Core Cross‐Linked Polymeric Micelles for Specific Iron Delivery: Inducing Sterile Inflammation in Macrophages

Abstract

Iron is an essential co-factor for cellular processes. In the immune system, it can activate macrophages and represents a potential therapeutic for various diseases. To specifically deliver iron to macrophages, iron oxide nanoparticles are embedded in polymeric micelles of reactive polysarcosine-block-poly(S-ethylsulfonyl-l-cysteine). Upon surface functionalization via dihydrolipoic acid, iron oxide cores act as crosslinker themselves and undergo chemoselective disulfide bond formation with the surrounding poly(S-ethylsulfonyl-l-cysteine) block, yielding glutathione-responsive core cross-linked polymeric micelles (CCPMs). When applied to primary murine and human macrophages, these nanoparticles display preferential uptake, sustained intracellular iron release, and induce a strong inflammatory response. This response is also demonstrated in vivo when nanoparticles are intratracheally administered to wild-type C57Bl/6N mice. Most importantly, the controlled release concept to deliver iron oxide in redox-responsive CCPMs induces significantly stronger macrophage activation than any other iron source at identical iron levels (e.g., Feraheme), directing to a new class of immune therapeutics.

GSH-Responsive Nanoprodrug to Inhibit Glycolysis and Alleviate Immunosuppression for Cancer Therapy

“…Several polymeric micelles with excellent biocompatibility and improved drug circulation properties to form nanoparticles have been applied for the delivery of various drugs. − Nevertheless, the poor drug loading efficiency with direct encapsulation is of particular concern. Connecting two drugs with a linker to form dimeric prodrug is a novel drug synthesis strategy, which can exert the synergistic effect of two drugs simultaneously.…”

From Self‐Organization to Tumor‐Immune Therapy: How Things Started and How They Evolved

“…[ 79–82 ] Based on this chemical tool box Matthias Barz synthesized core‐crosslinked polymeric micelles, [ 79,83–85 ] polymersomes, [ 86 ] nanohydrogels and polyplexes, [ 87 ] lipid nanoparticles, [ 88 ] molecular polymer brushes [ 89–91 ] and organic‐inorganic hybrid systems. [ 89–91 ] In line with Rudolf Zentel's vision that every system shall be designed to fulfil a rational need, Matthias Barz's systems enable therapeutic interventions, e.g., in cancer diagnosis [ 89 ] and therapy, [ 92 ] (immune) therapy [ 91,93,94 ] and bacterial infections. [ 95–97 ] With polysarcosine [ 77 ] as hydrophilic, stealth‐like polymer material (as relevant substitute to PEG [ 91,98–100 ] with an improved immunogenicity profile [ 88,101 ] ) multiple biomedical research projects have been initiated by him that are also applicable to large scale GMP production.…”

Local detection of pH-induced disaggregation of biocompatible micelles by fluorescence switch ON

“…[4][5][6][7][8][9] Amphiphilic block co-polymers have emerged as one of the most promising approaches for the design of these stimuli-responsive nanotheranostic agents, as they can assemble into NPs of controlled size and surface properties. 10 Additionally, the stability of these self-assembled NPs can be controlled 11 by tuning parameters like the block co-polymer composition, 12,13 the chain-length or the polymerization method. 14 As a consequence, stimuli-induced changes in the block co-polymer composition can be easily exploited to decrease NP stability inducing disassembly.…”