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.

项目摘要/摘要细菌性肺炎会导致肺部严重的局部炎症，如果离开的话，可能会导致严重的并发症未选中。尽管抗生素通常是一种有效的治疗方法，但不反应的耐药细菌按照护理标准代表了一个主要威胁。细菌包含许多与病原体相关的分子在激活免疫系统方面高效的模式，以及促炎性的过度生产因素可能具有有害影响，例如导致肺部内的空气囊到充满液体。到解决这些负面影响，皮质类固醇已被用作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在严重疾病的情况下，死亡率和有益作用最为明显。尽管他们优势，类固醇是广泛的免疫抑制，不能以高剂量或以上进行长时间没有副作用。在此提案中，我们的目标是采用基因工程创建下一代蜂窝纳米颗粒（CNP）平台的方法，该平台可以专门针对位点炎症。 CNP是利用仿生原理的新兴纳米载体类，它们是对药物递送申请表现出了很大的希望。他们的制造涉及与天然衍生的细胞膜合成的纳米核心核，该膜固有地提供伪装的多功能和多古层。我们将通过基因进一步推进CNP概念设计纳米颗粒以表达特定的膜结合靶向蛋白。利用这一事实激活的内皮细胞在炎症部位上调其细胞粘附分子的表达CNP 将使用已设计以表达同源配体的细胞膜制造。每个触发炎症的CNP配方将装有皮质类固醇，将有效载荷精确提供给最需要的地方。通过改善这些药物的治疗指数，我们希望防止有害与过度炎症有关的影响，同时减少任何与治疗相关的副作用。如果成功，这种方法可能会在各种炎症驱动的病理中应用。