Abstract
Small interfering RNA (siRNA) has increased the hope for highly-efficient treatment of gene-related diseases. However, the stable and efficient delivery of therapeutic nucleic acids is a prerequisite for the successful clinical translation of RNA interfering therapy. To achieve this, we condensed the low molecular weight polyethyleneimine (PEI, Mw < 2000) with 2,6-pyridinedicarboxaldehyde (PDA) to synthesize a biologically responsive and degradable cationic polymer (abbreviated to PDAPEI) which was utilized as a gene vector for the delivery of a VEGF-A shRNA expression plasmid DNA (pDNA). The resulting electrostatic interaction between PDAPEI and pDNA led to the self-assembly of nanoscale polyplexes with suitable particle size and stable zeta potential. The PDAPEI/pDNA polyplexes demonstrated an outstanding gene transfection and silencing efficiency at 30 w/w ratio, as well as negligible cytotoxicity. Also, the designed polymer showed no stimulation to the innate immune system. Moreover, compared with PEI 25 KDa, the polyplexes accomplished comparatively better anti-angiogenesis efficacy, which resulted in the inhibition of tumor growth in subcutaneous tumor mice models. In conclusion, PDAPEI has great potential to be a gene delivery vector for cancer therapy.
Highlights
The process of tumor angiogenesis is generally divided into two phases: non-vascular phase and vascular phase[1]
The Dicer hands off the Small interfering RNA (siRNA) to RNA-induced silencing complex (RISC), which combines with the target mRNA by intermolecular base pairing[20,21]
The agarose gel electrophoresis result proved that polycationic material PDAPEI can effectively condense plasmid DNA at a small ratio
Summary
The process of tumor angiogenesis is generally divided into two phases: non-vascular phase and vascular phase[1]. Polyethylenimine (PEI) consisting of repeating units of amine group and -CH2CH2- group is a representative polycationic vector, whose transfection efficiency increases with the increase of molecular weight, while accompanied by higher cytotoxicity[22,23]. To solve these problems, a safe and effective gene vector is required to achieve intracellular bioactivity. We combined the positive charged PEI (any of Mw < 2000) with PDA to obtain a new vector, PDAPEI, for the targeted delivery of plasmid to tumor cells (Fig. 1). Previous studies demonstrated that PDA cross-linked with PEI could metabolize itself into low-molecular-weight PEI of negligible cytotoxicity and PDA in the acidic environment[24,25]
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