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/文摘