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Abstract
The efficient delivery of sufficient amounts of nucleic acids into target cells is critical for successful gene therapy and gene knockdown. The DNA/siRNA co-delivery system has been considered a promising approach for cancer therapy to simultaneously express and inhibit tumor suppressor genes and overexpressed oncogenes, respectively, triggering synergistic anti-cancer effects. Polyethylenimine (PEI) has been identified as an efficient non-viral vector for transgene expression. In this study, we created a very high efficient DNA/siRNA co-delivery system by incorporating a negatively-charged poly-γ-glutamic acid (γ-PGA) into PEI/nucleic acid complexes. Spherical nanoparticles with about 200 nm diameter were formed by mixing PEI/plasmid DNA/siRNA/γ-PGA (dual delivery nanoparticles; DDNPs) with specific ratio (N/P/C ratio) and the particles present positive surface charge under all manufacturing conditions. The gel retardation assay shows both nucleic acids were effectively condensed by PEI, even at low N/P ratios. The PEI-based DDNPs reveal excellent DNA/siRNA transfection efficiency in the human hepatoma cell line (Hep 3B) by simultaneously providing high transgene expression efficiency and high siRNA silencing effect. The results indicated that DDNP can be an effective tool for gene therapy against hepatoma.
Highlights
Gene therapy is a promising strategy to treat challenging diseases by correcting or silencing defective genes
The results indicated that dual-delivery nanoparticle (DDNP) can be an effective tool for gene therapy against hepatoma
We present a novel effective PEI-based delivery system for co-delivery of gene and small interferenceRNA (siRNA) within one nanovehicle, which in the future may become a useful tool for anti-cancer gene therapy, providing synergistic therapeutic effects via simultaneous expression and silencing of target genes
Summary
Gene therapy is a promising strategy to treat challenging diseases by correcting or silencing defective genes. The therapeutic effects come from introducing genetic materials (DNA or RNA) to encode the correct version of mRNA and proteins that is missed/mutated in abnormal cells [1,2,3]. In addition to transfect cells with plasmid DNA carrying a specific gene, introducing the small interference. RNA (siRNA) is an alternative gene therapy which can knockdown the overexpressed defective genes [4,5,6]. The mechanism of the RNA interference (RNAi) technique is to induce gene-specific silencing via the cleavage of mRNA by RNA complexed with Dicer and other nucleases [7,8]. A pivotal challenge of gene-based therapy is to development safe and effective delivery vehicles. Viral vectors are efficient in gene delivery, there are several drawbacks, e.g., limited DNA packaging capacity, difficulty of vector production, and the safety issues such as virus insertion caused mutagenesis, Molecules 2017, 22, 86; doi:10.3390/molecules22010086 www.mdpi.com/journal/molecules
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