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

使用连接开放剂共轭脂质氧化铁纳米颗粒 (JOC-LION) 靶向卵巢癌并对其进行成像

• 批准号: 10324316
• 负责人: Amit Praful Khandhar
• 金额: $ 39.93万
• 依托单位: HDT BIO CORPORATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10324316
• 关键词: 3-Dimensional; Affect; Antineoplastic Agents; Apical; Basal Cell; Binding; Cancer Model; Cancer Prognosis; Carcinoma; Cell Adhesion Molecules; Cells; Clinical; Disease; Drops; Engineering; Epithelial; Epithelial Cells; Formulation; Goals; Human; Hydrophobicity; Image; Immune; Immune system; Immunocompetent; Immunologics; Innate Immune System; Intercellular Junctions; Lead; Legal patent; Link; Lipids; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of ovary; Membrane Proteins; Mus; Names; Opsonin; Ovarian; Particle Size; Patients; Penetration; Pharmaceutical Preparations; Phase; Plasma; Proteins; Selection Criteria; Small Business Innovation Research Grant; Solid Neoplasm; Squalene; Structure; Sulfhydryl Compounds; Surface; Survival Rate; Technology; Therapeutic; Tight Junctions; Tissues; Transgenic Organisms; Treatment Efficacy; Universities; Viral; Visualization; Washington; antitumor drug; base; cancer cell; cancer therapy; commercialization; design; desmoglein 2; functional group; improved; innovation; iron oxide nanoparticle; lead candidate; monolayer; mouse model; multimodality; nanoparticle; novel; overexpression; particle; polarized cell; prevent; product development; recruit; superparamagnetism; targeted imaging; targeted treatment; tumor; tumor microenvironment

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.

项目概要/摘要 需要有效的靶向治疗来提高晚期卵巢患者的生存率 和其他上皮来源的实体瘤癌症的特征是上皮癌。 肿瘤紧密连接的过度表达，特别是细胞粘附蛋白 desmoglein-2 (DSG2) 与正常上皮细胞不同，上皮癌细胞的特征是异常。 DSG2的表达，将蛋白质三维地展示在细胞外 因此，DSG2 是一种有吸引力的靶向治疗肿瘤特异性蛋白。 开发了一种 DSG2 靶向蛋白，称为“可与 x 缀合的连接开启剂”， 或 JOC-x，顾名思义，JOC-x 的一个关键特征是能够与任何部分缀合。 在此阶段 I SBIR 中，我们将 将 JOC-x 与 HDT Bio Corp 正在申请专利的脂质氧化铁纳米颗粒共价连接 (LIONTM) 配方。LION 配方的核心是多功能纳米颗粒平台。 LION由广泛使用的免疫增强分子角鲨烯和超顺磁性分子组成 氧化铁 (SPIO) 纳米颗粒使 LION 能够影响组织的磁性对比度 通过将 JOC-x 与 LION 共价结合，我们建议（具体） 目标 1) 合成并彻底表征 JOC-LION 颗粒，以证明胶体 血浆稳定性和与 DSG2 的有效结合，（具体目标 2.1）使用 3T。 在华盛顿大学的临床 MRI 扫描仪中，我们将评估五名患者的能力 候选 JOC-LION 颗粒靶向人类 DSG2 过度表达的卵巢癌细胞 最后，在表达转基因人类 DSG2 的小鼠模型中，角鲨烯被递送到体内。 纳米粒子是先天免疫系统的有效激活剂，我们将（具体目标2.2） 评估候选 JOC-LION 颗粒诱导抗肿瘤活性的潜力 通过打开紧密连接在物理上和免疫学上使肿瘤更容易接近， 通过在肿瘤微环境中招募免疫细胞这是第一阶段的最终目标。 建议开发一个主要的 JOC-LION 候选者，该候选者表现出高度的选择性 DSG2 过度表达上皮肿瘤中的积累，也可能提供抗肿瘤作用 在第二阶段的活动中，我们将把我们的主要 JOC-LION 候选者与传统和新颖结合起来。 癌症疗法证明我们新型肿瘤连接开口的临床产品开发是合理的 成像纳米颗粒技术。