Inflammation-targeted delivery of corticosteroids using genetically engineered cellular nanoparticles

使用基因工程细胞纳米颗粒靶向炎症递送皮质类固醇

基本信息

批准号：
10646914
负责人：
Ronnie H Fang
金额：
$ 19.75万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-08 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10646914
关键词：
Address Adrenal Cortex Hormones Adverse effects Air Sacs Anti-Inflammatory Agents Antibiotic Therapy Antibiotics Artificial nanoparticles Attenuated Bacteria Bacterial Counts Bacterial Pneumonia Binding Biochemistry Biodistribution Biomimetics Blood Cell Count Blood Circulation Cell Adhesion Molecules Cell membrane Cells Cellular Membrane Cessation of life Clinical Communities Data Dendritic Cells Disease Drug Delivery Systems Endothelial Cells Endotoxins Engineering Formulation Genetic Engineering Goals Gram-Positive Bacteria Histology Hospitals Immune Immune system Immunologic Adjuvants Immunosuppressive Agents In Vitro Infection Inflammation Inflammatory Inflammatory Response Integrin alpha4beta1 Left Ligands Liquid substance Lung Lung infections Membrane Methods Modeling Molecular Morbidity - disease rate Morphology Mus Nanodelivery Nanotechnology Nature Organ Organ failure P-selectin ligand protein Pathologic Pathology Patients Pattern Performance Pharmaceutical Preparations Play Production Proteins Pseudomonas aeruginosa Pulmonary Inflammation Role Safety Serum Site Source Steroids Streptococcus pyogenes Surface Therapeutic Index Time Treatment Efficacy Treatment Side Effects Vascular Cell Adhesion Molecule-1 cell type cellular engineering cellular targeting cytokine dosage drug resistant bacteria effective therapy efficacy evaluation fabrication human disease immune activation improved in vivo interest intravenous administration intravenous injection methicillin resistant Staphylococcus aureus mortality mouse model nanocarrier nanoformulation nanoparticle nanoparticulate next generation pathogen prevent protein expression response side effect standard of care targeted delivery zeta potential

项目摘要

PROJECT SUMMARY/ABSTRACT Bacterial pneumonia causes severe local inflammation in the lungs that can result in serious complications if left unchecked. While antibiotics are oftentimes an effective treatment, drug-resistant bacteria that do not respond to the standard of care represent a major threat. Bacteria contain a number of pathogen-associated molecular patterns that are highly efficient at activating the immune system, and the overproduction of proinflammatory factors can have deleterious effects such as causing the air sacs within the lungs to become filled with fluid. To address these negative effects, corticosteroids have been employed as an adjunct therapy in combination with antibiotic treatment. There is clinical evidence that supplemental anti-inflammatories can reduce patient morbidity and mortality, and the beneficial effects are the most pronounced in cases of severe disease. Despite their advantages, steroids are broadly immunosuppressive and cannot be administered at high dosages or over extended periods of time without side effects. In this proposal, our goal is to employ a genetic engineering approach for creating a next-generation a cellular nanoparticle (CNP) platform that can specifically target sites of inflammation. CNPs are an emerging class of nanocarrier that utilize the principles of biomimicry, and they have demonstrated considerable promise for drug delivery applications. Their fabrication involves the coating of synthetic nanoparticulate cores with naturally derived cellular membrane, which provides an inherently multifunctional and multi-antigenic layer of camouflage. We will further advance the CNP concept by genetically engineering the nanoparticles to express specific membrane-bound targeting proteins. Leveraging the fact that activated endothelial cells at sites of inflammation upregulate their expression of cell adhesion molecules, CNPs will be fabricated using cell membrane that has been engineered to express the cognate ligands. Each inflammation-targeting CNP formulation will be loaded with corticosteroids, delivering the payloads precisely to where they are most needed. By improving the therapeutic index of these drugs, we hope to prevent the harmful effects associated with excessive inflammation while reducing any treatment-related side effects. If successful, this approach could potentially be applied across a wide range of inflammation-driven pathologies.

项目概要/摘要细菌性肺炎会引起肺部严重的局部炎症，如果不及时治疗可能会导致严重的并发症未经检查。虽然抗生素通常是一种有效的治疗方法，但对耐药细菌没有反应护理标准构成重大威胁。细菌含有许多与病原体相关的分子高效激活免疫系统的模式，以及促炎物质的过度产生这些因素可能会产生有害影响，例如导致肺部气囊充满液体。到为了解决这些负面影响，皮质类固醇已被用作联合治疗的辅助疗法抗生素治疗。有临床证据表明补充抗炎药可以降低患者的发病率和死亡率，并且在严重疾病的情况下，有益效果最为明显。尽管他们的优点是，类固醇具有广泛的免疫抑制作用，不能高剂量或过量施用长时间服用无副作用。在这个提案中，我们的目标是采用基因工程创建下一代细胞纳米颗粒（CNP）平台的方法，该平台可以专门针对位点炎症。 CNP 是一类新兴的纳米载体，利用仿生学原理，它们已在药物输送应用中表现出巨大的前景。它们的制造涉及涂层具有天然来源的细胞膜的合成纳米颗粒核心，提供了固有的多功能和多抗原的伪装层。我们将通过基因技术进一步推进CNP理念设计纳米颗粒以表达特定的膜结合靶向蛋白。利用这一事实炎症部位活化的内皮细胞上调细胞粘附分子 (CNP) 的表达将使用经过工程改造以表达同源配体的细胞膜来制造。每个靶向炎症的 CNP 制剂将装载皮质类固醇，将有效负载精确地传递到最需要他们的地方。通过提高这些药物的治疗指数，我们希望能够预防有害的疾病与过度炎症相关的影响，同时减少任何与治疗相关的副作用。如果成功的话，这种方法有可能广泛应用于炎症驱动的病理学。