Abstract
RNA interference (RNAi) has significant therapeutic promise for the genetic treatment of hepatocellular carcinoma (HCC). Targeted vectors are able to deliver small interfering RNA (siRNA) into HCC cells with high transfection efficiency and stability. The tripeptide arginine glycine aspartic acid (RGD)-modified non-viral vector, polyethylene glycol-grafted polyethylenimine functionalized with superparamagnetic iron oxide nanoparticles (RGD-PEG-g-PEI-SPION), was constructed as a magnetic resonance imaging (MRI)-visible nanocarrier for the delivery of Survivin siRNA targeting the human HCC cell line Bel-7402. The biophysical characterization of the RGD-PEG-g-PEI-SPION was performed. The RGD-modified complexes exhibited a higher transfection efficiency in transferring Survivin siRNA into Bel-7402 cells compared with a non-targeted delivery system, which resulted in more significant gene suppression at both the Survivin mRNA and protein expression levels. Then, the level of caspase-3 activation was significantly elevated, and a remarkable level of tumor cell apoptosis was induced. As a result, the tumor growth in the nude mice Bel-7402 hepatoma model was significantly inhibited. The targeting ability of the RGD-PEG-g-PEI-SPION was successfully imaged by MRI scans performed in vitro and in vivo. Our results strongly indicated that the RGD-PEG-g-PEI-SPION can potentially be used as a targeted non-viral vector for altering gene expression in the treatment of hepatocellular carcinoma and for detecting the tumor in vivo as an effective MRI probe.
Highlights
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third most common cause of cancerrelated deaths worldwide [1]
The overlapping of the red and green fluorescence of cells incubated with RGD-polyethylene glycol (PEG)-gPEI-superparamagnetic iron oxide nanoparticles (SPION)/small interfering RNA (siRNA) generated yellow stains in the merged images. These results indicate that the RGD-modified non-viral vector, RGD-PEG-g-PEI-SPION, can deliver more siRNA into Bel-7402 cells compared to the PEG-g-PEI-SPION
Our results showed that this vector could effectively deliver a therapeutic gene into neuroblastoma cells, which resulted in a satisfactory antitumor effect and a tumor MR imaging effect [14].This inspiring success led us to further explore targeted gene therapy and MR localization of hepatocellular carcinoma
Summary
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and the third most common cause of cancerrelated deaths worldwide [1]. Diabetes, obesity and excessive alcohol intake, the incidence of HCC is steadily increasing [2]. Conventional surgical management in the early stages of HCC includes local excision, liver transplantation, radiofrequency ablation and ethanol injection. More than half of the HCC patients are diagnosed too late to benefit from these curative therapies [3]. The majority of patients with advanced HCC do not have a curative response to palliative treatments, such as radiotherapy and chemotherapy, which can only afford a modest survival benefit for some HCC patients. To attain better treatments for hepatocellular carcinoma, gene therapy has been explored
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