Systemic lupus erythematosus (SLE) is disease in which the immune system mistakenly attacks healthy tissues, resulting in inflammation and tissue damage. Current treatments are focused on suppression of the immune system, but these therapies can leave patients vulnerable to infection. Michael Look, Tarek Fahmy, and colleagues developed a nanogel-based delivery system that delivers an immunosuppressive drug (mycophenolic acid) directly to tissues associated with immune cells. A nanogel is composed of a polymer containing pores that can be loaded with drug compounds. Look and colleagues tested the mycophenolic acid-loaded nanogel in a mouse model of lupus. Mice treated with the nanogel lived longer than untreated mice or mice treated with mycophenolic acid alone. Additionally, the onset of kidney damage, a common complication of lupus, was delayed in nanogel-treated mice. The accompanying illustration (provided by the authors) depicts the use of nanoparticles that target and suppress immune cells that cause lupus. Nanoparticles (white spheres) are loaded with a toxic drug, mycophenolic acid (yellow-green molecule), and treat disease (in mice) with greater potency and less toxicity than conventional regimens that do not use nanoparticles. The particles are engulfed by dendritic cells (violet cell on the left) or bind CD4 T cells (purple cell on the right). These immune cells are acutely affected by nanotherapy because of the particles' unique homing ability. This nanoparticle system may hold promise in providing new therapeutic strategies for lupus patients and others with autoimmune disease. Illustration by Nicolle R. Fuller, Sayo-Art LLC, 2013.
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.
Michael Look, Eric Stern, Qin A. Wang, Leah D. DiPlacido, Michael Kashgarian, Joe Craft, Tarek M. Fahmy