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.

项目概要 感染性休克仍然是全世界发病和死亡的主要原因。细菌不断增多 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 治疗并非旨在解决败血性休克的生理机制，该机制有助于 低血压和器官衰竭。即使采取以下干预措施，炎症反应也是一个限制因素 肾脏替代治疗和体外膜肺氧合。 Vivacelle Bio 已获得 VBI-1 专利， 新型抗炎磷脂纳米粒子悬浮液，旨在调节生物利用度 一氧化氮 (NO) 会导致血管过度舒张、低血压或危险的再灌注损伤 导致感染性休克中的器官衰竭。初步数据支持VBI-1具有维持生命的能力 大量的氧气并可逆地快速吸收 NO。由于这种可逆性，VBI-1 代表 一种调节 NO 的新方法，可在不停止其生产或其生物利用度的情况下降低其生物利用度 自分泌或旁分泌作用。通过吸收和释放 NO，VBI-1 充当高容量 NO 调制器。同时，VBI-1可以携带氧气，实现复苏过程中的氧气输送 治疗。 VBI-1 还抑制炎症反应，减少缺血再灌注损伤和器官 功能障碍。此外，VBI-1 的小纳米颗粒尺寸和高乳化剂含量保证了更长的稳定性 与目前使用的复苏液相比，其升高血压的功效更高。最后， VBI-1 基于非过敏性大豆油胶束和由磷脂双层组成的脂质体， 使新配方具有高度的生物相容性。 VBI-1配方已被成功证明可以治疗 失血性休克，血容量置换高达 55%，且无脂肪栓塞、毒性或证据 肺损伤。在这笔 SBIR 拨款中，Vivacelle Bio 将验证 VBI-1 作为血管内容量的优质产品 与目前的复苏液体（例如白蛋白或盐水）相比，在治疗感染性休克时是一种替代液体。到 为了确定这种方法的可行性，我们提出以下两个具体目标：1）证明 VBI-1 在体内用于严重感染性休克盲肠结扎穿刺 (CLP) 大鼠模型时的功效 2) 通过在同一 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和 获得 FDA 许可，将其用作降低炎症过程强度的液体 血管内空间。