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 1

Fabrication and characterization of MPA-loaded nanogels.

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Fabrication and characterization of MPA-loaded nanogels. (A) Nanogels we...
(A) Nanogels were fabricated by remotely loading liposomes with MPA solubilized within cyclodextrin, oligomers of lactic acid-poly(ethylene glycol) that were terminated with an acrylate end group, and Irgacure 2959 photoinitiator. Particles were then exposed to ultraviolet light to induce photopolymerization of the PEG oligomers. (B) Transmission electron microscopic image of nanogels. Nanogels were fixed in Epon resin, sectioned at 60 nm, and then stained with osmium tetroxide. Scale bar: 200 nm. (C) Hydrodynamic size distribution. The nanogel size was measured in PBS (pH 7.4) using single-particle motion-tracking methods. The median diameter was approximately 203 nm. (D) MPA release profile from nanogels. The cumulative release of drug was performed by dialyzing particles against PBS at 37°C. The mean amount of release is shown, with error bars indicating the standard deviation of triplicate measurements from 1 representative experiment that was repeated at least 3 times. The average loading of MPA in particles was approximately 6.65 ± 3.82 μg MPA/mg particle (mean ± standard deviation) among all batches used in experiments.