Synthesis, characterization, and surface modification of degradable polar hydrophobic ionic polyurethane nanoparticles for the delivery of therapeutics to vascular tissue

Degradable polar hydrophobic ionic polyurethanes (D-PHI) are an emerging class of biomaterials with particular significance for blood-contacting applications due to their immunomodulatory effects and highly customizable block chemistry. In this manuscript, D-PHI polymer was formulated as a nanoparticle excipient for the first time by inverse emulsion polymerization. The nanoparticles were optimized with consideration of diameter, surface charge, size variability, and yield as a delivery vehicle for a custom vascular therapeutic peptide. A layer-by-layer (LBL) surface modification technique using poly-L-lysine was integrated within the nanoparticle design to optimize therapeutic loading efficiency. Solvent pH played a pivotal role in emulsion micelle formation, LBL polymer secondary structure, and the polymer functional group interactions critical for high therapeutic loading. The resulting nanoparticle platform met target size (200 ± 20 nm), polydispersity (<0.07), and storage stability standards, was nontoxic, and did not affect therapeutic peptide bioactivity in vitro. Surface-modified D-PHI nanoparticles can be reproducibly manufactured at low cost, generating a highly customizable excipient platform suitable for delivery of biomolecular therapeutics. These nanoparticles have potential applications in vascular drug delivery via localized infusion, drug eluting stents, and drug-coated angioplasty balloons. STATEMENT OF SIGNIFICANCE: Nanoscale excipients have become critical in the delivery of many therapeutics to enhance drug stability and targeted biodistribution through careful design of nanoparticle composition, surface chemistry, and size. This manuscript describes the development of a nanoparticle excipient derived from an immunomodulatory degradable polar hydrophobic ionic polyurethane, in combination with a layer-by-layer surface modification approach utilizing poly-L-lysine, to transport a mimetic peptide targeting smooth muscle cell migration in vascular disease. The nanoparticle platform draws on the effect of pH to maximize drug loading and tailor particle properties. The low cost and easily reproducible system presents a highly customizable platform that can be adapted for therapeutic delivery across a wide range of clinical indications.