Nanogel-based delivery of mycophenolic acid ameliorates systemic lupus erythematosus in mice
Michael Look, … , Joe Craft, Tarek M. Fahmy
Michael Look, … , Joe Craft, Tarek M. Fahmy
Published March 1, 2013
Citation Information: J Clin Invest. 2013;123(4):1741-1749. https://doi.org/10.1172/JCI65907.
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Research Article Autoimmunity

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

Michael Look, Eric Stern, Qin A. Wang, Leah D. DiPlacido, Michael Kashgarian, Joe Craft, Tarek M. Fahmy

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Figure 4

Biodistribution of nanogels.

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Biodistribution of nanogels. Rhodamine-loaded nanogels were injected int...
Rhodamine-loaded nanogels were injected intraperitoneally into 12-week-old NZB/W F1 mice. (A) Organ-specific fluorescence was measured and rhodamine encapsulated in nanoparticles (both CD4-targeted and nontargeted) had statistically significantly higher accumulations than free rhodamine. Targeted particles had statistically significantly higher accumulation than nontargeted particles as well (P < 0.05 by Student’s 2-tailed t test for all organs). Trace amounts of fluorescence could be detected in particle groups at 48 and 72 hours (not shown). Error bars represent the standard deviation. The sample size is 3 or 4 mice per group. The localization of rhodamine nanogels within the spleen was also analyzed by immunofluorescence histology (B and C). Histological analysis of spleens was performed 1 hour after rhodamine nanoparticle (red) injection, and stained for, in B, CD4 T cells (green) and F4/80 macrophages (blue); or in C, CD4 T cells (green), and CD19 B cells (blue). Scale bars (B and C): 100 μm. (D) Rhodamine-loaded nanogels were injected intraperitoneally into C57BL/6 mice that had been vaccinated with sheep red blood cells 7 days earlier. Approximately 2–3 hours later, the percentage of rhodamine-positive immune cells in the spleen and the lymph nodes (pooled inguinal, cervical, and brachial) was quantified by flow cytometry. CD4-targeted and nontargeted particles had greater binding with immune cells, particularly in the spleen compared with lymph nodes. P < 0.05 by 1-way ANOVA comparison between particles and free rhodamine for both spleen and lymph node. Error bars represent the standard error measurement, with a sample size of 4 mice per group.