期刊
BIOMACROMOLECULES
卷 14, 期 10, 页码 3723-3730出版社
AMER CHEMICAL SOC
DOI: 10.1021/bm401098w
关键词
-
资金
- National Natural Science Foundation of China [NSFC 51003070, 51103093, 51173126, 51273137, 51273139]
- National Science Fund for Distinguished Young Scholars [51225302]
- Priority Academic Program Development of Jiangsu Higher Education Institutions
The therapeutic performance of biodegradable micellar drugs is far from optimal due to existing challenges like poor tumor cell uptake and intracellular drug release. Here, we report on ligand-directed reduction-sensitive shell-sheddable biodegradable micelles based on poly(ethylene glycol)-poly(epsilon-caprolactone) (PEG-PCL) copolymer actively delivering doxorubicin (DOX) into the nuclei of target cancer cells, inducing superb in vitro antitumor effects. The micelles were constructed from PEG-SS-PCL and galactose-PEG-PCL (Gal-PEG-PCL) block copolymers, in which Gal-PEG-PCL was designed with a longer PEG than that in PEG-SS-PCL (6.0 vs 5.0 kDa) to fully expose Gal ligands onto the surface of micelles for effective targeting to hepatocellular carcinoma cells. PEG-SS-PCL combining with 10 or 20 wt % of Gal-PEG-PCL formed uniform micelles with average sizes of 56.1 and 58.2 nm (denoted as PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20, respectively). The in vitro release studies showed that about 81.1 and 75.0% DOX was released in 12 h from PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under a reducing condition containing 10 mM dithiothreitol (DTT). In contrast, minimal DOX release (<12%) was observed for PEG-SS-PCL/Gal10 and PEG-SS-PCL/Gal20 micelles under nonreducing conditions as well as for reduction-insensitive Gal-PEG-PCL and PEG-PCL/Gal20 micelles in the presence of 10 mM DTT. MTT assays in HeLa and HepG2 cells showed that DOX-loaded PEG-SS-PCL/Gal20 micelles exhibited apparent targetability and significantly enhanced antitumor efficacy toward asialoglycoprotein receptor (ASGP-R)-overexpressing HepG2 cells with a particularly low half maximal inhibitory concentration (IC50) of 1.58 mu g DOX equiv/mL, which was comparable to free DOX and approximately six times lower than that for nontargeting PEG-SS-PCL counterparts under otherwise the same conditions. Interestingly, confocal microscopy observations using FITC-labeled PEG-SS-PCL/Gal20 micelles showed that DOX was efficiently delivered and released into the nuclei of HepG2 cells in 8 h. Flow cytometry revealed that cellular DOX level in HepG2 cells treated with DOX-loaded PEG-SS-PCL/Gal20 micelles was much greater than that with reduction-insensitive PEG-PCL/Gal20 and nontargeting PEG-SS-PCL controls, signifying the importance of combining shell-shedding and active targeting. Ligand-directed, reduction-sensitive, shell-sheddable, and biodegradable micelles have emerged as a versatile and potent platform for targeted cancer chemotherapy.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据