Abstract
The delivery of small interfering RNAs (siRNA) is an efficient method for gene silencing through the induction of RNA interference (RNAi). It critically relies, however, on efficient vehicles for siRNA formulation, for transfection in vitro as well as for their potential use in vivo. While polyethylenimines (PEIs) are among the most studied cationic polymers for nucleic acid delivery including small RNA molecules, polypropylenimines (PPIs) have been explored to a lesser extent. Previous studies have shown the benefit of the modification of small PEIs by tyrosine grafting which are featured in this paper. Additionally, we have now extended this approach towards PPIs, presenting tyrosine-modified PPIs (named PPI-Y) for the first time. In this study, we describe the marked improvement of PPI upon its tyrosine modification, leading to enhanced siRNA complexation, complex stability, siRNA delivery, knockdown efficacy and biocompatibility. Results of PPI-Y/siRNA complexes are also compared with data based on tyrosine-modified linear or branched PEIs (LPxY or PxY). Taken together, this establishes tyrosine-modified PPIs or PEIs as particularly promising polymeric systems for siRNA formulation and delivery.
Highlights
Severe diseases including cancer are often associated with the aberrant or uncontrolled expression of pathologically relevant genes
As shown previously, and in this paper, the tyrosine modification of branched or linear, small PEIs markedly improves their efficacy and biocompatibility. We have extended this approach for the first time towards a Polypropylenimine dendrimers (PPI) dendrimer and present the superior properties of a tyrosine-modified fourth generation PPI (“PPI-G4-Y”)
0.2 μg small interfering RNAs (siRNA) was complexed in a total volume of 25 μL as described above at the different polymer/siRNA mass ratios indicated in the figure
Summary
Severe diseases including cancer are often associated with the aberrant or uncontrolled expression of pathologically relevant genes. We selected a range of branched low molecular weight PEIs (2, 5, and 10 kDa) which were modified with tyrosine at the primary amines, yielding the tyrosine-grafted PEIs P2Y, P5Y and P10Y, respectively This modification strongly enhanced siRNA-mediated knockdown efficiencies of different target genes in various cell lines at very low polymer/siRNA ratios, with a 70–90% target gene downregulation. As shown previously, and in this paper, the tyrosine modification of branched or linear, small PEIs markedly improves their efficacy and biocompatibility Based on these findings, we have extended this approach for the first time towards a PPI dendrimer and present the superior properties of a tyrosine-modified fourth generation PPI (“PPI-G4-Y”). In combination with first in vivo biocompatibility studies, our data identify PPI-G4-Y dendrimers as versatile and promising siRNA delivery platform
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