期刊
ADVANCED FUNCTIONAL MATERIALS
卷 25, 期 18, 页码 2646-2659出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/adfm.201404629
关键词
-
类别
资金
- NCI/SBIR [HHSN261201300078C]
- NIH/NIGMS [R01GM089918]
- NIH/NIDDK [R41DK094571]
- NIH/NCI [U54CA112970]
- Prospect Creek Foundation
- OHSU's KCI pilot award
- OHSU's VPR fund
In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. A new nanoparticle construct that is engineered for efficient delivery of siRNA to tumors is now described. The construct comprises a 47-nm mesoporous silica nanoparticle core coated with a crosslinked polyethyleneimine-polyethyleneglycol copolymer, carrying siRNA against the human epidermal growth factor receptor type 2 (HER2) oncogene, and coupled to the anti-HER2 monoclonal antibody (trastuzumab). The construct is engineered to increase siRNA blood half-life, enhance tumor-specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti-HER2 nanoparticles produce apoptotic death in HER2 positive (HER2(+)) breast cancer cells grown in vitro, but not in HER2 negative (HER2(-)) cells. One dose of the siHER2-nanoparticles reduces HER2 protein levels by 60% in trastuzumab-resistant HCC1954 xenografts. Administration of multiple intravenous doses over 3 weeks significantly inhibits tumor growth (p < 0.004). The siHER2-nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch-to-batch reproducibility and the production methods are suitable for large-scale production. These results suggest that this siHER2-nanoparticle is ready for clinical evaluation.
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