期刊
BIOMATERIALS
卷 35, 期 26, 页码 7543-7552出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2014.05.021
关键词
Targeted gene delivery; Cancer gene therapy; RGD peptides; VEGF siRNA; Bio-reducible polymer
资金
- NIH [CA107070]
Targeted delivery of therapeutic genes to the tumor site is critical for successful and safe cancer gene therapy. The arginine grafted bio-reducible poly (cystamine bisacrylamide-diaminohexane, CBA-DAH) polymer (ABP) conjugated poly (amido amine) (PAMAM), PAM-ABP (PA) was designed previously as an efficient gene delivery carrier. To achieve high efficacy in cancer selective delivery, we developed the tumor targeting bio-reducible polymer, PA-PEG(1k)-RGD, by conjugating cyclic RGDfC (RGD) peptides, which bind alpha(v)beta(3/5) integrins, to the PAM-ABP using polyethylene glycol (PEG, 1 kDa) as a spacer. Physical characterization showed nanocomplex formation with bio-reducible properties between PA-PEG(1k)-RGD and plasmid DNA (pDNA). In transfection assays, PA-PEG(1k)-RGD showed significantly higher transfection efficiency in comparison with PAM-ABP or PA-PEGll,-RAD in alpha(v)beta(3/5) positive MCF7 breast cancer and PANC-1 pancreatic cancer cells. The targeting ability of PA-PEGik-RGD was further established using a competition assay. To confirm the therapeutic effect, the VEGF siRNA expressing plasmid was constructed and then delivered into cancer cells using PA-PEGik-RGD. PA-PEGik-RGD showed 20-59% higher cellular uptake rate into MCF7 and PANC-1 than that of non-targeted polymers. In addition, MCF7 and PANC-1 cancer cells transfected with PA-PEGik-RGD/pshVEGF complexes had significantly decreased VEGF gene expression (51-71%) and cancer cell viability (35-43%) compared with control. These results demonstrate that a tumor targeting bio-reducible polymer with an anti-angiogenic therapeutic gene could be used for efficient and safe cancer gene therapy. (C) 2014 Elsevier Ltd. All rights reserved.
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