Targeting and Imaging Ovarian Cancer with Junction Opener Conjugated-Lipid Iron Oxide Nanoparticles (JOC-LIONs)

项目摘要/摘要 需要有效的靶向治疗来提高晚期卵巢癌患者的存活率 以及其他起源于上皮性实体瘤的癌症。上皮性癌症的特征是 肿瘤紧密连接的过度表达，特别是细胞黏附蛋白Desmoglein-2 (DSG2)。与正常上皮细胞不同，上皮性癌细胞的特征是异常 DSG2的表达，在细胞外立体展示该蛋白 因此，DSG2是一种有吸引力的肿瘤特异性蛋白，可用于靶向治疗。我们 已经开发出一种以DSG2为靶点的蛋白质，称为“可与x接合的连接开放因子”， 或者JOC-x。JOC-x的一个关键特性，顾名思义，就是能够将任何部分与 在JOC-x上的工程游离巯基的官能团。在第一阶段SBIR中，我们将 将JOC-x共价连接到HDT Bio公司正在申请专利的脂质氧化铁纳米颗粒 (LIONTM)配方。狮子制剂是一种多功能纳米颗粒平台。在它的核心， Lion由广泛使用的免疫增强分子角鲨烯和超顺磁性物质组成 氧化铁(SPIO)纳米颗粒，使狮子能够影响组织的磁对比度 磁共振成像(MRI)。通过将JOC-x与LION共价结合，我们建议(具体 目的1)合成显示胶体的JOC-Lion颗粒并对其进行表征 血浆中的稳定性和与DSG2的有效结合。此外，(特定目标2.1)使用3T 在华盛顿大学的临床MRI扫描仪上，我们将评估五种能力 JOC-LION候选颗粒靶向高表达人DSG2卵巢癌细胞 在转基因人DSG2表达的小鼠模型中。最后，由于角鲨烯在 纳米粒子是天然免疫系统的有效激活剂，我们会的(具体目标2.2) JOC-LION候选颗粒诱导抗肿瘤活性的实验研究 使肿瘤更容易接近，无论是身体上，通过打开紧密的连接，还是在免疫上， 通过在肿瘤微环境中招募免疫细胞。这一阶段的最终目标是 提议是培养一名领导JOC-Lion候选人，展示出高度的选择性 DSG2在过表达的上皮性肿瘤中的积聚并潜在地提供抗肿瘤作用 活动。在第二阶段，我们将把我们的主要JOC-Lion候选人与传统和新颖结合起来 癌症治疗证明我们新的肿瘤连接开放和临床产品开发是合理的 成像纳米颗粒技术。

PROJECT SUMMARY/ABSTRACT Effective targeted treatments are needed to improve survival of patients with late stage ovarian and other solid tumor cancers of epithelial origin. Epithelial cancers are characterized by an overexpression of tumor tight junctions, specifically the cell adhesion protein desmoglein-2 (DSG2). Unlike in normal epithelial cells, epithelial cancer cells are characterized by abnormal expression of DSG2, displaying the protein three-dimensionally and outside intercellular junctions; as a result, DSG2 is an attractive tumor-specific protein for targeted therapies. We have developed a DSG2-targeting protein called the “junction opener conjugatable to x”, or JOC-x. A key feature of JOC-x, as its name implies, is the ability to conjugate any moiety with functional groups to the engineered free sulfhydryl group on JOC-x. In this phase I SBIR, we will covalently link JOC-x to HDT Bio Corp’s patent-pending Lipid Iron Oxide Nanoparticle (LIONTM) formulation. The LION formulation is a multifunctional nanoparticle platform. At its core, LION consists of the widely used immune potentiating molecule squalene and superparamagnetic iron oxide (SPIO) nanoparticles that give LION the ability to affect tissue contrast in magnetic resonance imaging (MRI). By covalently combining JOC-x with LION, we propose to (specific aim 1) synthesize and thoroughly characterize JOC-LION particles that demonstrate colloidal stability in plasma and effective binding with DSG2. Moreover, (specific aim 2.1) using a 3T clinical MRI scanner at the University of Washington, we will evaluate the ability of five candidate JOC-LION particles to target human DSG2 overexpressing ovarian cancer cells in a transgenic human DSG2 expressing murine model. Finally, since squalene delivered in nanoparticles is an effective activator of the innate immune system, we will (specific aim 2.2) evaluate the potential for induction of anti-tumor activity of candidate JOC-LION particles make the tumor more accessible, both physically, by opening tight junctions, and immunologically, by recruiting immune cells in the tumor microenvironment. The ultimate goal of this phase I proposal is to develop a lead JOC-LION candidate that demonstrates a high degree of selective accumulation in DSG2 overexpressing epithelial tumors and potentially also provides anti-tumor activity. In phase II, we will combine our lead JOC-LION candidate with both traditional and novel cancer therapies to justify clinical product development of our novel tumor junction opening and imaging nanoparticle technology.