2021, Muljajew, Irina, Huschke, Sophie, Ramoji, Anuradha, Cseresnyés, Zoltán, Hoeppener, Stephanie, Nischang, Ivo, Foo, Wanling, Popp, Jürgen, Figge, Marc Thilo, Weber, Christine, Bauer, Michael, Schubert, Ulrich S., Press, Adrian T.

Dye-loaded micelles of 10 nm diameter formed from amphiphilic graft copolymers composed of a hydrophobic poly(methyl methacrylate) backbone and hydrophilic poly(2-ethyl-2-oxazoline) side chains with a degree of polymerization of 15 were investigated concerning their cellular interaction and uptake in vitro as well as their interaction with local and circulating cells of the reticuloendothelial system in the liver by intravital microscopy. Despite the high molar mass of the individual macromolecules (Mn ≈ 20 kg mol-1), backbone end group modification by attachment of a hydrophilic anionic fluorescent probe strongly affected the in vivo performance. To understand these effects, the end group was additionally modified by the attachment of four methacrylic acid repeating units. Although various micelles appeared similar in dynamic light scattering and cryo-transmission electron microscopy, changes in the micelles were evident from principal component analysis of the Raman spectra. Whereas an efficient stealth effect was found for micelles formed from polymers with anionically charged or thiol end groups, a hydrophobic end group altered the micelles' structure sufficiently to adapt cell-type specificity and stealth properties in the liver. © 2021 The Authors. Published by American Chemical Society.

2021, Press, Adrian T., Babic, Petra, Hoffmann, Bianca, Müller, Tina, Foo, Wanling, Hauswald, Walter, Benecke, Jovana, Beretta, Martina, Cseresnyés, Zoltán, Hoeppener, Stephanie, Nischang, Ivo, Coldewey, Sina M., Gräler, Markus H., Bauer, Reinhard, Gonnert, Falk, Gaßler, Nikolaus, Wetzker, Reinhard, Figge, Marc Thilo, Schubert, Ulrich S., Bauer, Michael

Jaundice, the clinical hallmark of infection-associated liver dysfunction, reflects altered membrane organization of the canalicular pole of hepatocytes and portends poor outcomes. Mice lacking phosphoinositide 3-kinase-γ (PI3Kγ) are protected against membrane disintegration and hepatic excretory dysfunction. However, they exhibit a severe immune defect that hinders neutrophil recruitment to sites of infection. To exploit the therapeutic potential of PI3Kγ inhibition in sepsis, a targeted approach to deliver drugs to hepatic parenchymal cells without compromising other cells, in particular immune cells, seems warranted. Here, we demonstrate that nanocarriers functionalized through DY-635, a fluorescent polymethine dye, and a ligand of organic anion transporters can selectively deliver therapeutics to hepatic parenchymal cells. Applying this strategy to a murine model of sepsis, we observed the PI3Kγ-dependent restoration of biliary canalicular architecture, maintained excretory liver function, and improved survival without impairing host defense mechanisms. This strategy carries the potential to expand targeted nanomedicines to disease entities with systemic inflammation and concomitantly impaired barrier functionality.