Abstract
The biggest challenge in the field of gene therapy is how to effectively deliver target genes to special cells. This study aimed to develop a new type of poly(D,L-lactide-co-glycolide) (PLGA)-based nanoparticles for gene delivery, which are capable of overcoming the disadvantages of polyethylenimine (PEI)- or cationic liposome-based gene carrier, such as the cytotoxicity induced by excess positive charge, as well as the aggregation on the cell surface. The PLGA-based nanoparticles presented in this study were synthesized by emulsion evaporation method and characterized by transmission electron microscopy, dynamic light scattering, and energy dispersive spectroscopy. The size of PLGA/PEI nanoparticles in phosphate-buffered saline (PBS) was about 60 nm at the optimal charge ratio. Without observable aggregation, the nanoparticles showed a better monodispersity. The PLGA-based nanoparticles were used as vector carrier for miRNA transfection in HepG2 cells. It exhibited a higher transfection efficiency and lower cytotoxicity in HepG2 cells compared to the PEI/DNA complex. The N/P ratio (ratio of the polymer nitrogen to the DNA phosphate) 6 of the PLGA/PEI/DNA nanocomplex displays the best property among various N/P proportions, yielding similar transfection efficiency when compared to Lipofectamine/DNA lipoplexes. Moreover, nanocomplex shows better serum compatibility than commercial liposome. PLGA nanocomplexes obviously accumulate in tumor cells after transfection, which indicate that the complexes contribute to cellular uptake of pDNA and pronouncedly enhance the treatment effect of miR-26a by inducing cell cycle arrest. Therefore, these results demonstrate that PLGA/PEI nanoparticles are promising non-viral vectors for gene delivery.
Highlights
MicroRNAs are small, highly conserved, noncoding RNAs that regulate gene expression at the posttranscriptional level
In order to overcome these hurdles in gene therapy and improve gene delivery efficiency, we developed novel non-liposome-based cationic polymers which are composed of PLGA as the core and cationic PEI as the shell
PLGA nanoparticles with smaller size below 100 nm have been proved to gain higher gene transfection efficiency than those of 200 nm [28,29]
Summary
MicroRNAs (miRNAs) are small, highly conserved, noncoding RNAs that regulate gene expression at the posttranscriptional level. They involve in various cellular mechanisms including development, differentiation, proliferation, and apoptosis. The disadvantages of viral vectors limited their application in gene delivery, such as immunogenic/ inflammatory responses, low loading capacity, large scale manufacturing, and quality control [5]. Polyethylenimine (PEI) is water-soluble, linear, or branched polymers with a protonable amino group [14,15]. Due to their high cationic charge density at physiological pH, PEIs are able to form non-covalent complexes with DNA, siRNA, and antisense oligodeoxynucleotide
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