Polysaccharide-based endotoxin antagonist for the treatment of sepsis

多糖内毒素拮抗剂治疗脓毒症

• 批准号: 8954737
• 负责人: Yoon Yeo
• 金额: $ 19.38万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8954737
• 关键词: Acids; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Therapy; Antibiotics; Antibodies; Antigens; Attenuated; Benchmarking; Binding; Blood; CD14 Antigen; CD14 gene; Caring; Cause of Death; Charge; Chitosan; Clinical; Complement; Complex; Critical Care; Development; Dose; Effectiveness; Electrostatics; Elements; Endotoxins; Glycolipids; Goals; Human; Hydrogen Bonding; Hydrophobic Interactions; Hydrophobicity; In Vitro; Inflammatory; Investigation; Life; Ligation; Lipid A; Lipopolysaccharides; Liquid substance; Metabolic; Mission; Modeling; Modification; Molecular Weight; Monitor; Mus; Organ; Outcome; Phase; Physiological; Polymyxin B; Polysaccharides; Procedures; Production; Property; Protein Binding; Proteins; Public Health; Puncture procedure; Research; Resources; Resuscitation; Sepsis; Septic Shock; Signal Pathway; Structure; Systemic Therapy; TLR4 gene; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tissues; Toxic effect; United States National Institutes of Health; Water; Work; amidation; base; cytokine; extracellular; hemodynamics; human disease; hydroxyl group; improved; in vivo; macrophage; mortality; mouse model; novel; novel therapeutics; prevent; public health relevance; receptor; response; standard care; standard of care; water solubility

 DESCRIPTION (provided by applicant): Severe sepsis and septic shock are life-threatening problems frequently encountered in the critical care unit. Current treatments based on antibiotic therapy, inotropes, fluid resuscitation, and end-organ support are not always effective, and there is an urgent need for new therapies to reduce sepsis mortality. One ongoing effort is to remove or inactivate circulating endotoxins (or lipopolysaccharides, LPS), which are primarily responsible for the pathophysiological derangements seen in gram-negative sepsis. Several compounds that can bind to lipid A, an anionic glycolipid serving as a toxic element of LPS, via antigen-antibody interactions, electrostatic interactions, or hydrophobic interactions have been explored for the treatment of sepsis. However, these therapies have made little clinical impacts. The difficulties partly arise from their hydrophobicity and cationic charge, the very properties used for interaction with LPS, as they cause toxicity and non-specific interactions with proteins and other blood components. We propose to develop a new therapeutic agent for systemic sepsis treatment based on our chitosan derivative, which we call zwitterionic chitosan (ZWC). ZWC is created by partial amidation of low molecular weight chitosan (CS) but distinct from CS by the charge profile and water solubility. Unlike CS, ZWC is negatively charged and water-soluble at physiological pH and thus compatible with blood components. Importantly, it suppresses the production of pro-inflammatory cytokines by LPS-challenged macrophages via extracellular interaction with LPS. Moreover, IP-administered ZWC mitigated systemic effect of LPS or attenuated the onset of LPS-induced sepsis in mice, with no signs of adverse tissue responses seen with CS. These features well justify the investigation of ZWC as a novel LPS antagonist. Our long-term goal is to develop a new systemic treatment for sepsis based on ZWC. The objective of this study is to produce a ZWC, comparable or superior to polymyxin B in efficacy and potency but with no systemic toxicities, and to investigate the utility of ZWC as a systemic therapy of sepsis. Our central hypothesis is that ZWC suppresses LPS activity via direct interaction with LPS and binding to receptors of LPS/TLR4 signaling pathways; therefore, ZWC modifications to increase these properties will improve the potency and efficacy of ZWC. To test this hypothesis, we will modify ZWC with additional hydroxyl groups and hydrophobic pendants and evaluate its in vitro anti-LPS activity of optimized ZWC benchmarking it against polymyxin B (Aim 1) and in vivo therapeutic effects of the optimized ZWC in a mouse model of severe sepsis as a standalone therapy as well as a supplement to standard care procedure (Aim 2). The proposed work is expected to optimize the properties of ZWC for best therapeutic outcomes and prove the effectiveness of ZWC in systemic treatments of sepsis. Successful accomplishment of this study will provide a new way to neutralize LPS and reduce the sepsis-related mortality, complementing the current standard of care of sepsis.

 描述（由申请人提供）：严重败血症和败血性休克是重症监护病房中经常遇到的危及生命的问题，目前基于抗生素治疗、正性肌力药、液体复苏和终末器官支持的治疗并不总是有效，并且存在一些问题。迫切需要新的疗法来降低败血症死亡率，一项持续的努力是消除或灭活循环内毒素（或脂多糖，LPS），它是病理生理学的主要原因。一些化合物可以通过抗原-抗体相互作用、静电相互作用或疏水相互作用与脂质 A（一种阴离子糖脂，作为 LPS 的毒性成分）结合，用于治疗脓毒症。这些疗法几乎没有产生临床影响，部分原因在于它们的疏水性和阳离子电荷，这些特性正是与脂多糖相互作用的特性，因为它们会引起毒性以及与蛋白质和其他血液成分的非特异性相互作用。基于我们的壳聚糖衍生物的新型全身性脓毒症治疗剂，我们称之为两性离子壳聚糖 (ZWC)，它是通过低分子量壳聚糖 (CS) 的部分酰胺化而产生的，但与 CS 的电荷分布和水溶性不同。 ZWC 带负电荷，在生理 pH 值下呈水溶性，因此与血液成分相容，重要的是，它通过细胞外相互作用抑制 LPS 攻击的巨噬细胞产生促炎细胞因子。此外，IP 给药的 ZWC 减轻了 LPS 的全身效应或减弱了 LPS 诱导的小鼠脓毒症的发作，而 CS 没有出现不良组织反应的迹象，这些特征充分证明了 ZWC 作为新型 LPS 拮抗剂的研究是合理的。我们的长期目标是开发一种基于 ZWC 的新的脓毒症全身治疗方法。本研究的目的是生产一种在功效和效力上与多粘菌素 B 相当或优于多粘菌素 B，但没有全身毒性的 ZWC，并进行研究。 ZWC 作为脓毒症全身治疗的用途是 ZWC 通过与 LPS 直接相互作用并与 LPS/TLR4 信号通路受体结合来抑制 LPS 活性；因此，对 ZWC 进行修饰以增加这些特性将提高效力和功效。为了检验这一假设，我们将用额外的羟基和疏水性侧链修饰 ZWC，并以多粘菌素 B（目标 1）为基准评估其体外抗 LPS 活性。优化的 ZWC 作为独立疗法以及标准护理程序的补充在严重脓毒症小鼠模型中的体内治疗效果（目标 2）预计将优化 ZWC 的特性以获得最佳治疗结果并证明ZWC 在脓毒症全身治疗中的有效性。这项研究的成功完成将提供一种中和 LPS 并降低脓毒症相关死亡率的新方法，补充目前的脓毒症护理标准。