Development and Characterization of CD4+ T Cell Targeting Nanoparticles for Therapeutic Delivery of Immunomodulatory Drugs

Abstract

T cell activity is dysregulated in a number of autoimmune diseases for which systemic lupus erythematosus is a prime example. Treatment options are limited and usually consist of overt immune suppression and compromised immunity. A potential mechanism for autoimmune lymphocyte survival is dysfunctional hedgehog (Hh) signaling. Hh signaling is implicated in the activation of CD4+ T cells and the maintenance of germinal center B cells, while dysfunctional Hh signaling is associated with human autoimmunity. In this work we developed CD4 targeted, biodegradable nanoparticles from FDA-approved polymers to enable therapeutic delivery of eggmanone, a Hh inhibitor discovered at Vanderbilt University. We were able to achieve high levels of CD4+ T cell targeting specificity and minimal non-specific particle binding. Furthermore, we have demonstrated antigen specific inhibition of CD4+ T cell activation mediated by nanoparticle formulated eggmanone. Collectively, this work represents the research and development of a rationally designed nanoparticle delivery vehicle intended for therapeutic administration of eggmanone, and other hydrophobic agents with immunomodulatory potential, to CD4+ T cells.