Controlling complement to unleash nanomedicine for acute critical illnesses

控制补体释放纳米药物治疗急性危重疾病

基本信息

批准号：
10340537
负责人：
Jacob Brenner
金额：
$ 62.62万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10340537
关键词：
Acute Acute Respiratory Distress Syndrome Adopted Affect Air Sacs Alveolar Alveolus Amino Acid Motifs Anaphylaxis Antibodies Artificial nanoparticles Binding Binding Proteins Biological Assay Blood Blood Proteins Blood capillaries C3bi COVID-19 COVID-19 mortality Cause of Death Cells Cessation of life Complement Complement 3a Complement Activation Complement Factor H Complement component C1 Critical Care Critical Illness Disease Drug Carriers Drug Delivery Systems Endothelial Cells Endothelium Engineering Functional disorder Genetic Complementation Test Human Hypersensitivity Hypotension Immune In Vitro Inflammatory Injections Knock-out Lead Leukocytes Life Ligands Liposomes Lung Macrophage-1 Antigen Malignant Neoplasms Measures Membrane Proteins Microbe Modeling Monoclonal Antibodies Mus Myocardial Infarction Nanotechnology Nebulizer Oleic Acids Organ Outcome Outpatients Patients Pharmaceutical Preparations Phenotype Physicians Plasma Plasma Proteins Play Properdin Pulmonary Inflammation Reaction Recombinants Reporting Role Sepsis Serum Side Spleen Stroke Technology Testing Therapeutic Therapeutic Effect Wild Type Mouse Work antibody conjugate base clinical translation complement 3 regulator complement pathway cytokine density design experimental study human tissue improved in vitro testing in vivo lung injury mouse model nanocarrier nanomedicine nanoparticle neutralizing antibody neutrophil prevent receptor side effect standard measure tissue resource translational potential uptake

项目摘要

ABSTRACT / SUMMARY Acute critical illnesses rapidly lead to severe organ damage and loss of life. These illnesses include sepsis, stroke, and acute respiratory distress syndrome (ARDS). Here we focus on ARDS, which is acute inflammation of the lungs’ air sacs, and the cause of death in COVID-19. For ARDS and these other diseases, we have developed ligand-targeted nanocarriers that localize drugs to the inflamed microvasculature of affected organs. As we moved towards clinical translation, we found the key step is gaining control of complement, a set of plasma proteins that bind microbes and aid their clearance. But we found complement-nanoparticle interactions are a “double-edged sword”, with both benefits to optimize, and deleterious features to resolve. First, we found that complement protein C3 rapidly opsonizes particular nanoparticles, and that such C3- opsonized nanoparticles then act as “decoys” to ameliorate ARDS mouse models (e.g., nebulized LPS) by ~75%. The C3-coated nanoparticles accumulate in marginated leukocytes, which are key to ARDS pathophysiology, and cause those cells to leave the lungs. However, C3 opsonization induces an anaphylaxis-like reaction called CARPA (complement-activation-related pseudo-allergy). Therefore, in Aim 1, we will engineer nanoparticles that can function like C3-coated decoys to ameliorate ARDS, but without CARPA. We will also investigate the mechanism underlying nanoparticle decoy therapy. Then we will test the translational potential of these optimized decoy nanoparticles by testing them in fresh, perfused, ex vivo human lungs. Second, we found that the ligand-targeted nanoparticles we have been developing for drug delivery for years also induce CARPA. Therefore, in Aim 2, we will re-engineer our ligand-targeted nanoparticles to prevent CARPA. We will test a drug carrier we have previously used to concentrate drugs in the alveolar microvasculature of the lungs: liposomes conjugated to anti-PECAM antibodies that bind endothelial cells. We will test in vitro and in vivo in mice whether various engineered versions of anti-PECAM liposomes can evade C3 opsonization and CARPA, and thereby achieve more specific delivery to the lungs. Lastly, we will test these CARPA-avoiding nanoparticles with plasma from ARDS patients, as such patients have perturbed complement. Upon completion of these two Aims, we will have developed two technologies that may aid therapy of ARDS: 1) Decoy nanoparticles that safely cause marginated leukocytes to leave the lungs, and thereby ameliorate ARDS-like phenotypes; 2) A technology for preventing complement side effects such as CARPA when delivering ligand-targeted nanoparticles. As marginated leukocytes play pivotal roles in most acute critical illnesses, and CARPA sensitivity is common to those as well, the technologies developed here may impact not only ARDS, but also sepsis, stroke, and more.

摘要/总结急性危重疾病会迅速导致严重的器官损伤和死亡。败血症、中风和急性呼吸窘迫综合征 (ARDS) 在这里我们重点关注急性呼吸窘迫综合征 (ARDS)。肺部气囊炎症以及 COVID-19 的死亡原因。我们开发了配体靶向纳米载体，将药物定位到受影响的发炎微血管系统当我们走向临床转化时，我们发现关键的一步是获得补体的控制，这是一组补体。但我们发现了与微生物结合并帮助其清除的血浆蛋白。交互是一把“双刃剑”，既有需要优化的好处，也有需要解决的有害功能。首先，我们发现补体蛋白 C3 快速调理特定的纳米颗粒，并且这种 C3- 然后，调理纳米颗粒充当“诱饵”，将 ARDS 小鼠模型（例如雾化 LPS）改善约 75%。 C3 涂层纳米粒子在边缘白细胞中积聚，这是 ARDS 病理生理学的关键，并导致这些细胞离开肺部。然而，C3 调理作用会诱发一种称为过敏反应的反应。因此，在目标 1 中，我们将设计纳米颗粒。它可以像 C3 涂层诱饵一样发挥作用来改善 ARDS，但没有 CARPA。然后我们将测试这些纳米颗粒诱饵疗法的转化潜力。通过在新鲜的、灌注的、离体人肺中测试它们来优化诱饵纳米粒子。其次，我们发现我们一直在开发用于药物输送的配体靶向纳米颗粒因此，在目标 2 中，我们将重新设计我们的配体靶向纳米颗粒以防止出现这种情况。 CARPA。我们将测试我们之前用于将药物浓缩在肺泡中的药物载体。肺微血管系统：与结合内皮细胞的抗 PECAM 抗体缀合的脂质体。将在小鼠体内和体外测试各种工程版本的抗 PECAM 脂质体是否可以逃避 C3 调理作用和 CARPA，从而实现更具体的递送到肺部最后，我们将测试这些。避免 CARPA 的纳米颗粒与来自 ARDS 患者的血浆，因为此类患者的补体受到干扰。完成这两个目标后，我们将开发出两项可能有助于治疗的技术 ARDS：1) 诱饵纳米颗粒安全地导致边缘白细胞离开肺部，从而改善ARDS样表型；2）预防补体副作用的技术，例如CARPA 当递送配体靶向纳米颗粒时，边缘白细胞在最紧急的关键时刻发挥着关键作用。的生命，并且 CARPA 敏感性对这些人来说也是常见的，这里开发的技术可能会影响不不仅包括急性呼吸窘迫综合征，还包括败血症、中风等。