Development of NAD+ loaded nanoparticles as a safe and efficient strategy to combat sepsis.

开发负载 NAD 的纳米粒子作为对抗脓毒症的安全有效策略。

• 批准号: 10448923
• 负责人: SHAOQIN GONG
• 金额: $ 19.44万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-22 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448923
• 关键词: Address; Anabolism; Antibiotic Therapy; Antibiotics; Apoptosis; Bacteria; Behavior; Biodistribution; Blood Vessels; Bone Marrow; Cell Death; Cell membrane; Cells; Cessation of life; Clinical Research; Coin; Complex; Data; Development; Disease; Dose; Drug Kinetics; Endothelial Cells; Endothelium; Energy Supply; Escherichia coli; Family; Financial Hardship; Formulation; Functional disorder; Future; Goals; Healthcare Systems; Homeostasis; Hydrogen Peroxide; Immune; Immune response; Immune system; In Vitro; Infection; Inflammasome; Inflammation; Inflammatory; Injections; Lead; Lipids; Maximum Tolerated Dose; Medicare; Modeling; Mus; Oxidative Stress; Pathway interactions; Performance; Pharmaceutical Preparations; Preparation; Process; Prognosis; Property; Reporting; Resuscitation; Rifampin; Safety; Sepsis; System; TNF gene; Therapeutic; Therapeutic Studies; Transportation; Treatment Efficacy; Vascular System; Work; biomaterial compatibility; calcium phosphate; cecal ligation puncture; cell injury; clinical application; clinical translation; combat; cost; cytokine; delivery vehicle; drug release profile; effective therapy; efficacious treatment; endothelial dysfunction; extracellular; hemodynamics; improved; in vivo; innovation; macrophage; nanoparticle; nanoparticle delivery; nicotinamide-beta-riboside; novel therapeutics; organ injury; preclinical study; prevent; success; therapeutic nanoparticles; therapeutically effective; uptake

Project Summary Sepsis is a complex disorder caused by a dysregulated host response to infection. Current sepsis therapeutic strategies do not adequately address immune dysregulation and endothelial dysfunction. NAD+ can potentially be an efficient therapeutic molecule for sepsis, but its therapeutic efficacy is hindered by its inability to pass through the cell membrane. Extracellular NAD+ has to be degraded into NAD+ precursors (e.g., nicotinamide and nicotinamide riboside), which can be taken up by cells and subsequently enhance intracellular NAD+ biosynthesis. However, this conversion process is inefficient. Such a limitation in NAD+ intracellular transportation drastically decreases the bioactivity of NAD+ and necessitates an extremely high dose for effective therapy. We aim to develop an innovative, safe, and effective sepsis therapy utilizing NAD+ delivery nanoparticles (NPs), which can directly (i.e., without being converted to NAD+ precursors) and efficiently replenish the cellular NAD+ pool, in combination with a broad-spectrum antibiotic. To achieve this goal, we formulated a family of NAD+ or NAD+/antibiotic (e.g., rifampicin (Rif)) loaded lipid (LP)-coated calcium phosphate nanoparticles (NPs) (coined as NAD+ loaded NPs including NAD+-LP-CaP and NAD+-Rif-LP-CaP). The NAD+ loaded NPs possess a number of desirable properties including high loading content, high stability, pH-responsive drug release profiles, and endosomal escape capability. Despite the therapeutic potential of NAD+, there is no prior report on in vivo studies using NAD+ NPs for therapeutic studies including sepsis. Our preliminary data has demonstrated that NAD+-LP- CaP can suppress the release of pro-inflammatory cytokines and prevent inflammation-induced cell death and endothelium disruption. Therefore, NAD+ loaded NPs can potentially help maintain homeostasis of both the immune system and the vascular system. Our NAD+ loaded NPs successfully treated LPS- and bacteria-induced sepsis in vivo. They were able to accumulate in the sepsis injured organs and mitigate multiple organ injury. Compared with free NAD+, NAD+ loaded NPs showed significantly improved therapeutic efficacies. For this proposed work, we plan to further optimize the NAD+ loaded NPs to achieve even higher drug loading content and efficiency (Aim 1). The therapeutic mechanism of NAD+-LP-CaP will be studied in vitro in order to gain a better understanding of how the NAD+ loaded NPs suppress inflammation and also protect cells including immune cells and endothelial cells from inflammation-induced cell damage (Aim 2). Finally, we will systematically determine the safety, pharmacokinetics, and therapeutic efficacy of the NAD+ loaded NPs in two representative mouse sepsis models, and also study the NP’s impact on immune and vascular homeostasis (Aim 3). If successful, this proposed study will create an innovative, safe, and effective therapeutic approach for treating sepsis. A translational success of this paradigm-shift therapy for sepsis could significantly improve the prognosis of this serious disease that causes one in five deaths around the world and decrease the tremendous financial burden it brings to the healthcare systems (e.g., around $41.5 billion cost in Medicare in the US).

项目摘要 败血症是由宿主对感染的反应失调引起的复杂疾病。当前的败血症治疗 策略不能充分解决免疫失调和内皮功能障碍。 NAD+可能会 成为败血症的有效热分子，但其治疗效率无法通过 通过细胞膜。细胞外NAD+必须降解为NAD+前体（例如烟酰胺和 烟酰胺核苷），可以通过细胞吸收并随后增强细胞内NAD+生物合成。 但是，这种转换过程效率低下。 NAD+细胞内转运的这种限制很大 降低NAD+的生物活性，并需要极高的剂量以进行有效治疗。 我们旨在开发使用NAD+递送纳米颗粒（NP）的创新，安全和有效的败血症治疗 可以直接（即，不转换为NAD+前体）并有效复制细胞NAD+ 池，结合广谱抗生素。为了实现这一目标，我们制定了一个NAD+的家庭 NAD+/抗生素（例如，利福平（RIF））负载脂质（LP）涂层磷酸钙纳米颗粒（NPS）（固定 作为NAD+加载的NP，包括NAD+-LP-CAP和NAD+-RIF-LP-CAP）。 NAD+加载的NP具有一个数字 理想的特性，包括高负载含量，高稳定性，pH响应性药物释放曲线和 内体逃生能力。尽管NAD+具有治疗潜力，但没有关于体内研究的事先报告 使用NAD+ NP进行包括败血症在内的治疗研究。我们的初步数据表明NAD+-LP- CAP可以抑制促炎性细胞因子的释放，并防止注射诱导的细胞死亡和 内皮破坏。因此，NAD+负载的NP可以有助于维持这两者的体内平衡 我们的NAD+负载NP成功处理了LPS和细菌诱导的 体内败血症。他们能够在败血症受伤的器官中积聚并减轻多器官损伤。 与游离NAD+相比，NAD+加载的NP显示出明显提高的治疗效率。 对于这项提议的工作，我们计划进一步优化NAD+加载的NP，以实现更高的药物加载 内容和效率（目标1）。 NAD+-LP-CAP的理论机制将在体外研究 更好地了解NAD+加载的NP抑制注射，还可以保护细胞 免疫细胞和内皮细胞来自炎症引起的细胞损伤（AIM 2）。最后，我们将系统地 确定两个代表性的NAD+负载NP的安全性，药代动力学和治疗效率 小鼠败血症模型，还研究了NP对免疫和血管稳态的影响（AIM 3）。 如果成功，这项拟议的研究将创建一种创新，安全和有效的治疗方法 败血症。这种范式转移疗法对败血症的转化成功可以显着改善预后 这种严重疾病会导致世界各地五分之一的死亡并减少巨大的财务状况 它给医疗保健系统带来的负担（例如，美国的Medicare成本约为415亿美元）。