443032 Design of Layer-By-Layer Thin Films for pH-Triggered Release of Endosomolytic Nanoparticles

Monday, November 9, 2015
Exhibit Hall 1 (Salt Palace Convention Center)
Harrison Paul1, Duncan Morgan2, Gilda Naka3, Daniel Shae2, Max Jacobson1 and John Wilson1, (1)Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, (2)Vanderbilt University, (3)Chemical Engineering, Vanderbilt University, Nashville, TN

The use of vaccines to prevent infectious diseases is an important part of modern medicine. Many approved and experimental vaccine formulations are based on particles that are endocytosed by phagocytic antigen presenting cells. Loading of particles with antigens and molecular adjuvants has been widely explored as a mechanism to bolster vaccine efficacy, but the majority of particulate vaccines lack an active mechanism through which to efficiently transport drug cargo to the cytosol. The overall goal of this project is to develop a polymer coating that promotes more efficient delivery of particles and/or their cargo into the cytosol. Towards this end, we are developing layer-by-layer polymer thin films comprising pH-responsive and endosome destabilizing polymers. We first synthesized dimethylaminoethyl methacrylate (DMAEMA) with butyl methacrylate (BMA) to make DMAEMA-b-(DEAEMA-co-BMA) and DMAEMA-b-(PAA-c-BMA-c-DMAEMA) polymers through reversible addition fragmentation chain transfer (RAFT) polymerization.  These polymers self-assemble into micelllar nanoparticles that were used as polycations to generate polyelectrolyte multilayer films via layer-by-layer deposition with the anionic polymers, polyacrylic acid, polymethylacrylic acid, or polypropylacrylic acid.  The film growth was first characterized on planar substrates with a Quartz Crystal Microbalance, which demonstrated an increase in polymer deposition with increasing layer number.  After film growth was confirmed, the pH of the solution was reduced in a stepwise fashion to determine the pH value at which the layers showed release from the surface.  Upon demonstrating film growth and pH-triggered disassembly on planar supports, the films were grown on a three-dimensional platform, 3 µm CaCO3 microparticles.  Growth onto the particles was determined via fluorescence spectroscopy and microscopy that could detect a fluorescence label on the polymer, and experiments demonstrated an exponential growth pattern. A pH release mechanism was also tested with these films to demonstrate that the PMAA films release between 5.8 and 5.4 while the PPAA films show little to no release above pH 5.0.  The next step is to begin loading biologically relevant drugs into the film and particle and to assess the ability of polymer films to enhance cytosolic delivery. These versatile thin film coatings could one day help improve vaccine efficacy by providing a mechanism to increase deliver of immunomodulatory cargo to the cytosol and thereby enhance the efficacy of particle-based vaccines.

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