title: Targeted delivery of glucocorticoids to macrophages in a mouse model of multiple sclerosis using inorganic-organic hybrid nanoparticles.
abstract: Glucocorticoids (GC) are widely used to treat acute relapses in multiple sclerosis (MS) patients, but their application is accompanied by side effects due to their broad spectrum of action. Here, we report on the therapeutic option to apply GC via inorganic-organic hybrid nanoparticles (IOH-NP) with the composition [ZrO]2+[(BMP)0.9(FMN)0.1]2-(designated BMP-NP with BMP: betamethasone phosphate; FMN: flavinmononucleotide). We found that these BMP-NP have an increased cell type-specificity compared to free GC while retaining full therapeutic efficacy in a mouse model of MS. BMP-NP were preferentially taken up by phagocytic cells and modulated macrophages in vivo more efficiently than T cells. When GC were applied in the form of BMP-NP, treatment of neuroinflammatory disease in mice exclusively depended on the control of macrophage function whereas effects on T cells and brain endothelial cells were dispensable for therapeutic efficacy. Importantly, BMP-NP were not only active in mice but also showed strong activity towards monocytes isolated from healthy human volunteers. We conclude that application of GC via IOH-NP has the potential to improve MS therapy in the future.
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany; Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Montes-Cobos
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ring
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany; Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Henrike J
authors.initials: HJ
authors.lastname: Fischer
authors.affiliation: Institute of Inorganic Chemistry, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Heck
authors.affiliation: Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Judith
authors.initials: J
authors.lastname: Strauß
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23562 Lübeck, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Sybille D
authors.initials: SD
authors.lastname: Reichardt
authors.affiliation: Institute of Inorganic Chemistry, Karlsruhe Institute of Technology, 76131 Karlsruhe, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Feldmann
authors.affiliation: Institute for Multiple Sclerosis Research and Neuroimmunology, University Medical Center Göttingen, 37073 Göttingen, Germany.
authors.forename: Fred
authors.initials: F
authors.lastname: Lühder
authors.affiliation: Institute for Cellular and Molecular Immunology, University Medical Center Göttingen, 37073 Göttingen, Germany. Electronic address: hreichardt@med.uni-goettingen.de.
authors.forename: Holger M
authors.initials: HM
authors.lastname: Reichardt
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001623:Betamethasone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D002470:Cell Survival / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D005486:Flavin Mononucleotide / Q000008:administration & dosage* / Q000737:chemistry; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000008:administration & dosage*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy*; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011965:Receptors, Glucocorticoid / Q000235:genetics; D013601:T-Lymphocytes / Q000187:drug effects; D015040:Zirconium / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D005938:Glucocorticoids; D011965:Receptors, Glucocorticoid; C028994:betamethasone sodium phosphate; D005486:Flavin Mononucleotide; D001623:Betamethasone; D015040:Zirconium
keywords: Experimental autoimmune encephalomyelitis; Glucocorticoids; Hybrid nanoparticles; Macrophages; Multiple sclerosis; T cells