title: Development of a nanoparticulate formulation of retinoic acid that suppresses Th17 cells and upregulates regulatory T cells.
abstract: Retinoic acid (RA) is a small molecule capable of shunting developing T cells away from the Th17 lineage and towards the Treg phenotype, making it a potentially useful therapeutic for autoimmune and inflammatory diseases. However, therapy can be complicated by systemic toxicity and unpredictable bioavailability, making a targeted drug delivery vehicle for local therapy desirable. A promising approach is the use of nanoparticles, which have been demonstrated to increase potency and decrease toxicity of therapies in a variety of disease models including Th17 mediated diseases. Nanoparticles can also be targeted to specific cell types via surface modification, further increasing the potential specificity of this approach. We therefore constructed a nanoparticulate drug delivery platform from poly(lactic-co-glycolic acid) (PLGA) capable of encapsulating and releasing RA. Here we report the fabrication, characterization, and in vitro bioactivity of this platform. We demonstrate that RA containing PLGA nanoparticles suppress IL-17 production and ROR-γ(t) expression in T cells polarized towards the Th17 phenotype in vitro with similar potency to that of free drug. Furthermore, we show that these particles enhance TGF-β dependent Foxp3 expression and IL-10 production of T cells in vitro with similar potency to free RA. Finally, we demonstrate that T cells polarized towards the Th17 phenotype in the presence of free and nanoparticulate RA have similarly suppressed ability to induce IL-6 production by fibroblasts. Our findings demonstrate the feasibility of RA delivery via biodegradable nanoparticles and represent an exciting technology for the treatment of autoimmune and inflammatory diseases.
authors.affiliation: Department of Biomedical Engineering, Yale University; New Haven, CT USA.
authors.forename: Noah A
authors.initials: NA
authors.lastname: Capurso
authors.forename: Michael
authors.initials: M
authors.lastname: Look
authors.forename: Laura
authors.initials: L
authors.lastname: Jeanbart
authors.forename: Heba
authors.initials: H
authors.lastname: Nowyhed
authors.forename: Clara
authors.initials: C
authors.lastname: Abraham
authors.forename: Joe
authors.initials: J
authors.lastname: Craft
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy