期刊
BIOCONJUGATE CHEMISTRY
卷 25, 期 2, 页码 414-423出版社
AMER CHEMICAL SOC
DOI: 10.1021/bc400552t
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资金
- National Key Basic Research Program of China [2013CB932502]
- National Science Foundation of China [30772655, 81101807]
- National Science and Technology Major Project [2012ZX09304004]
- Foundation Program of Key Laboratory of Smart Drug Delivery of the Ministry of Education [SDD2011-03]
- Fudan University Key Laboratory
The development of nonviral gene delivery vectors offers the potential to provide effective treatment for glioblastoma in the form of gene therapy. Here, we report the use of retro-inverso C-end rule (CendR) peptide (D)(RPPREGR) as a targeting ligand to prepare a (D)(RPPREGR)PEG-PEI gene vector. (D)(RPPREGR) peptide specifically recognized the neuropilin-1 receptor that was overexpressed on U87 glioma cells, and showed enhanced tumor spheroid penetration ability. Compared with parental RGERPPR, (D)(RPPREGR) possessed improved biological stability and had a higher affinity for U87 glioma cells; it also showed enhanced penetration of the tumor spheroid. mPEG-PEI/pDNA and (D)(RPPREGR)PEG-PEI/pDNA complexes were prepared and MTT assay results revealed that the cytotoxicity of (D)(RPPREGR)-PEG-PEI complexes was significantly lower than that of PEI complexes, with cell survival rates above 80%. Qualitative and quantitative in vitro transfection results revealed that (D)(RPPREGR)-PEG-PEI complex transfection efficiencies were 1.9 times higher than those of mPEG-PEI. Fluorescent imaging and frozen sections of brain tissue demonstrated that the (D)(RPPREGR) modification improved the in vivo transfection efficiency of mPEG-PEI in nude mice bearing U87 gliomas. An antiglioblastoma assay revealed that (D)(RPPREGR)-PEG-PEI carrying the therapeutic gene pORF-hTRAIL significantly prolonged the survival time of intracranial U87 glioma-bearing mice from 25 to 30 days. Therefore, (D)(RPPREGR)-PEG-PEI appears to be suitable for use as a safe and efficient gene delivery vehicle with potential applications in glioblastoma gene therapy.
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