Abstract
The efficient delivery of therapeutic genes into cells of interest is a critical challenge to broad application of non-viral vector systems. In this research, a novel TPGS-b-(PCL-ran-PGA) nanoparticle modified with polyethyleneimine was applied to be a vector of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and endostatin for cervical cancer gene therapy. Firstly, a novel biodegradable copolymer, TPGS-b-(PCL-ran-PGA), was synthesized and characterized. The nanoparticles were fabricated by an emulsion/solvent evaporation method and then further modified with polyethyleneimine (PEI) carrying TRAIL and/or endostatin genes. The uptake of pIRES2-EGFP and/or pDsRED nanoparticles by HeLa cells were observed by fluorescence microscopy and confocal laser scanning microscopy. The cell viability of TRAIL/endostatin-loaded nanoparticles in HeLa cells was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay. Severe combined immunodeficient mice carrying HeLa tumor xenografts were treated in groups of six including phosphate-buffered saline control, blank TPGS-b-(PCL-ran-PGA) nanoparticles, blank TPGS-b-(PCL-ran-PGA)/PEI nanoparticles, and three types of gene nanoparticles. The activity was assessed using average increase in survival time, body weight, and solid tumor volume. All the specimens were then prepared as formalin-fixed and paraffin-embedded tissue sections for hematoxylin-eosin staining. The data showed that the nanoparticles could efficiently deliver plasmids into HeLa cells. The cytotoxicity of the HeLa cells was significantly increased by TRAIL/endostatin-loaded nanoparticles when compared with control groups. The use of TPGS in combination with TRAIL and endostatin had synergistic antitumor effects. In conclusion, the TRAIL/endostatin-loaded nanoparticles offer considerable potential as an ideal candidate for in vivo cancer gene delivery.
Highlights
Cervical cancer caused by high-risk human papillomavirus (HPV) infection constitutes a major problem in women's health worldwide and is the fifth leading cause of cancer deaths among females [1,2]
For the first time, a novel Tocopheryl polyethylene glycol succinate (TPGS)-b-(PCL-ran-PGA) nanoparticle modified with polyethyleneimine was applied to be a vector of Tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and endostatin for cervical cancer gene therapy
The data showed that the nanoparticles could efficiently deliver plasmids into HeLa cells and the expression of TRAIL and endostatin was verified by RT-polymerase chain reaction (PCR) and Western blot analysis
Summary
Cervical cancer caused by high-risk human papillomavirus (HPV) infection constitutes a major problem in women's health worldwide and is the fifth leading cause of cancer deaths among females [1,2]. The binding of tumor necrosis factor and Fas ligand leads to the damage of normal tissues in addition to their proapoptotic effect on transformed cells [5,6], limiting their clinical applications. It was found to be a potent inhibitor of angiogenesis in vitro, and to have significant antitumor effects in a variety of xenograft-based cancer models and clinical trials [17]. These promising results lead to the rapid advance of this agent into the clinical test [17,18]. The use of endostatin in combination with other anticancer agents such as gemcitabine had synergistic antitumor activities [20]
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