Development of novel RNA delivery platforms for inflammatory bowel disease therapeutics

The use of Lipid Nanoparticle (LNP) systems, sophisticated non-viral nucleic acid delivery vehicles, have been rising in recent decades, mainly due to their efficiency and clinical relevance in the field of gene therapy.

Despite the exciting advances in the field of LNPs for genetic modification, challenges in its delivery still prevent it from reaching its full potential. Most prominent among these challenges is the rapid rate of elimination of LNPs from the bloodstream. Namely, nanomaterials researchers have demonstrated that intravenously (i.v.) injected LNPs, are largely distributed in the major organs of the mononuclear phagocyte system (i.e. liver and spleen), with lower percentages reaching the intended site of action 1.

We hypothesize that the development of a Drug Delivery Systems (DDS) with a slow-release (SR) profile, might be an appropriate solution for the challenges raised in the previous paragraph, as It has been demonstrated that the longer the circulation time of nanoparticles, the higher the chance for it to accumulate within the tumor through the Enhanced Permeability and Retention (EPR) effect 2. This is true for other disorders that demonstrate EPR effect, i.e inflammatory diseases.

This research is set out to investigate SR-DDS of siRNA-loaded LNPs. Pluronic F-127, an FDA approved biodegradable polymer, will be used as the backbone of a temperature-sensitive hydrogel to encapsulate RNAi-loaded LNPs.

We`ve managed thus far to demonstrate a slow-release profile of the LNPs in-vitro, furthermore, our preliminary data suggests that the LNPs maintain their silencing ability upon release.

References:

1. Zhou, Y. & Dai, Z. New Strategies in the Design of Nanomedicines to Oppose Uptake by the Mononuclear Phagocyte System and Enhance Cancer Therapeutic Efficacy. Chem. - An Asian J. 13, 3333–3340 (2018).

2. Nakamura, Y., Mochida, A., Choyke, P. L. & Kobayashi, H. Nanodrug Delivery: Is the Enhanced Permeability and Retention Effect Sufficient for Curing Cancer? Bioconjug. Chem. 27, 2225–2238 (2016).