Self-assembling polymeric nanoparticles for enhanced intra-articular anti-inflammatory protein delivery

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Whitmire, Rachel Elisabeth
García, Andrés J.
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The goal of this thesis was to develop a new drug-delivering material to deliver anti-inflammatory protein for treating OA. Our central hypothesis for this work is that a controlled release/presentation system will more effectively deliver anti-inflammatory protein therapies to the OA joint. The primary goal of this work was to synthesize a block copolymer that could self-assemble into injectable, sub-micron-scale particles and would allow an anti-inflammatory protein, IL-1ra, to be tethered to its surface for efficient protein delivery. The block copolymer incorporated an oligo-ethylene monomer for tissue compatibility and non-fouling behavior, a 4-nitrophenol group for efficient protein tethering, and cyclohexyl methacrylate, a hydrophobic monomer, for particle stability. We engineered the copolymer and tested it in both in vitro culture experiments and an in vivo model to evaluate protein retention in the knee joint. The rationale for this project was that the rational design and synthesis of a new drug- and protein-delivering material can create a modular polymer particle that can deliver multi-faceted therapies to treat OA. This work characterizes the in vitro and in vivo behavior of our polymer particle system. The protein tethering strategy allows IL-1ra protein to be tethered to the surface of these particles. Once tethered, IL-1ra maintains its bioactivity and actively targets synoviocytes, cells crucial to the OA pathology. This binding happens in an IL-1-dependent manner. Furthermore, IL-1ra-tethered particles are able to inhibit IL-1beta-induced NF-kappaB activation. These studies show that this particle system has the potential to deliver IL-1ra to arthritic joints and that it has potential for localizing/targeting drugs to inflammatory cells of interest as a new way to target OA drug treatments.
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