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

• 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
• 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

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.

项目总结/摘要 细菌性肺炎会导致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，但不起作用的耐药细菌 是一个重大威胁细菌中含有大量病原体相关分子 这些模式在激活免疫系统方面非常有效，并且过度产生促炎性细胞因子。 这些因素可能具有有害的影响，例如导致肺内的气囊充满流体。到 为了解决这些负面影响，皮质类固醇已被用作与以下药物组合的辅助疗法： 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，有益的效果是最明显的。尽管他们 优点是，类固醇广泛地具有免疫抑制性，并且不能以高剂量或超过 长时间无副作用。在这个提议中，我们的目标是利用基因工程 一种创建下一代细胞纳米颗粒（CNP）平台的方法，该平台可以特异性靶向位点 炎症。CNP是一类新兴的纳米载体，其利用仿生学原理，并且它们 已经证明了药物递送应用的相当大的前景。它们的制造涉及到涂层， 具有天然来源的细胞膜的合成纳米颗粒核心，其提供固有的 多功能和多抗原伪装层。我们将进一步推进CNP概念， 工程化纳米颗粒以表达特异性膜结合靶向蛋白。充分利用了 炎症部位的活化内皮细胞上调其细胞粘附分子CNP的表达 将使用已经被工程化以表达同源配体的细胞膜来制造。每个 炎症靶向CNP制剂将装载皮质类固醇，将有效载荷精确地递送至 在最需要他们的地方。通过提高这些药物的治疗指数，我们希望防止有害的 与过度炎症相关的影响，同时减少任何治疗相关的副作用。如果成功， 这种方法可以潜在地应用于广泛的炎症驱动的病理。