Poole Kristin M, Nelson Christopher E, Joshi Rucha V, Martin John R, Gupta Mukesh K, Haws Skylar C, Kavanaugh Taylor E, Skala Melissa C, Duvall Craig L
Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, PMB 351631, 2301 Vanderbilt Place, Nashville, TN 37235-1631, USA.
Biomedical Engineering, Vanderbilt University, 5824 Stevenson Center, PMB 351631, 2301 Vanderbilt Place, Nashville, TN 37235-1631, USA.
Biomaterials. 2015 Feb;41:166-75. doi: 10.1016/j.biomaterials.2014.11.016. Epub 2014 Dec 9.
A new microparticle-based delivery system was synthesized from reactive oxygen species (ROS)-responsive poly(propylene sulfide) (PPS) and tested for "on demand" antioxidant therapy. PPS is hydrophobic but undergoes a phase change to become hydrophilic upon oxidation and thus provides a useful platform for ROS-demanded drug release. This platform was tested for delivery of the promising anti-inflammatory and antioxidant therapeutic molecule curcumin, which is currently limited in use in its free form due to poor pharmacokinetic properties. PPS microspheres efficiently encapsulated curcumin through oil-in-water emulsion and provided sustained, on demand release that was modulated in vitro by hydrogen peroxide concentration. The cytocompatible, curcumin-loaded microspheres preferentially targeted and scavenged intracellular ROS in activated macrophages, reduced in vitro cell death in the presence of cytotoxic levels of ROS, and decreased tissue-level ROS in vivo in the diabetic mouse hind limb ischemia model of peripheral arterial disease. Interestingly, due to the ROS scavenging behavior of PPS, the blank microparticles also showed inherent therapeutic properties that were synergistic with the effects of curcumin in these assays. Functionally, local delivery of curcumin-PPS microspheres accelerated recovery from hind limb ischemia in diabetic mice, as demonstrated using non-invasive imaging techniques. This work demonstrates the potential for PPS microspheres as a generalizable vehicle for ROS-demanded drug release and establishes the utility of this platform for improving local curcumin bioavailability for treatment of chronic inflammatory diseases.
一种基于活性氧（ROS）响应性聚硫化丙烯（PPS）合成的新型微粒递送系统，用于“按需”抗氧化治疗测试。PPS具有疏水性，但氧化后会发生相变变为亲水性，从而为ROS需求型药物释放提供了一个有用的平台。该平台用于递送有前景的抗炎和抗氧化治疗分子姜黄素，姜黄素目前由于药代动力学性质不佳，其游离形式的使用受到限制。PPS微球通过水包油乳液有效地包封了姜黄素，并提供了持续的、按需释放，其在体外可由过氧化氢浓度调节。具有细胞相容性的、负载姜黄素的微球优先靶向并清除活化巨噬细胞内的ROS，在存在细胞毒性水平的ROS时减少体外细胞死亡，并在糖尿病小鼠后肢缺血外周动脉疾病模型中降低体内组织水平的ROS。有趣的是，由于PPS的ROS清除行为，空白微粒在这些试验中也显示出与姜黄素作用协同的固有治疗特性。从功能上讲，如使用非侵入性成像技术所证明的，局部递送姜黄素-PPS微球加速了糖尿病小鼠后肢缺血的恢复。这项工作证明了PPS微球作为ROS需求型药物释放通用载体的潜力，并确立了该平台用于提高局部姜黄素生物利用度以治疗慢性炎症性疾病的实用性。
