Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis
Abstract 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 exc...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-09-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114436 |
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| author | Adrian T Press Petra Babic Bianca Hoffmann Tina Müller Wanling Foo Walter Hauswald Jovana Benecke Martina Beretta Zoltán Cseresnyés Stephanie Hoeppener Ivo Nischang Sina M Coldewey Markus H Gräler Reinhard Bauer Falk Gonnert Nikolaus Gaßler Reinhard Wetzker Marc Thilo Figge Ulrich S Schubert Michael Bauer |
| author_facet | Adrian T Press Petra Babic Bianca Hoffmann Tina Müller Wanling Foo Walter Hauswald Jovana Benecke Martina Beretta Zoltán Cseresnyés Stephanie Hoeppener Ivo Nischang Sina M Coldewey Markus H Gräler Reinhard Bauer Falk Gonnert Nikolaus Gaßler Reinhard Wetzker Marc Thilo Figge Ulrich S Schubert Michael Bauer |
| author_sort | Adrian T Press |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-0fad10ab812d436c8a511f93c2eb66d8 |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-0fad10ab812d436c8a511f93c2eb66d82025-08-20T02:11:22ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-09-01131011710.15252/emmm.202114436Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsisAdrian T Press0Petra Babic1Bianca Hoffmann2Tina Müller3Wanling Foo4Walter Hauswald5Jovana Benecke6Martina Beretta7Zoltán Cseresnyés8Stephanie Hoeppener9Ivo Nischang10Sina M Coldewey11Markus H Gräler12Reinhard Bauer13Falk Gonnert14Nikolaus Gaßler15Reinhard Wetzker16Marc Thilo Figge17Ulrich S Schubert18Michael Bauer19Department of Anesthesiology and Intensive Care Medicine, Jena University HospitalDepartment of Anesthesiology and Intensive Care Medicine, Jena University HospitalResearch Group Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology ‐ Hans Knoell InstituteDepartment of Anesthesiology and Intensive Care Medicine, Jena University HospitalDepartment of Anesthesiology and Intensive Care Medicine, Jena University HospitalLeibniz Institute of Photonic TechnologyDepartment of Anesthesiology and Intensive Care Medicine, Jena University HospitalDepartment of Anesthesiology and Intensive Care Medicine, Jena University HospitalResearch Group Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology ‐ Hans Knoell InstituteJena Center for Soft Matter (JCSM), Friedrich Schiller University JenaJena Center for Soft Matter (JCSM), Friedrich Schiller University JenaDepartment of Anesthesiology and Intensive Care Medicine, Jena University HospitalDepartment of Anesthesiology and Intensive Care Medicine, Jena University HospitalInstitute of Molecular Cell Biology, Jena University HospitalDepartment of Anesthesiology and Intensive Care Medicine, Jena University HospitalSection of Pathology, Institute of Forensic Medicine, Jena University HospitalDepartment of Anesthesiology and Intensive Care Medicine, Jena University HospitalCenter for Sepsis Control and Care, Jena University HospitalCenter for Sepsis Control and Care, Jena University HospitalDepartment of Anesthesiology and Intensive Care Medicine, Jena University HospitalAbstract 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.https://doi.org/10.15252/emmm.202114436cholestasisdrug deliveryliver failurePI3Ksepsis |
| spellingShingle | Adrian T Press Petra Babic Bianca Hoffmann Tina Müller Wanling Foo Walter Hauswald Jovana Benecke Martina Beretta Zoltán Cseresnyés Stephanie Hoeppener Ivo Nischang Sina M Coldewey Markus H Gräler Reinhard Bauer Falk Gonnert Nikolaus Gaßler Reinhard Wetzker Marc Thilo Figge Ulrich S Schubert Michael Bauer Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis EMBO Molecular Medicine cholestasis drug delivery liver failure PI3K sepsis |
| title | Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis |
| title_full | Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis |
| title_fullStr | Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis |
| title_full_unstemmed | Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis |
| title_short | Targeted delivery of a phosphoinositide 3‐kinase γ inhibitor to restore organ function in sepsis |
| title_sort | targeted delivery of a phosphoinositide 3 kinase γ inhibitor to restore organ function in sepsis |
| topic | cholestasis drug delivery liver failure PI3K sepsis |
| url | https://doi.org/10.15252/emmm.202114436 |
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