Macromol. Rapid Commun. 24/2014

Abstract

Back Cover: The synthetic approach toward degradable cationic nanohydrogel particles for siRNA delivery is extended by introducing disulfide‐modified spermine cross‐linkers. Redox‐triggered release of the nanogel's oligonucleotide payload as well as nanoparticle degradation into its single polymer components can be monitored by various methods under reductive conditions of the cytoplasm. Further details can be found in the article by L. Nuhn,* L. Braun, I. Overhoff, A. Kelsch, D. Schaeffel, K. Koynov, and R. Zentel* on page 2057.

Cationic Nanohydrogel Particles for Therapeutic Oligonucleotide Delivery

“…Beside that also bifunctional moieties can be used as CL whereof a few examples are shown in Figure B which can form a covalent network inside the core between single polymer chains. This ability is used to prepare the above‐mentioned nanohydrogel particles by cross‐linking the preaggregated micellar systems with a reactive ester core ( Figure 5 A) . Spermine, an oligoamine with high complexation tendencies for nucleic acids can be used to build stable carriers, as it is equipped with two primary amines, that preferentially react faster with the reactive esters and assure cross‐linking, as well as two secondary amines for switching the polarity of the core from hydrophobic to cationic under physiological conditions (p K a of secondary amines ≈8.4) .…”

“…Figure 9 A shows scanning electron microscopy (SEM) images of them before and after degradation with DTT. In this context, special attention should be paid to the properties of the crosslinker: Its cationic domains that guide siRNA complexation to the nanocarriers are linked via disulfide bonds and get cleaved off from the macromolecules after reduction, which could also be verified by the rapid release of siRNA after treatment with reductive equivalents . Complexation studies revealed, however, low complexation capabilities with high ratios of NP:siRNA of about 100:1.…”

“…This drawback is probably due to the increased hydrophobicity of the cross‐linker originating from the incorporated disulfides. Moreover, reduced access to the reductive milieu of the cytoplasm further limits the application of these carriers for biological applications …”

“…C) Release study of ketal crosslinked particles by fluorescence correlation spectroscopy investigating fluorescently labeled siRNA. Reprinted (adapted) with permission . Copyright 2016, Elsevier B.V and Copyright 2015, Wiley‐VCH.…”

Improved SiRNA Loading of Cationic Nanohydrogel Particles by Variation of Crosslinking Density

“…However, they are protonated under physiological conditions, and thus, enable the complexation of negatively charged siRNA by electrostatic interactions. The use of spermine as first‐generation crosslinker leads to particles which can complex siRNA sufficiently but also other crosslinkers, like a disulfide‐containing crosslinker developed by Nuhn et al or a ketal‐containing crosslinker synthesized by Leber et al have been studied. However, all these second‐generation crosslinkers led to particles with decreased siRNA loading compared to the spermine particles.…”