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，脂质包裹的细胞物质存在于人体血液中，这些颗粒可以影响凝血和稳定性。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，肿瘤产生了一小部分非常小的颗粒（30-100纳米），并构成了肿瘤细胞之间的新型通信网络。这些小泡被称为“外泌体”，研究表明肿瘤外泌体被编程将活性生物分子（RNA，蛋白质）转移到体内的特定部位，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著的优势，包括增强的血清稳定性，低免疫原性，以及肺，肝脏和脾脏的最小清除率。除了这些有益的特征外，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”并不是因为非特异性摄取的固有能力更大，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。在小鼠模型中，肿瘤外泌体回家到亲本肿瘤的能力将通过PET成像进行量化，肿瘤归巢行为将通过利用外泌体在荷瘤小鼠中传递化疗药物来利用。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，该囊泡含有赋予外泌体以肿瘤归巢能力的成分。

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.