Tumor-Homing Exosomes for Drug Delivery

描述(申请人提供)：几十年来，人们已经认识到人类血液中存在脂类包裹的细胞物质，这些颗粒会影响凝血和稳定性。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微粒(30-100 nm)，并构成了肿瘤细胞之间的新型通讯网络。这些小泡被称为外切体，研究表明，肿瘤外切体被编程将活性生物分子(RNA、蛋白质)转移到体内特定的位置，并与转移有关。最近的体内研究表明，与合成给药系统相比，外切体具有显著的优势，包括提高血清稳定性，降低免疫原性，以及最小限度地清除肺、肝和脾。除了这些有益的特征，我们的初步数据表明，与其他细胞系相比，来自肿瘤细胞的外切体被亲本肿瘤细胞类型摄取的程度要大得多。这种“归巢”并不是由于与生俱来的更大的非特异性摄取能力，拟议的研究进一步表征了这种效应，并调查了导致这种取向的蛋白质和脂肪成分。在小鼠模型中，肿瘤外切体与亲本肿瘤的归宿能力将通过PET成像进行量化，并将通过利用外切体在荷瘤小鼠中传递化疗药物来利用肿瘤归巢行为。利用从蛋白质组和脂体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可能性，该合成囊泡包含使外切酶体具肿瘤归宿能力的成分。

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.