Core Cross‐Linked Polymeric Micelles for Specific Iron Delivery: Inducing Sterile Inflammation in Macrophages
Advanced Healthcare Materials, vol. 10, pp. e2100385
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.
Authors 17
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Leiden University · Johannes Gutenberg University Mainz
Affiliation as printed
Department of Chemistry Johannes Gutenberg University Mainz Duesbergweg 10‐14 Mainz 55128 Germany
Leiden Academic Centre for Drug Research (LACDR) Leiden University Einsteinweg 55 Leiden 2333CC The Netherlands
Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, Mainz, 55128 Germany
Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, Leiden, 2333CC The Netherlands
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Heidelberg University · German Center for Lung Research · European Molecular Biology Laboratory
Affiliation as printed
European Molecular Biology Laboratory (EMBL) Collaboration for Joint PhD Degree between EMBL and the Faculty of Biosciences University of Heidelberg Meyerhofstr.1 Heidelberg 69117 Germany
Molecular Medicine Partnership Unit (MMPU) Otto‐Meyerhof‐Zentrum Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) University of Heidelberg Im Neuenheimer Feld 350 Heidelberg 69120 Germany
European Molecular Biology Laboratory (EMBL), Collaboration for Joint PhD Degree between EMBL and the Faculty of Biosciences, University of Heidelberg, Meyerhofstr.1, Heidelberg, 69117 Germany
Molecular Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
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Heidelberg University · University Hospital Heidelberg
Affiliation as printed
Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology Heidelberg University Hospital Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Molecular Medicine Partnership Unit (MMPU) Otto‐Meyerhof‐Zentrum Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
Molecular Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
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Affiliation as printed
Department of Molecular Thoracic Oncology German Cancer Research Center (DKFZ) Im Neuenheimer Feld 280 Heidelberg 69120 Germany
Department of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120 Germany
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Heidelberg University · University Hospital Heidelberg
Affiliation as printed
Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology Heidelberg University Hospital Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Molecular Medicine Partnership Unit (MMPU) Otto‐Meyerhof‐Zentrum Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
Molecular Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
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Heidelberg University · University Hospital Heidelberg
Affiliation as printed
Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology Heidelberg University Hospital Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Molecular Medicine Partnership Unit (MMPU) Otto‐Meyerhof‐Zentrum Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
Molecular Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
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Max Planck Institute for Polymer Research
Affiliation as printed
Max Planck Institute for Polymer Research Ackermannweg 10 Mainz 55128 Germany
Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz, 55128 Germany
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Johannes Gutenberg University Mainz
Affiliation as printed
Department of Chemistry Johannes Gutenberg University Mainz Duesbergweg 10‐14 Mainz 55128 Germany
Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, Mainz, 55128 Germany
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Max Planck Institute for Polymer Research
Affiliation as printed
Max Planck Institute for Polymer Research Ackermannweg 10 Mainz 55128 Germany
Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz, 55128 Germany
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Max Planck Institute for Polymer Research
Affiliation as printed
Max Planck Institute for Polymer Research Ackermannweg 10 Mainz 55128 Germany
Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz, 55128 Germany
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Affiliation as printed
Department for Biosciences University of Oslo Blindernveien 31 Oslo 0371 Norway
Department for Biosciences, University of Oslo, Blindernveien 31, Oslo, 0371 Norway
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Johannes Gutenberg University Mainz
Affiliation as printed
Institute of Physics Johannes Gutenberg University Mainz Staudingerweg 9 Mainz 55128 Germany
Institute of Physics, Johannes Gutenberg University Mainz, Staudingerweg 9, Mainz, 55128 Germany
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Affiliation as printed
Institute of Biochemistry I Faculty of Medicine Goethe‐University Frankfurt Theodor‐Stern‐Kai 7 Frankfurt am Main 60590 Germany
Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, Frankfurt am Main, 60590 Germany
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German Cancer Research Center · Heidelberg University · German Center for Lung Research
Affiliation as printed
Department of Molecular Thoracic Oncology German Cancer Research Center (DKFZ) Im Neuenheimer Feld 280 Heidelberg 69120 Germany
Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) University of Heidelberg Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Department of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120 Germany
Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
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Matthias W. Hentze corresponding
Heidelberg University · European Molecular Biology Laboratory
Affiliation as printed
European Molecular Biology Laboratory (EMBL) Collaboration for Joint PhD Degree between EMBL and the Faculty of Biosciences University of Heidelberg Meyerhofstr.1 Heidelberg 69117 Germany
European Molecular Biology Laboratory (EMBL), Collaboration for Joint PhD Degree between EMBL and the Faculty of Biosciences, University of Heidelberg, Meyerhofstr.1, Heidelberg, 69117 Germany
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Martina Ulrike Muckenthaler corresponding
Heidelberg University · University Hospital Heidelberg · German Center for Lung Research
Affiliation as printed
Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology Heidelberg University Hospital Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Molecular Medicine Partnership Unit (MMPU) Otto‐Meyerhof‐Zentrum Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Translational Lung Research Center Heidelberg (TLRC) German Center for Lung Research (DZL) University of Heidelberg Im Neuenheimer Feld 350 Heidelberg 69120 Germany
Department of Pediatric Oncology, Hematology, Immunology, and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
Molecular Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, Im Neuenheimer Feld 350, Heidelberg, 69120 Germany
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Leiden University · Johannes Gutenberg University Mainz
Affiliation as printed
Department of Chemistry Johannes Gutenberg University Mainz Duesbergweg 10‐14 Mainz 55128 Germany
Leiden Academic Centre for Drug Research (LACDR) Leiden University Einsteinweg 55 Leiden 2333CC The Netherlands
Department of Chemistry, Johannes Gutenberg University Mainz, Duesbergweg 10-14, Mainz, 55128 Germany
Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, Leiden, 2333CC The Netherlands
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