Tumor-Homing Exosomes for Drug Delivery

用于药物输送的肿瘤归巢外泌体

• 批准号: 8900283
• 负责人: THOMAS ANCHORDOQUY
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900283
• 关键词: Acute; Adverse effects; Affect; Antibodies; Binding; Biodistribution; Blood; Blood Circulation; Caliber; Cancer Patient; Cell Line; Cell membrane; Cells; Characteristics; Coagulation Process; Communication; Data; Development; Disease; Drug Carriers; Drug Delivery Systems; Drug resistance; Encapsulated; Environment; Extracellular Space; Goals; Harvest; Health; Home environment; Homing; Homing Behavior; Human; Immune response; Immunocompetent; Ligand Binding; Ligands; Lipids; Liposomes; Liver; Lung; Malignant Neoplasms; Messenger RNA; MicroRNAs; Multivesicular Body; Mus; Neoplasm Metastasis; Normal Cell; Nude Mice; Parents; Particle Size; Particulate; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Positron-Emission Tomography; Process; Production; Proteins; Proteomics; RNA; Reporting; Research Design; Research Personnel; Role; Serum; Site; Spleen; Staging; System; Therapeutic; Tissues; Transferrin; Transportation; Tropism; Tumor Cell Line; Vesicle; Work; base; cancer cell; cell type; clinically significant; immunogenicity; in vivo; information gathering; intercellular communication; interest; intravenous injection; mouse model; nanoparticle; neoplastic cell; novel; particle; programs; receptor; synthetic drug; targeted delivery; tumor; uptake; vesicular release

DESCRIPTION (provided by applicant): It has been recognized for decades that lipid-encapsulated cellular material is present in human blood, and that these particles can affect coagulation and stability. Although these "microparticles" have been traditionally thought to be cellular debris, more recent studies have demonstrated that a fraction of very small particles (30-100 nm) are produced by tumors and comprise a novel communication network among tumor cells. These small vesicles are termed "exosomes", and studies have shown that tumor exosomes are programmed to transfer active biomolecules (RNA, proteins) to specific sites in vivo and have been implicated in metastasis. Recent in vivo studies have reported that exosomes offer significant advantages over synthetic drug delivery systems including enhanced serum stability, low immunogenicity, and minimal clearance by lung, liver, and spleen. In addition to these beneficial characteristics, our preliminary data indicate that exosomes from tumor cells are taken up to a much greater extent by the parent tumor cell type as compared to other cell lines. This "homing" is not due to an inherently greater capacity for non-specific uptake, and the proposed studies further characterize this effect as well as investigate the protein and lipid components that are responsible for this tropism. The ability of tumor exosomes to home to the parent tumor in a mouse model will be quantified with PET imaging, and the tumor-homing behavior will be exploited by utilizing exosomes to deliver chemotherapeutics in tumor-bearing mice. Using the information gathered from proteomic and lipidomic analyses, the work also explores the potential of developing a synthetic vesicle containing the components that endow exosomes with their ability to home to tumors.

描述（由申请人提供）：几十年来，人们已经认识到人类血液中存在脂质封装的细胞材料，并且这些颗粒可以影响凝血和稳定性。尽管这些“微粒”传统上被认为是细胞碎片，但最近的研究表明，一小部分非常小的颗粒（30-100 nm）是由肿瘤产生的，并构成了肿瘤细胞之间的新型通讯网络。这些小囊泡被称为“外泌体”，研究表明肿瘤外泌体被编程为将活性生物分子（RNA、蛋白质）转移到体内特定位点，并与转移有关。最近的体内研究报道，外泌体比合成药物递送系统具有显着优势，包括增强的血清稳定性、低免疫原性以及最小的肺、肝和脾清除率。除了这些有益的特征之外，我们的初步数据表明，与其他细胞系相比，来自肿瘤细胞的外泌体被亲本肿瘤细胞类型吸收的程度要大得多。这种“归巢”并不是由于固有的更大的非特异性吸收能力，并且拟议的研究进一步表征了这种效应，并研究了导致这种趋向性的蛋白质和脂质成分。肿瘤外泌体在小鼠模型中归巢到母体肿瘤的能力将通过 PET 成像进行量化，并且通过利用外泌体在荷瘤小鼠中递送化疗药物来利用肿瘤归巢行为。利用从蛋白质组学和脂质组学分析中收集的信息，这项工作还探索了开发一种合成囊泡的潜力，该合成囊泡含有赋予外泌体靶向肿瘤能力的成分。