Plasmid pORF-hTRAIL and doxorubicin co-delivery targeting to tumor using peptide-conjugated polyamidoamine dendrimer

被引:172
作者
Han, Liang [1 ]
Huang, Rongqin [1 ]
Li, Jianfeng [1 ]
Liu, Shuhuan [1 ]
Huang, Shixian [1 ]
Jiang, Chen [1 ]
机构
[1] Fudan Univ, Sch Pharm, Dept Pharmaceut, Shanghai 201203, Peoples R China
基金
国家高技术研究发展计划(863计划); 中国国家自然科学基金;
关键词
Combination cancer therapy; Co-delivery; Transferrin receptor; Peptide; Doxorubicin; pORF-hTRAIL; DNA-LOADED NANOPARTICLES; GENE DELIVERY; TRANSFERRIN-RECEPTOR; DRUG-DELIVERY; CANCER; CELLS; THERAPY;
D O I
10.1016/j.biomaterials.2010.09.070
中图分类号
R318 [生物医学工程];
学科分类号
0831 ;
摘要
A combination cancer therapy was investigated via co-delivery of therapeutic gene encoding human tumor necrosis factor-related apoptosis-inducing ligand (pORF-hTRAIL) and doxorubicin (DOX) using a tumor-targeting carrier, peptide HAIYPRH (T7)-conjugated polyethylene glycol-modified polyamidoamine dendrimer (PAMAM-PEG-T7). T7, a transferrin receptor-specific peptide, was chosen as the ligand to target the co-delivery system to the tumor cells expressing transferrin receptors. The result of fluorescence scanning showed that about 375 DOX molecules were bound to one pORF-hTRAIL molecule. The co-delivery system was constructed based on the electrostatic interactions between pORF-hTRAIL DOX complex and cationic PAMAM-PEG-T7. T7-modified co-delivery system showed higher efficiency in cellular uptake and gene expression than unmodified co-delivery system in human liver cancer Bel-7402 cells, and accumulated in tumor more efficiently in vivo. In comparison with single DOX or pORF-hTRAIL delivery system, co-delivery system induced apoptosis of tumor cells in vitro and inhibited tumor growth in vivo more efficiently. In mice bearing Bel-7402 xenografts, lower doses of co-delivery system (4 mu g DOX/mouse, about 0.16 mg/kg) effectively inhibited tumor growth comparable to high doses (5 mg/kg) of free doxorubicin (77% versus 69%). These results suggested that T7-mediated co-delivery system of DOX and pORF-hTRAIL was a simply prepared, combined delivery platform which can significantly improve the anti-tumor effect. This co-delivery system might widen the therapeutic window and allow for the selective destruction of cancer cells. Crown Copyright (C) 2010 Published by Elsevier Ltd. All rights reserved.
引用
收藏
页码:1242 / 1252
页数:11
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