title: Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice.
abstract: The ability to selectively inactivate immune cells with immunosuppressants is a much sought-after modality for the treatment of systemic lupus erythematosus and autoimmunity in general. Here, we designed and tested a novel nanogel drug delivery vehicle for the immunosuppressant mycophenolic acid (MPA). Treatment with MPA-loaded nanogels increased the median survival time (MST) of lupus-prone NZB/W F1 mice by 3 months with prophylactic use (MST was 50 weeks versus 38 weeks without treatment), and by 2 months when administered after the development of severe renal damage (MST after proteinuria onset was 12.5 weeks versus 4 weeks without treatment). Equivalent and greater doses of MPA administered in buffer were not efficacious. Nanogels had enhanced biodistribution to organs and association with immune cells. CD4-targeted nanogels yielded similar therapeutic results compared with nontargeted formulations, with protection from glomerulonephritis and decreases in IFN-γ-positive CD4 T cells. DCs that internalized nanogels helped mediate immunosuppression, as they had reduced production of inflammatory cytokines such as IFN-γ and IL-12. Our results demonstrate efficacy of nanogel-based lupus therapy and implicate a mechanism by which immunosuppression is enhanced, in part, by the targeting of antigen-presenting cells.
authors: Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.
authors: Michael
authors: M
authors: Look
authors: Eric
authors: E
authors: Stern
authors: Qin A
authors: QA
authors: Wang
authors: Leah D
authors: LD
authors: DiPlacido
authors: Michael
authors: M
authors: Kashgarian
authors: Joe
authors: J
authors: Craft
authors: Tarek M
authors: TM
authors: Fahmy
mesh_terms: D000818:Animals; D001806:Blood Urea Nitrogen; D002478:Cells, Cultured; D003505:Cyclodextrins / Q000737:chemistry; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D019344:Lactic Acid / Q000737:chemistry; D008081:Liposomes; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009173:Mycophenolic Acid / Q000008:administration & dosage* / Q000493:pharmacokinetics; D053769:Nanocapsules; D058726:Nanoconjugates / Q000737:chemistry / Q000648:ultrastructure; D011091:Polyesters; D011092:Polyethylene Glycols / Q000737:chemistry; D011108:Polymers / Q000737:chemistry; D011507:Proteinuria / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D003505:Cyclodextrins; D008081:Liposomes; D053769:Nanocapsules; D058726:Nanoconjugates; D011091:Polyesters; D011108:Polymers; D019344:Lactic Acid; D011092:Polyethylene Glycols; C033616:poly(lactide); D009173:Mycophenolic Acid