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：
10557895
负责人：
Jacob Brenner
金额：
$ 69.51万
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/10557895
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 Critical Care Critical Illness Disease Drug Carriers Drug Delivery Systems Endothelial Cells Endothelium Engineering Functional disorder Genetic Complementation Test Human 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 Perfusion 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 clinical translation complement 3 regulator complement pathway cytokine density design ex vivo perfusion experimental study human tissue improved in vitro testing in vivo inhibitor lung injury migration 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 /摘要急性重症疾病迅速导致严重的器官损害和生命损失。这些疾病包括败血症，中风和急性呼吸窘迫综合征（ARDS）。在这里，我们专注于ARDS，这很敏锐肺囊的炎症和Covid-19的死亡原因。对于ARDS和其他疾病，我们已经开发了以配体为靶向的纳米载体，将药物定位于受影响的微脉管系统器官。当我们朝着临床翻译转向临床翻译时，我们发现关键步骤是获得完成的控制，这是一套结合微生物并有助于清除的血浆蛋白。但是我们发现完成纳米颗粒互动是一把“双刃剑”，两者都可以优化，也可以解决有害的功能。首先，我们发现补体C3迅速调整了特定的纳米颗粒，并且这种C3-- 然后，调向化的纳米颗粒充当“诱饵”，以减轻约75％的减轻ARDS小鼠模型（例如，雾化的LPS）。 C3涂层的纳米颗粒积聚在边缘的白细胞中，这是病理生理的关键，并导致这些细胞离开肺部。然而，C3打击诱导了一种过敏反应，称为 Carta（补体激活相关的伪过敏）。因此，在AIM 1中，我们将设计纳米颗粒这可以像C3涂层的诱饵一样起作用，可以改善弧形，但没有腕骨。我们还将调查纳米颗粒诱饵疗法的机制。然后，我们将测试这些翻译潜力通过在新鲜的，灌注的，体内人类肺中测试诱饵纳米颗粒。其次，我们发现我们一直在为药物递送的配体靶向纳米颗粒几年也影响了鲤鱼。因此，在AIM 2中，我们将重新设计我们的配体纳米颗粒以防止鲤鱼。我们将测试以前用来将药物浓缩在肺泡中的药物载体肺的微脉管系统：结合内皮细胞的抗PECAM抗体的脂质体。我们将在小鼠的体外和体内测试各种抗PECAM脂质体是否可以逃避 C3调整和鲤鱼，从而实现了对肺部的更具体分娩。最后，我们将测试这些避免腕纳米颗粒具有来自ARDS患者血浆的纳米颗粒，因为此类患者已经干扰了完成。完成这两个目标后，我们将开发两种技术，可以帮助治疗 ARDS：1）安全导致少量白细胞离开肺的诱饵纳米颗粒，从而改善弧形表型； 2）一种防止补体副作用的技术，例如鲤鱼传递靶向配体的纳米颗粒时。随着边缘的白细胞在大多数急性关键中扮演关键角色疾病和鲤鱼的敏感性也很常见，这里开发的技术可能不会影响只有ards，但败血症，中风等等。