An innovative hemoperfusion nanotrap for sepsis treatment.

用于脓毒症治疗的创新血液灌流纳米陷阱。

• 批准号: 9974537
• 负责人: Juntao Luo
• 金额: $ 38.02万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974537
• 关键词: Address; Adsorption; Affinity; Anti-Inflammatory Agents; Attenuated; Bacteria; Binding; Blood; Blood Circulation; Blood Vessels; Burn Trauma; Cardiac Surgery procedures; Cell Culture Techniques; Cells; Cessation of life; Charge; Clinic; Coagulation Process; Complex; Controlled Clinical Trials; Critical Illness; DNA; Data; Devices; Diffuse; Diffusion; Disease; Double-Blind Method; Engineering; Etiology; Europe; Evaluation; Excision; Extravasation; Failure; Future; Gene Expression; Gram-Negative Bacteria; Grant; Hemostatic function; Hydrogels; Hydrophobic Interactions; Hydrophobicity; Immune; Immune Plasma; Immune Tolerance; Immune response; Immunization; Immunologic Tests; In Vitro; Infection; Inflammation; Inflammatory; Intervention; Japan; Lead; Lipopolysaccharides; Liquid substance; Mediator of activation protein; Mitochondrial DNA; Modeling; Molecular; Molecular Weight; Monitor; Morbidity - disease rate; Multiple Organ Failure; Mus; Nature; Nuclear; Nuclear Proteins; Pathogenicity; Pathologic; Pathway interactions; Patients; Pattern; Plant Resins; Plasma; Polymyxin B; Proteins; Rattus; Risk; Sepsis; Septic Shock; Signaling Molecule; TLR9 gene; Techniques; Testing; Tissues; Translating; base; biomaterial compatibility; cancer immunotherapy; cecal ligation puncture; clinical translation; combinatorial; comparative efficacy; cytokine; cytokine release syndrome; efficacy study; experimental study; high risk; immunomodulatory therapies; immunoreaction; immunoregulation; improved; in vivo; innovation; insight; mechanical properties; mortality; nanotechnology platform; novel; organ injury; pathogen; physical property; prevent; research clinical testing; septic; septic patients; tool

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.

抽象的 败血症每年在美国造成> 250,000人死亡。脂多糖（LPS），由革兰氏阴性 单独的细菌足以诱导细胞因子风暴和败血症。意思是，许多其他感染和 疾病也会引起败血症。败血症在病因和病因和 进展，导致几乎所有单峰免疫调节疗法的失败。系统性 脓毒症中的高炎症通常由循环的LP，致病和损伤分子以及 信号分子（例如细胞因子）。因此，从 血液是败血症治疗的有效方法。多粘蛋白B涂层的墨盒TorayMyXin®已用于 通过hemoperfusion（HP）专门删除LPS。最近，一只墨盒盒有大孔 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 在最新的双盲对照临床试验中，败血症治疗失败，这可能是由于 中等效率和有限的两个墨盒的吸附曲线。另外，各种促炎 还应去除损伤分子以使治疗有效。因此，我们假设 从循环中有效，简单地去除化粪池和介体 控制败血症中的过度炎症，从而降低了与之相关的发病率和死亡率 严重的败血症和败血性休克。 PI已开发了一种多功能的Telodendrimer（TD）纳米板的 通过多价和协同作用的组合，有效地与LPS，细胞因子和DNA片段结合 电荷和疏水相互作用。这样的TD纳米胶质可以连接到尺寸排定的水凝胶上 树脂以靶向这些小型促炎分子。这些Nanotrap树脂能够选择性地 清除LPS和促炎细胞因子在化粪池中有效的血液中有效得多 效率比现有商业树脂的效率。纳米图中的电荷和疏水部分可以是 易于设计以靶向一组特定的炎症分子以优化败血症治疗。目标1，我们 将重点侧重于具有不同电荷和疏水部分的TD纳米饰面的合成和优化 水凝胶树脂并表征吸附LPS，潮湿/PAMP和细胞因子的选择性和效率； AIM 2，我们将进行全面的体外研究，以表征精制的纳米饰吸附和 了解衰减超免疫反应的分子基础； AIM 3，我们将研究 Cecal结扎和穿刺（CLP）化粪池模型中的纳米图HP方法，并表征体内 免疫反应和预防多器官衰竭的病理改善。这些研究将铺路 将这种创新的HP Nanotrap技术转化为诊所的方法，以提高患者的生存率 严重的败血症和败血性休克。它也可以用来治疗具有细胞因子风暴的高风险的患者，例如 心脏手术，烧伤，创伤和CAR-T癌免疫疗法。