(476e) Biofunctionalized Stimuli-Responsive Hydrogel Nanoparticles for RNAi Based Therapy in Inflammatory Bowel Diseases

Inflammatory Bowel Diseases (IBDs) are a group of chronic, relapsing conditions characterized by the inflammation of the gastrointestinal tract. As the disease is idiopathic in nature, the development of treatments with long-term efficacy has been challenging. Current therapies are reportedly only effective in a fraction of the ailing population in addition to reports of undesirable side effects. RNA interference (RNAi) has emerged as a new approach to mitigate the aberrant cytokine signaling that is observed in the pathogenesis of IBDs. Through the use of synthetically derived RNA molecules called small-interfering RNAs (siRNAs), undesirable genes can be silenced through the directed degradation of the mRNAs encoded by those genes. These siRNAs however are susceptible to enzymatic degradation and rapid clearance by the excretory system in vivo hence there is a need for adequate carriers to ensure the delivery of these agents to the desired site of action. In RNAi, localization of the siRNA molecule within the cytosol is required for the activation of its gene silencing machinery. Thus, the optimal drug delivery carrier would ensure the siRNA payload is protected extracellularly and then release the siRNA upon endocytosis for RNAi purposes.

In this work, we discuss the synthesis and optimization of functionalized hydrogel nanoparticle (nanogel) carriers for the targeted, intracellular delivery of siRNA. These nanogels are synthesized via an ARGET ATRP emulsion polymerization scheme and exhibit pH-dependent properties such that they protect the siRNA payload extracellularly and release its cargo upon cellular internalization. Furthermore, reactive monomers have been incorporated into the nanogels architecture for the subsequent conjugation of targeting ligands. The need for cell-specific targeting approaches for effective RNAi treatment is highlighted by the occurrence of off-target effects and non-specific toxicities due to the localization of these siRNA molecules in undesirable areas. To diminish these off-targets, it is imperative that siRNA molecules preferentially localize within the cell types of interest. In the case of IBDs, the cells of the innate immune system i.e. macrophages have been reported to play a pivotal role in the aberrant cytokine signaling observed during chronic inflammation in the gut. Therefore, a targeted approach which promotes the uptake of the functionalized siRNA loaded nanogels into macrophages could serve as a promising approach for more effective RNAi based therapies in IBDs.