Department of Chemical Engineering, University of Michigan, 2300 Hayward Avenue, Ann Arbor, MI, 48105, USA.
Department of Biomedical Engineering, University of Michigan, 1119 Carl A. Gerstacker Building, 2200 Bonisteel Boulevard, Ann Arbor, MI, 48109-2099, USA.
Biomaterials. 2019 Oct;218:119333. doi: 10.1016/j.biomaterials.2019.119333. Epub 2019 Jul 4.
Developing biomaterials to control the responsiveness of innate immune cells represents a clinically relevant approach to treat diseases with an underlying inflammatory basis, such as sepsis. Sepsis can involve activation of Toll-like receptor (TLR) signaling, which activates numerous inflammatory pathways. The breadth of this inflammation has limited the efficacy of pharmacological interventions that target a single molecular pathway. Here, we developed cargo-less particles as a single-agent, multi-target platform to elicit broad anti-inflammatory action against innate immune cells challenged by multiple TLR agonists. The particles, prepared from poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA), displayed potent molecular weight-, polymer composition-, and charge-dependent immunomodulatory properties, including downregulation of TLR-induced costimulatory molecule expression and cytokine secretion. Particles prepared using the anionic surfactant poly(ethylene-alt-maleic acid) (PEMA) significantly blunted the responses of antigen presenting cells to TLR4 (lipopolysaccharide) and TLR9 (CpG-ODN) agonists, demonstrating broad inhibitory activity to both extracellular and intracellular TLR ligands. Interestingly, particles prepared using poly(vinyl alcohol) (PVA), a neutrally-charged surfactant, only marginally inhibited inflammatory cytokine secretions. The biochemical pathways modulated by particles were investigated using TRanscriptional Activity CEll aRrays (TRACER), which implicated IRF1, STAT1, and AP-1 in the mechanism of action for PLA-PEMA particles. Using an LPS-induced endotoxemia mouse model, administration of PLA-PEMA particles prior to or following a lethal challenge resulted in significantly improved mean survival. Cargo-less particles affect multiple biological pathways involved in the development of inflammatory responses by innate immune cells and represent a potentially promising therapeutic strategy to treat severe inflammation.
开发能够控制固有免疫细胞反应性的生物材料是一种有临床意义的方法，可以治疗以炎症为基础的疾病，如败血症。败血症可能涉及 Toll 样受体 (TLR) 信号的激活，该信号激活了许多炎症途径。这种炎症的广泛性限制了针对单一分子途径的药物干预的疗效。在这里，我们开发了无载体颗粒作为单一制剂、多靶点平台，以针对多种 TLR 激动剂挑战的固有免疫细胞产生广泛的抗炎作用。这些颗粒由聚（乳酸-共-羟基乙酸）（PLGA）和聚乳酸（PLA）制成，具有强大的分子量、聚合物组成和电荷依赖性的免疫调节特性，包括下调 TLR 诱导的共刺激分子表达和细胞因子分泌。使用阴离子表面活性剂聚（乙烯-共-马来酸）（PEMA）制备的颗粒显著减弱了抗原呈递细胞对 TLR4（脂多糖）和 TLR9（CpG-ODN）激动剂的反应，表明对细胞外和细胞内 TLR 配体均具有广泛的抑制活性。有趣的是，使用带中性电荷的表面活性剂聚乙烯醇（PVA）制备的颗粒仅轻微抑制了炎症细胞因子的分泌。使用转录活性细胞阵列（TRACER）研究了颗粒调节的生化途径，该途径表明 PLA-PEMA 颗粒的作用机制涉及 IRF1、STAT1 和 AP-1。在 LPS 诱导的内毒素血症小鼠模型中，在致命挑战之前或之后给予 PLA-PEMA 颗粒可显著提高平均存活率。无载体颗粒影响固有免疫细胞炎症反应发展中涉及的多个生物学途径，代表了一种有前途的治疗严重炎症的策略。
