Nitric Oxide redistribution by a phospholipid nanoparticle colloid to treat septic shock.

通过磷脂纳米粒子胶体重新分布一氧化氮来治疗感染性休克。

• 批准号: 10321061
• 负责人: Cuthbert Ormond Simpkins
• 金额: $ 25.19万
• 依托单位: VIVACELLE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-06-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321061
• 关键词: Address; Albumins; Allergic Reaction; Animal Model; Anti-Inflammatory Agents; Antibiotic Resistance; Antibiotics; Area; Bacterial Antibiotic Resistance; Biological Assay; Biological Availability; Biological Markers; Biophysics; Blood; Blood Chemical Analysis; Blood Pressure; Blood Volume; Caliber; Cardiovascular system; Cause of Death; Cessation of life; Characteristics; Clinical; Clinical Trials; Colloids; Dangerousness; Data; Detection; Development; Drug Kinetics; Embolism; Emulsions; Ensure; Environment; Exhalation; Extracorporeal Membrane Oxygenation; Failure; Fatty acid glycerol esters; Formulation; Functional disorder; Future; Grant; Growth; Health; Hemorrhage; Hemorrhagic Shock; Human; Hydrophobicity; Hypotension; Hypovolemia; Immunologics; Inflammatory; Inflammatory Response; Infusion procedures; Injury to Kidney; Intellectual Property; International; Intervention; Lactated Ringer' s Solution; Legal patent; Licensing; Licensure; Life; Liposomes; Liquid substance; Mass Spectrum Analysis; Measures; Metabolism; Methemoglobin; Methods; Micelles; Mitochondria; Modeling; Monitor; Morbidity - disease rate; Nitrates; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Nitrites; Organ; Organ failure; Outcome; Oxygen; Pathologic; Pathway interactions; Perfusion; Pharmacologic Substance; Phase; Phospholipids; Physiological; Plasma; Plasmapheresis; Privatization; Process; Production; Prognosis; Property; Rattus; Refractory; Renal Replacement Therapy; Reperfusion Injury; Respiration; Rest; Resuscitation; Safety; Saline; Sepsis; Septic Shock; Small Business Innovation Research Grant; Sodium Cholate; Soybean Oil; Spectrophotometry; Survival Rate; Suspensions; Therapeutic; Therapeutic Embolization; Time; Tissues; Toxic effect; Treatment Cost; Treatment outcome; Validation; Vasoconstrictor Agents; Vasodilation; Work; aqueous; autocrine; base; bile salts; biomaterial compatibility; blood filtration; cecal ligation puncture; design; efficacy study; experimental study; health organization; improved; improved outcome; in vivo; lung injury; mortality; nano; nanoparticle; novel; novel strategies; novel therapeutics; oxygen transport; paracrine; particle; pre-clinical; pre-clinical assessment; sheep model; uptake; vasoconstriction

PROJECT SUMMARY Septic shock continues to be a leading cause of morbidity and mortality worldwide. The increasing bacterial antibiotic resistance is forcing the search for new methods to improve prognosis. Traditional resuscitation therapy is not designed to address the physiological mechanisms of septic shock that contribute to hypotension and organ failure. The inflammatory response is a limiting factor even with interventions such as renal replacement therapy and extracorporeal membrane oxygenation. Vivacelle Bio has patented VBI-1, a novel anti-inflammatory suspension of phospholipid nanoparticles designed to modulate the bioavailability of nitric oxide (NO) responsible for excessive vasodilatation, hypotension, or dangerous reperfusion injury that leads to organ failure in septic shock. Preliminary data support the ability of VBI-1 to carry life-sustaining amounts of oxygen and to absorb reversibly and quickly NO. Because of this reversibility, VBI-1 represents a novel approach to the modulation of NO that reduces its bioavailability without stopping its production or its autocrine or paracrine effects. Through its NO uptake and release, VBI-1 acts as a high-capacity NO modulator. At the same time, VBI-1 can carry oxygen and enable oxygen transport during resuscitation therapy. VBI-1 also inhibits the inflammatory response, reducing ischemia-reperfusion injury and organ dysfunction. Also, the small nanoparticle size and high emulsifier content of VBI-1 guarantee longer stability and higher efficacy in raising blood pressure when compared to currently used resuscitation fluids. Finally, VBI-1 is based on non-allergic soybean-oil micelles and liposomes comprised of phospholipid bilayers which make the new formulation highly biocompatible. VBI-1 formulation has been successfully proven to treat hemorrhagic shock with up to 55% replacement of blood volume without evidence of fat emboli, toxicity, or lung injury. In this SBIR grant, Vivacelle Bio will validate VBI-1 as a superior product for intravascular volume replacement compared to current resuscitation fluids, such as albumin or saline, in treating septic shock. To establish the feasibility of this approach, we propose the following two specific aims: 1) demonstrate the efficacy of VBI-1 when used in vivo on a Cecal Ligation Puncture (CLP) rat model of severe septic shock and 2) validate in vivo the NO modulatory effect by measuring NO biomarkers in the same CLP rat model. This work will be preparatory for further studies in Phase II, aimed at optimizing the formulation of VBI-1 and obtaining an FDA licensure for its use as a fluid for reducing the intensity of the inflammatory process in the intravascular space.

项目摘要 脓毒性休克仍然是世界范围内发病率和死亡率的主要原因。越来越多的细菌 抗生素耐药性迫使人们寻找新的方法来改善预后。传统复苏 治疗的目的不是为了解决脓毒性休克的生理机制， 低血压和器官衰竭。炎症反应是一个限制因素，即使有干预措施，如 肾脏替代治疗和体外膜氧合。Vivacelle Bio已获得VBI-1专利， 设计用于调节生物利用度的磷脂纳米颗粒的新型抗炎混悬液 一氧化氮（NO）导致过度血管舒张、低血压或危险的再灌注损伤， 导致败血性休克时器官衰竭初步数据支持VBI-1携带维持生命的能力。 由于这种可逆性，VBI-1代表了 一种调节NO的新方法，该方法降低其生物利用度而不停止其产生或其 自分泌或旁分泌作用。VBI-1通过其NO的吸收和释放，充当高容量的NO 调制器。同时，VBI-1可以携带氧气并在复苏过程中实现氧气运输 疗法VBI-1还抑制炎症反应，减少缺血再灌注损伤和器官损伤。 功能障碍此外，小纳米颗粒尺寸和高乳化剂含量的VBI-1保证更长的稳定性 并且与目前使用的复苏液体相比，在升高血压方面具有更高的功效。最后， VBI-1是基于非过敏性大豆油胶束和脂质体组成的磷脂双层， 使新制剂具有高度生物相容性。VBI-1制剂已被成功证明可治疗 出血性休克，血容量置换高达55%，无脂肪栓塞、毒性或 肺损伤在此次SBIR资助中，Vivacelle Bio将验证VBI-1作为血管内容量的上级产品 在治疗败血性休克中，与目前的复苏液体（如白蛋白或盐水）相比，到 建立这种方法的可行性，我们提出了以下两个具体目标：1）证明 VBI-1在体内用于严重脓毒性休克的盲肠结扎穿刺（CLP）大鼠模型时的功效， 2)通过在相同的CLP大鼠模型中测量NO生物标志物来验证体内NO调节作用。这 工作将为第二阶段的进一步研究做准备，旨在优化VBI-1的配方， 获得FDA许可，将其用作流体，用于降低炎症过程的强度， 血管内空间