Research Project
10282408
SUMMARY The overall goal of the Lipid-Based Self-Assembled Materials and Characterization Core (LBSAMCC) is to synthesize, characterize, and deliver highly novel therapeutics for ameliorating the devastating effects of nitrogen and sulfur mustards to the eye (Project 1) and skin (Project 2). High-density lipoproteins (HDL) are small nanoparticles that solubilize and transport cholesterol and lipids, are integral in modulating the innate immune system, and function to enhance the integrity of epithelial barriers. The development and delivery of novel materials that mimic these key functional features of HDLs and, importantly, enable targeting of appropriate cell types (e.g. innate immune cells, keratocytes, and keratinocytes) in the eye and skin, highly differentiate this platform from others to ameliorate injuries caused by mustards. The Thaxton lab pioneered the synthesis of HDL-like synthetic biologics (HDL NPs) with an inert, solid core gold nanoparticle (AuNP) upon which the self- assembly of lipid and protein cargos of HDLs can chemically attach. The overall size and surface chemistry can be strictly controlled to resemble native HDLs enabling these first-generation materials to be tailorable, such that any number of phospholipids, sterols, and/ or small molecule drugs (e.g. siRNA or microRNA) may be added. Recent collaborations between the Thaxton and Nguyen labs further demonstrated that the AuNP of first- generation materials can be swapped out for size-controlling organic core (oc) scaffolds, which can be used to control biological function (e.g. cholesterol uptake and anti-inflammatory) and opens up the opportunity to load and unload the core of these targeted materials with relevant therapies (e.g. vitamin D). Ultimately, synthetic HDL biologics offer a tremendous opportunity for developing novel therapies against eye and/or skin injuries that occur due to exposure to mustards. The LBSAMCC will be directly responsible for synthesizing a suite of organic cores (Specific Aim 1) to be used as templates to produce a library of ocHDL NPs with and without small- molecule and lipid-conjugated drugs and formulated to be topically applied to the eye and skin (Specific Aim 2). Furthermore, the LBSAMCC will facilitate the complete physicochemical and functional screening of the ocHDL NPs (Specific Aim 3) so that they can be confidently delivered and further developed in each of the Projects. As such, the LBSAMCC will deliver effective ocHDL NPs to remediate chemical mustard injuries to the eye and skin. The impact of this work is that a rigorous approach and step-wise method will produce effective topically delivered therapies for ameliorating the devastating injuries caused to the eye and skin by nitrogen and sulfur mustard.
