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 2

Nanogels (ngel) extend lupus survival better than equivalent and 16-fold greater doses of free MPA.

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Nanogels (ngel) extend lupus survival better than equivalent and 16-fold...
NZB/W F1 mice were treated with a lifelong weekly dose of MPA, at 0.625 mpk, using nanogels beginning at 18 to 20 weeks of age. MPA that was not encapsulated within particles, which is referred to as “free MPA,” was dosed at 0.625 mpk or at a 16 times greater dose at 10 mpk; vehicle controls are particles without MPA encapsulated, dosed at approximately 5 mg of particle per animal. The (A) Kaplan-Meier survival curve and (B) mean survival age are shown. Statistical analysis was performed using the log-rank test, with significance comparisons among groups indicated in B; *P < 0.05, with error bars in B representing the standard error measurement. The sample size is 9–19 animals per group. The use of CD4-targeted and nontargeted nanogels extended the mean survival time by approximately 2 to 3 months, whereas free drug doses were not efficacious. CD4-targeted and nontargeted treatment groups were not significantly (NS) different when compared with each other.