Institute of Biomedical Engineering, University of Toronto, Canada; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Canada.
Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Canada; Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Canada.
Acta Biomater. 2024 Oct 15;188:184-196. doi: 10.1016/j.actbio.2024.09.024. Epub 2024 Sep 18.
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.
可降解的极性疏水性离子型聚氨酯（D-PHI）是一类新兴的生物材料，由于其免疫调节作用和高度可定制的嵌段化学性质，对于与血液接触的应用具有特殊意义。在本手稿中，D-PHI 聚合物首次通过反相乳液聚合被配方制成纳米颗粒赋形剂。考虑到直径、表面电荷、粒径变异性和产率，对纳米颗粒进行了优化，作为一种定制的血管治疗肽的递药载体。聚 L-赖氨酸的层层（LBL）表面修饰技术被整合到纳米颗粒设计中，以优化治疗性载药效率。溶剂 pH 值在乳液胶束形成、LBL 聚合物二级结构以及对高治疗性载药至关重要的聚合物官能团相互作用中起着关键作用。所得纳米颗粒平台符合目标粒径（200 ± 20nm）、多分散性（<0.07）和储存稳定性标准，无毒性，并且不影响体外治疗性肽的生物活性。表面修饰的 D-PHI 纳米颗粒可以低成本、可重复地制造，生成适用于生物分子治疗药物递送的高度可定制的赋形剂平台。这些纳米颗粒具有通过局部输注、药物洗脱支架和药物涂层血管成形球囊进行血管内药物输送的潜在应用。
纳米级赋形剂在许多治疗药物的递送上变得至关重要，通过仔细设计纳米颗粒的组成、表面化学和粒径，可以增强药物稳定性和靶向生物分布。本文描述了一种源自免疫调节性可降解极性疏水性离子型聚氨酯的纳米颗粒赋形剂的开发，结合利用聚 L-赖氨酸的层层表面修饰方法，用于输送一种模拟肽，以靶向血管疾病中的平滑肌细胞迁移。该纳米颗粒平台利用 pH 值的影响来最大化药物载药量并调整颗粒特性。该低成本且易于重现的系统提供了一个高度可定制的平台，可适应广泛的临床适应症的治疗性药物输送。
