Tumor-Homing Exosomes for Drug Delivery

描述（由申请人提供）：几十年来人们已经认识到，人血液中存在脂质包封的细胞物质，这些颗粒可能影响凝血和稳定性。虽然这些“微粒”传统上被认为是细胞碎片，但最近的研究表明，一部分非常小的颗粒（30-100 nm）是由肿瘤产生的，并在肿瘤细胞之间构成了一个新的通讯网络。这些小囊泡被称为“外泌体”，并且研究已经表明肿瘤外泌体被编程为将活性生物分子（RNA、蛋白质）转移到体内的特定位点，并且已经涉及转移。最近的体内研究已经报道，外泌体提供了优于合成药物递送系统的显著优势，包括增强的血清稳定性、低免疫原性和肺、肝和脾的最小清除率。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在更大程度上被亲本肿瘤细胞类型摄取。这种“归巢”并不是由于非特异性摄取的固有能力更强，拟议的研究进一步表征了这种效应，并研究了导致这种向性的蛋白质和脂质组分。将用PET成像定量小鼠模型中肿瘤外泌体归巢至母体肿瘤的能力，并且将通过利用外泌体在荷瘤小鼠中递送化疗剂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，这种囊泡含有赋予外泌体归巢肿瘤能力的成分。

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.