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 在美国，脓毒症每年导致超过 250,000 人因革兰氏阴性菌排出的脂多糖 (LPS) 死亡。 细菌本身就足以诱发细胞因子风暴和败血症，同时，许多其他感染和 脓毒症的病因学和异质性是复杂的、动态的和异质性的。 进展，这导致几乎所有单模式免疫调节疗法的失败。 脓毒症中的过度炎症通常是由循环 LPS、致病性和破坏性分子以及 因此，这些脓毒症触发物和介质的物理清除。 血液是脓毒症治疗的有效方法，多粘菌素 B 涂层盒 Toraymyxin® 已被用于治疗脓毒症。 最近，一种装有大孔的 Cytosorb® 滤筒专门通过血液灌流 (HP) 去除 LPS。 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。 在最近的脓毒症治疗双盲对照临床试验中失败了，这可能是由于 两种墨盒的效率适中，吸附特性有限。此外，还存在各种促炎性。 为了使治疗有效，还应该去除损伤分子。因此，我们欺负了这一点。 从循环中有效、同时去除化脓性触发因素和介质将 控制脓毒症的过度炎症，从而降低与脓毒症相关的发病率和死亡率 PI 开发了一种多功能末端树枝状聚合物 (TD) 纳米平台。 通过多价和协同作用的组合，有效结合 LPS、细胞因子和 DNA 片段 这种 TD 纳米陷阱可以与尺寸排他性水凝胶结合。 这些纳米捕获树脂能够选择性地靶向这些小尺寸的促炎分子。 有效清除脓毒症小鼠血液中的 LPS 和促炎细胞因子 纳米陷阱中的电荷和疏水部分的效率可以高于现有的商业树脂。 我们可以轻松地设计针对一组特定的炎症分子来优化脓毒症治疗。 将重点关注具有不同电荷和疏水部分的TD纳米陷阱的合成和优化 水凝胶树脂并表征吸附 LPS、DAMP/PAMP 和细胞因子的选择性和效率； 目标 2，我们将进行全面的体外研究，以表征精制纳米陷阱的吸附和 了解减轻过度免疫反应的分子基础；目标 3，我们将研究其功效 Nanotrap HP 方法在盲肠结扎穿刺 (CLP) 脓毒症大鼠模型中的应用并表征体内 这些研究将为预防多器官衰竭的免疫反应和病理改善铺平道路。 将这种创新的 HP 纳米陷阱技术转化为临床以提高患有以下疾病的患者的生存率的方法 严重败血症和败血性休克也可用于治疗细胞因子风暴高风险患者，例如： 心脏手术、烧伤、创伤和 CAR-T 癌症免疫治疗。