Glycocalyx repair in sepsis using liposomal carriers of preassembled glycocalyx

使用预组装糖萼的脂质体载体修复脓毒症中的糖萼

• 批准号: 10218261
• 负责人: MICHAEL S GOLIGORSKY
• 金额: $ 54.12万
• 依托单位: NEW YORK MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-05 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218261
• 关键词: Affect; Antithrombin III; Bioavailable; Biodistribution; Blood Vessels; Carbohydrates; Cardiovascular Diseases; Cell Surface Receptors; Cell membrane; Competence; Detection; Dose; Electron Microscopy; Endothelial Cells; Endothelium; Exhibits; Feedback; Formulation; Functional disorder; Generations; Glycocalyx; Gold; Growth Factor; Half-Life; Heparin; Image; Impairment; Implant; In Vitro; Inflammatory; Intervention; Investigation; Kidney; Kidney Diseases; Label; Leukocyte Trafficking; Life; Liposomes; Measurement; Metabolic Clearance Rate; Metabolic Diseases; Microcirculation; Modification; Monitor; Morbidity - disease rate; Multiple Organ Failure; Mus; Nitric Oxide; Nitric Oxide Donors; Organ; Oxidative Stress; Pathogenicity; Pharmacology; Production; Renal function; Sepsis; Septicemia; Superoxide Dismutase; Surface; Survival Rate; Testing; Therapeutic; Vascular Permeabilities; Vasodilation; Vasodilator Agents; arteriole; base; chemokine; clinical practice; design; extracellular; functional restoration; glucuronyl glucosamine glycan sulfate; heart function; hemodynamics; improved; in vitro testing; in vivo; in vivo evaluation; intravenous injection; intravital imaging; liposome vector; liver function; mechanical force; mechanotransduction; mortality; nanoliposome; novel strategies; novel therapeutics; polymicrobial sepsis; prevent; pulmonary function; receptor; reconstitution; repaired; response; restoration; sensor; septic; shear stress; tool; vasomotion

ABSTRACT Endothelial glycocalyx (EG), a carbohydrate-rich outermost surface layer, is a guardian of vascular functions. It is a sensor of the shear stress-activated endothelial nitric oxide production and flow-induced vasodilation, harbinger of growth factors, extracellular superoxide dismutase and anti-thrombin III, EG is a regulator of vascular permeability and leukocyte trafficking across the vascular wall, and it protects receptors from hyperstimulation by shielding them. EG is degraded in diverse cardiovascular, metabolic and renal diseases, thus leading to impairment of all the above functions. One of these conditions precipitating the loss of EG is septicemia, which is associated with high morbidity and mortality. We observed that mice with the polymicrobial sepsis exhibit a drastic reduction in the global volume of EG. Therefore, expeditious restoration of EG represents a rational pathogenetic therapy. We have recently designed, synthesized and tested in vitro, ex vivo and in vivo liposomal nanocarriers of preassembled glycocalyx. This pharmacological intervention improved mechanotransduction and nitric oxide synthesis, flow-induced vasodilation and renal microcirculation in endotoxemic mice. We have presently designed and synthesized the second generation of liposomal nanocarriers of preassembled glycocalyx featuring “stealth” liposomes with increased half-life, gold-label, as well as an array of possible modifications and demonstrated that they significantly improved survival of mice injected with the lethal dose of LPS. The present proposal is aimed at exploration of validity and efficacy of this pharmacologic approach in sepsis. We describe the steps to refine liposomal nanocarriers of preassembled glycocalyx, monitoring of the fate of these gold-labeled liposomes – their fusion with the plasma membrane, intracellular traffic, half-life in the vasculature. Thereafter we shall determine the effect of intravenous injection of liposomal nanocarriers on the course of sepsis and associated with it hemodynamic perturbations and the rate of functional restoration of affected organs. Proposed studies should not only refine this novel therapeutic tool but may also establish a pharmacologic approach to ameliorate sepsis-induced multiorgan failure.

摘要 内皮糖萼（EG），一个富含碳水化合物的最外层，是一个守护者， 血管功能。它是剪切应力激活的内皮一氧化氮的传感器 产生和流动诱导的血管舒张，生长因子的先兆，细胞外 超氧化物歧化酶和抗凝血酶III，EG是血管通透性调节剂， 白细胞运输通过血管壁，它保护受体， 通过屏蔽它们来刺激大脑EG在各种心血管、代谢和代谢中降解， 和肾脏疾病，从而导致所有上述功能的损害。其中一 加速EG损失的条件是败血症，其与高 发病率和死亡率。我们观察到患有多微生物败血症的小鼠表现出一种 全球EG用量大幅减少。因此，迅速恢复执行小组 是一种合理的病理治疗方法。我们最近设计，合成， 在体外、离体和体内测试预组装糖萼的脂质体纳米载体。 这种药物干预改善了机械传导和一氧化氮 内毒素血症小鼠中的合成、流动诱导的血管舒张和肾微循环。我们 目前已设计并合成了第二代脂质体 预组装糖萼的纳米载体，其特征在于“隐形”脂质体， 半衰期，金标，以及一系列可能的修改，并证明， 它们显著提高了注射致死剂量LPS的小鼠的存活率。的 本建议旨在探索这种药理学的有效性和功效 脓毒症的治疗方法我们描述了改进脂质体纳米载体的步骤， 预组装的糖萼，监测这些金标记的脂质体的命运-它们的 与质膜的融合、细胞内运输、脉管系统中的半衰期。 此后，我们将确定静脉注射脂质体纳米载体的效果 对脓毒症的病程及其相关的血流动力学紊乱和 恢复受损器官的功能拟议中的研究不仅应该完善这一点， 一种新的治疗工具，但也可能建立一种药理学方法，以改善 败血症导致的多器官衰竭