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 3

Nanogel therapy delays the onset of renal damage.

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Nanogel therapy delays the onset of renal damage. NZB/W F1 mice were mon...
NZB/W F1 mice were monitored for the onset and severity of renal damage; weekly treatments with nanogels beginning at 18 to 20 weeks of age resulted in the delayed onset of (A) proteinuria (defined as ≥300 mg/dl of protein in urine), and (B) the presence of leukocyte esterase content in the urine (which corresponds to >10 leukocytes/μl in the urine), as determined by dry reagent Uristix assay. For urinalysis (A and B), treatment with CD4-targeted or nontargeted MPA particles compared with free MPA, buffer, and vehicle groups was statistically significant (P < 0.05 by 1-way ANOVA with Bonferroni’s multiple comparison test), though no significant difference was detected between CD4-targeted MPA particles compared with nontargeted ones. The sample size is 9–19 animals per group. (C) Renal function was assessed by BUN in mice at 36 to 40 weeks of age; an elevated BUN was defined as greater than the physiological reference range of 18 to 29 mg/dl. The sample size is 8 mice per group. *P < 0.05 by 2-tailed Student’s t-test. (D) Representative images of H&E-stained sections of kidneys from mice at 36 to 40 weeks of age. Mice that received nanogel MPA therapy had reduced nephritis. Scale bar: 500 μm.