An innovative hemoperfusion nanotrap for sepsis treatment.

摘要 在美国，败血症每年导致25万人死亡。革兰氏阴性菌分泌的脂多糖 细菌本身就足以引起细胞因子风暴和败血症。与此同时，许多其他感染和 疾病也会导致败血症。脓毒症是复杂的、动态的和异质性的，在病因和 进展，这导致几乎所有单峰免疫调节疗法的失败。系统性的 脓毒症的高度炎症通常由循环内毒素、致病和损伤分子和 信号分子(如细胞因子)。因此，这些败血症触发物和介体的物理清除 血液是治疗脓毒症的有效方法。多粘菌素B涂层的色谱盒Toraymysin®已用于 通过血液灌流(HP)特异性地清除内毒素。最近，一种填充了大孔的CytoSorb®墨盒 树脂用于通过非特异性疏水吸附去除细胞因子。不幸的是，这两种产品 在最近的败血症治疗双盲对照临床试验中失败，这可能是由于 两个墨盒的中等效率和有限的吸附曲线。此外，各种促炎性疾病 损伤分子也应该被移除，才能使治疗有效。因此，我们假设 有效和同时从循环中清除败血症触发因子和介体将 控制脓毒症的过度炎症，从而降低与以下疾病相关的发病率和死亡率 严重败血症和感染性休克。PI已经开发了一种多功能端粒(TD)纳米平台，用于 通过多价结合和协同作用有效结合内毒素、细胞因子和DNA片段 电荷和疏水相互作用。这种TD纳米捕捉器可以连接到尺寸专一的水凝胶上 以这些小尺寸促炎分子为靶点的树脂。这些纳米捕集树脂能够选择性地 能有效清除脓毒症小鼠血液中的内毒素和促炎细胞因子 比现有商业树脂的效率更高。纳米陷阱中的电荷和疏水部分可以是 易于设计，针对特定的炎症分子组，以优化脓毒症的治疗。目标1，我们 将着重于不同电荷和疏水基团的TD纳米陷阱的合成和优化 研究了水凝胶树脂对脂多糖、DAMP/PAMPs和细胞因子的选择性和吸附效率； 目的2，我们将进行全面的体外研究，以表征精制的纳米陷阱吸附和 了解减弱高免疫反应的分子基础；目标3，我们将研究 纳米捕捉器幽门螺杆菌在盲肠结扎穿孔(CLP)脓毒症大鼠模型中的应用 预防多器官功能衰竭的免疫反应和病理改善。这些研究将为 将这种创新的幽门螺杆菌纳米陷阱技术转化为临床以提高患者存活率的方法 严重败血症和感染性休克。它也可用于治疗细胞因子风暴的高危患者，例如 心脏手术、烧伤、创伤和CAR-T癌症免疫治疗。

Abstract Sepsis causes >250,000 deaths each year in the USA. Lipopolysaccharide (LPS), shed by gram-negative bacteria, alone is sufficient to induce cytokine storm and sepsis. Meanwhile, many other infections and diseases can also cause sepsis. Sepsis is complex, dynamic, and heterogeneous in both etiology and progression, which has led to failures of almost all unimodal immune modulation therapies. The systemic hyperinflammation in sepsis is generally induced by circulating LPS, pathogenic and damage molecules and signaling molecules (e.g. cytokines). Therefore, physical clearance of these septic triggers and mediators from blood is a valid approach for sepsis treatment. A polymyxin B-coated cartridge, Toraymyxin®, has been used to remove LPS specifically by hemoperfusion (HP). Recently, a Cytosorb® cartridge packed with macroporous resin is used to remove cytokines through nonspecific hydrophobic adsorption. Unfortunately, both products failed in the most recent double-blind controlled clinical trials for sepsis treatment, which is likely due to the moderate efficiency and limited adsorption profiles of both cartridges. In addition, various proinflammatory damage molecules should also be removed for the treatment to be effective. Therefore, we hypothesize that the efficient and simultaneous removal of both septic triggers and mediators from the circulation will control hyperinflammation in sepsis, and thus reducing both morbidity and mortality associated with severe sepsis and septic shock. The PI has developed a versatile telodendrimer (TD) nanoplatform for efficient binding to LPS, cytokines, and DNA fragments via the combination of multivalent and synergistic charge and hydrophobic interactions. Such TD nanotraps can be conjugated onto size-exclusive hydrogel resins to target these small-sized proinflammatory molecules. These nanotrap resins are able to selectively scavenge LPS and proinflammatory cytokines efficiently in the blood from septic mice with much higher efficiencies than existing commercial resins. The charge and hydrophobic moieties in the nanotrap can be easily engineered to target a specific group of inflammatory molecules to optimize sepsis treatment. Aim 1, we will focus on synthesis and optimization of TD nanotraps with different charges and hydrophobic moieties on hydrogel resins and characterize the selectivity and efficiency in adsorbing LPS, DAMP/PAMPs and cytokines; Aim 2, We will conduct comprehensive in vitro studies to characterize the refined nanotrap adsorption and understand the molecular basis in attenuating hyper-immune reactions; Aim 3, we will study the efficacy of nanotrap HP approach in Cecal Ligation and Puncture (CLP) septic rat model and characterize the in vivo immune reactions and pathological improvement in preventing multiple organ failure. These studies will pave the way to translate this innovative HP nanotrap technique into the clinic to improve the survival of patients with severe sepsis and septic shock. It can also be used to treat patients with high risk of a cytokine storm, e.g. cardiac surgery, burn, trauma and CAR-T cancer immunotherapy.