Pulmonary siRNA Delivery with Sophisticated Amphiphilic Poly(Spermine Acrylamides) for the Treatment of Lung Fibrosis

RNA interference (RNAi) is an efficient strategy to post-transcriptionally silence gene expression. While all siRNA drugs on the market target the liver, the lung offers a variety of currently undruggable targets, which can potentially be treated with RNA therapeutics. To achieve this goal, the synthesis of poly(spermine acrylamides) (P(SpAA) is reported herein. Polymers are prepared via polymerization of N-acryloxysuccinimide (NAS) and afterward this active ester is converted into spermine-based pendant groups. Copolymerizations with decylacrylamide are employed to increase the hydrophobicity of the polymers. After deprotection, polymers show excellent siRNA encapsulation to obtain perfectly sized polyplexes at very low polymer/RNA ratios. In vitro 2D and 3D cell culture, ex vivo and in vivo experiments reveal superior properties of amphiphilic spermine-copolymers with respect to delivery of siRNA to lung cells in comparison to commonly used lipid-based transfection agents. In line with the in vitro results, siRNA delivery to human lung explants confirm more efficient gene silencing of protease-activated receptor 2 (PAR2), a G protein-coupled receptor involved in fibrosis. This study reveals the importance of the balance between efficient polyplex formation, cellular uptake, gene knockdown, and toxicity for efficient siRNA delivery in vitro, in vivo, and in fibrotic human lung tissue ex vivo

Azide‐Modified Poly(diethyl vinylphosphonate) for Straightforward Graft‐to Carbon Nanotube Functionalization

Abstract Rare‐earth metal‐mediated group‐transfer polymerization (REM‐GTP) offers distinctive features over common polymerization techniques, such as living character, a broad scope of functional monomers, high activity, excellent control of the polymeric parameters as well as inherent chain‐end functionalization. Through the latter, polymers with reactive end‐groups become feasible, opening the pathway for further post‐polymerization functionalization. In this study, a straightforward graft‐to immobilization of the Michael‐type polymer poly(diethyl vinylphosphonate) (PDEVP) on multi‐walled carbon nanotubes (MWCNT) is reported. Hence, a customized azide initiator is synthesized and studied in the CH bond activation with various lanthanide‐based catalysts and the subsequent polymerization of diethyl vinylphosphonate (DEVP). The successful attachment of the azide end‐group is demonstrated via electrospray ionization mass spectrometry (ESI‐MS) and the synthesized polymers are subjected to immobilization on multi‐walled carbon nanotubes in a graft‐to approach. The prepared MWCNT:PDEVP composites are analyzed via thermogravimetric analysis (TGA), elemental analysis (EA), Raman spectroscopy, X‐Ray photoelectron spectroscopy (XPS), and transmission electron microscopy (TEM) and the versatility of this approach is shown via the stabilization of MWCNT dispersions in water