The AAPS Journal

, Volume 19, Issue 4, pp 1175–1185 | Cite as

Controlled Release of Second Generation mTOR Inhibitors to Restrain Inflammation in Primary Immune Cells

  • Emily A. Gosselin
  • Lisa H. Tostanoski
  • Christopher M. Jewell
Research Article

Abstract

Autoimmune disease occurs when the immune system incorrectly targets the body’s own tissue. Inflammatory CD4+ T cell phenotypes, such as TH1 and TH17, are key drivers of this attack. Recent studies demonstrate treatment with rapamycin—a key inhibitor of the mTOR pathway—can skew T cell development, moving T cell responses away from inflammatory phenotypes and toward regulatory T cells (TREGS). TREGS are important in inducing and maintaining tolerance to self-antigens, creating new potential to treat autoimmune diseases more effectively and specifically. Next generation analogs of rapamycin, such as everolimus and temsirolimus, confer increased potency with reduced toxicity, but are understudied in the context of autoimmunity. Further, these drugs are still broadly-acting and require frequent treatment due to short half-lives. Thus, there is strong interest in harnessing the unique properties of biomaterials—controlled drug release and targeting, for example, to improve autoimmune therapies. Using second generation mTOR inhibitors and rapamycin, we prepared sets of degradable polymer particles from poly(lactide-co-glycolide). We then used these materials to assess physicochemical properties and the ability to control autoimmune inflammation in a primary cell co-culture model. Treatment with particle formulations resulted in significant dose-dependent decreases in dendritic cell activation, T cell proliferation, inflammatory cytokines, and frequencies of inflammatory TH1 phenotypes. Considering the current limitations of rapamycin, and the potential of next-generation analogs, this work provides a screening platform for biomaterials and sets the stage for in vivo evaluation, where delivery kinetics, stability, and targeting could improve autoimmune therapies through biomaterial-enabled delivery.

KEY WORDS

controlled release immune tolerance and autoimmunity microparticle and nanoparticle rapamycin, everolimus, and temsirolimus vaccine and immunotherapy 

Supplementary material

12248_2017_89_MOESM1_ESM.pdf (479 kb)
ESM 1(PDF 478 kb)

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Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  1. 1.Fischell Department of BioengineeringUniversity of MarylandCollege ParkUSA
  2. 2.Department of Microbiology and ImmunologyUniversity of Maryland Medical SchoolBaltimoreUSA
  3. 3.Marlene and Stewart Greenebaum Cancer CenterBaltimoreUSA
  4. 4.United States Department of Veterans AffairsBaltimoreUSA

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