Document Detail


Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice.
MedLine Citation:
PMID:  23454752     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Michael Look; Eric Stern; Qin A Wang; Leah D DiPlacido; Michael Kashgarian; Joe Craft; Tarek M Fahmy
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-05-09     Completed Date:  2013-05-20     Revised Date:  2013-07-16    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1741-9     Citation Subset:  AIM; IM    
Affiliation:
Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Urea Nitrogen
Cells, Cultured
Cyclodextrins / chemistry
Dendritic Cells / immunology,  metabolism
Female
Kidney / drug effects,  pathology,  physiopathology
Lactic Acid / chemistry
Liposomes
Lupus Erythematosus, Systemic / drug therapy*,  immunology,  physiopathology
Mice
Mice, Inbred BALB C
Mycophenolic Acid / administration & dosage*,  pharmacokinetics
Nanocapsules
Nanoconjugates* / chemistry,  ultrastructure
Polyethylene Glycols / chemistry
Polymers / chemistry
Proteinuria / immunology,  physiopathology,  prevention & control
T-Lymphocytes / drug effects,  metabolism
Tissue Distribution
Grant Support
ID/Acronym/Agency:
AI075157/AI/NIAID NIH HHS; AR40072/AR/NIAMS NIH HHS; AR44076/AR/NIAMS NIH HHS; R01 AR040072/AR/NIAMS NIH HHS; R21 AR063942/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Cyclodextrins; 0/Liposomes; 0/Nanocapsules; 0/Nanoconjugates; 0/Polyethylene Glycols; 0/Polymers; 24280-93-1/Mycophenolic Acid; 26100-51-6/poly(lactic acid); 50-21-5/Lactic Acid
Comments/Corrections

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