoletetrazolium assay, and confocal microscopy, total internal reflection fluorescence microscopy, and flow cytometry were used to examine intracellular distribution and the cellular uptake mechanism. C57B1/6 mice (n = 10-40 per group) bearing subcutaneous or pulmonary Lewis lung carcinoma (LLC) tumors were treated with M-Dox or free doxorubicin, and tumor growth, doxorubicin pharmacokinetics, and mortality were compared. Toxicity was analyzed in tumor-free mice. All statistical tests were two-sided.Results Encapsulation of doxorubicin in PEG-PE micelles increased its internalization by A549 cells into lysosomes and enhanced cytotoxicity. Drug-encapsulated doxorubicin was more effective in inhibiting tumor growth in the subcutaneous LLC tumor model (mean tumor volumes in mice treated with 5 mg/kg M-Dox = 1126 mm(3) and in control mice = 3693 mm(3), difference = 2567 mm(3), 95% confidence interval [CI] = 2190 to 2943 mm(3), P