Tyrosine-Modification of Polypropylenimine (PPI) and Polyethylenimine (PEI) Strongly Improves Efficacy of siRNA-Mediated Gene Knockdown

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.

Nonviral Locally Injected Magnetic Vectors for In Vivo Gene Delivery: A Review of Studies on Magnetofection

“…As for the magnetic vector itself, these were transMAG PEI (Chemicell) particles—superparamagnetic iron oxide nanoparticles with an average size of 200 nm (by dynamic light scattering), coated with polyethylenimine (PEI, 800 kDa). PEI is the most effective nonviral vector due to its favorable characteristics of DNA protection, cell binding and uptake, and endosomal escape and release from the carrier [ 106 , 107 , 108 ]; an example of the structure of a PEI-coated magnetic particle is shown in Figure 2 . Therefore, in most studies, magnetic particles coated with PEI are used.…”

Advances in Nanomaterials in Biomedicine

“…The efficient delivery of therapeutic nucleic acids into cells is one of the most important problems, and numerous and diverse nanoconstructions are being created to solve it. In the Special Issue, in addition to carbon dots and polymer micelles, two more types of carriers are presented: dodecyl-containing oligonucleotides [ 16 ] and nanosystems based on tyrosine-modified polypropylenimine (PPI) and polyethylenimine (PEI) [ 17 ]. In the first, Pavlova and co-authors [ 16 ] showed the formation of micellar nanostructures by the self-assembly of amphiphilic “like-a-brush” oligonucleotide conjugates, and their penetration into HepG2 cells.…”

“…The authors of the second article exploit chemical modification to improve siRNA delivery with well-known cationic polymers, namely polyethylenimine (PEI) and polypropylenimine (PPI). Noske and co-authors [ 17 ] for the first time modified PPI, including dendrimer form, by tyrosine and showed that this modification significantly improved the siRNA complexation, complex stability, siRNA delivery, knockdown efficacy and biocompatibility. It should be noted that analysis of the effect of corresponding siRNAs on cytokines TNF-α and INF-γ was carried out in mice, which makes conclusions about the effect of tyrosine modification more convincing.…”

Advances in Nanomaterials in Biomedicine

“…The efficient delivery of therapeutic nucleic acids into cells is one of the most important problems, and numerous and diverse nanoconstructions are being created to solve it. In the Special Issue, in addition to carbon dots and polymer micelles, two more types of carriers are presented: dodecyl-containing oligonucleotides [16] and nanosystems based on tyrosine-modified polypropylenimine (PPI) and polyethylenimine (PEI) [17]. In the first, Pavlova and co-authors [16] showed the formation of micellar nanostructures by the selfassembly of amphiphilic "like-a-brush" oligonucleotide conjugates, and their penetration into HepG2 cells.…”

“…The authors of the second article exploit chemical modification to improve siRNA delivery with well-known cationic polymers, namely polyethylenimine (PEI) and polypropylenimine (PPI). Noske and coauthors [17] for the first time modified PPI, including dendrimer form, by tyrosine and showed that this modification significantly improved the siRNA complexation, complex stability, siRNA delivery, knockdown efficacy and biocompatibility. It should be noted that analysis of the effect of corresponding siRNAs on cytokines TNF-α and INF-γ was carried out in mice, which makes conclusions about the effect of tyrosine modification more convincing.…”