5-Fluorouracil nanoparticles inhibit hepatocellular carcinoma via activation of the p53 pathway in the orthotopic transplant mouse model.
5-Fluorouracil nanoparticles inhibit hepatocellular carcinoma via activation of the p53 pathway in the orthotopic transplant mouse model.
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DOI：
10.1371/journal.pone.0047115
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Ye T
中科院分区：
文献类型：
--
作者：
Cheng M;He B;Wan T;Zhu W;Han J;Zha B;Chen H;Yang F;Li Q;Wang W;Xu H;Ye T
可生物降解的聚合物纳米颗粒药物递送系统提供靶向药物递送、改善的药代动力学和生物分布、增强的药物稳定性和更少的副作用。这些药物递送系统广泛用于递送细胞毒性剂。本研究将半乳糖基化壳聚糖（GC）材料与5-FU复合，制备了GC/5-FU纳米粒，并进行了体内外抗肝癌实验。该缓释系统的体外抗癌作用具有剂量和时间依赖性，对肝癌细胞的细胞毒性高于对其他细胞类型。GC/5-FU在体内的分布显示在肝癌组织中的蓄积最大。GC/5-FU显著抑制了正交异性肝癌小鼠模型中的肿瘤生长，与5-FU单独给药相比，肿瘤重量显著减轻，存活时间延长。流式细胞术和TUNEL法检测表明，GC/5-FU与肝癌细胞G 0-G1期阻滞和凋亡率相关。凋亡途径分析表明，GC/5-FU上调p53蛋白和mRNA水平的表达。这反过来又降低Bcl-2/Bax表达，导致线粒体释放细胞色素C进入胞质溶胶，随后激活半胱天冬酶-3。caspase-3表达的上调在mRNA和蛋白水平上降低了聚ADP-核糖聚合酶1（PARP-1），进一步促进了细胞凋亡。这些发现表明，在小鼠正向异性肝癌小鼠模型中，GC/5-FU纳米颗粒的缓释比5-FU单药治疗更有效地靶向肝癌细胞。
Biodegradable polymer nanoparticle drug delivery systems provide targeted drug delivery, improved pharmacokinetic and biodistribution, enhanced drug stability and fewer side effects. These drug delivery systems are widely used for delivering cytotoxic agents. In the present study, we synthesized GC/5-FU nanoparticles by combining galactosylated chitosan (GC) material with 5-FU, and tested its effect on liver cancer in vitro and in vivo. The in vitro anti-cancer effects of this sustained release system were both dose- and time-dependent, and demonstrated higher cytotoxicity against hepatic cancer cells than against other cell types. The distribution of GC/5-FU in vivo revealed the greatest accumulation in hepatic cancer tissues. GC/5-FU significantly inhibited tumor growth in an orthotropic liver cancer mouse model, resulting in a significant reduction in tumor weight and increased survival time in comparison to 5-FU alone. Flow cytometry and TUNEL assays in hepatic cancer cells showed that GC/5-FU was associated with higher rates of G0–G1 arrest and apoptosis than 5-FU. Analysis of apoptosis pathways indicated that GC/5-FU upregulates p53 expression at both protein and mRNA levels. This in turn lowers Bcl-2/Bax expression resulting in mitochondrial release of cytochrome C into the cytosol with subsequent caspase-3 activation. Upregulation of caspase-3 expression decreased poly ADP-ribose polymerase 1 (PARP-1) at mRNA and protein levels, further promoting apoptosis. These findings indicate that sustained release of GC/5-FU nanoparticles are more effective at targeting hepatic cancer cells than 5-FU monotherapy in the mouse orthotropic liver cancer mouse model.
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DOI：
10.1158/1940-6207.capr-10-0006
发表时间：
2011-08
期刊：
Cancer prevention research (Philadelphia, Pa.)
影响因子：
--
作者：
Bansal SS;Goel M;Aqil F;Vadhanam MV;Gupta RC
通讯作者：
Gupta RC
影响因子：
14
作者：
Burke, Andrew R.;Singh, Ravi N.;Carroll, David L.;Wood, James C. S.;D'Agostino, Ralph B., Jr.;Ajayan, Pulickel M.;Torti, Frank M.;Torti, Suzy V.
通讯作者：
Torti, Suzy V.
影响因子：
5.8
作者：
Alex, Susan M.;Rekha, M. R.;Sharma, Chandra P.
通讯作者：
Sharma, Chandra P.
影响因子：
2.2
作者：
Lee, Jun Sik;Jung, Won-Kyo;Kim, Hyung Keun
通讯作者：
Kim, Hyung Keun
DOI：
10.1016/j.ejpb.2005.02.011
发表时间：
2005-08-01
影响因子：
4.9
作者：
Gao, SY;Chen, JN;Zhang, JF
通讯作者：
Zhang, JF