Renal Cell Carcinoma Surveillance by Immuno-Lipoplex Nanoparticle Platform

通过免疫脂质体纳米颗粒平台监测肾细胞癌

• 批准号: 10544876
• 负责人: Wen Jiang
• 金额: $ 19.15万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544876
• 关键词: Renal; Cell; Carcinoma; Surveillance; Immuno

Project Summary Kidney cancer is a common and deadly malignancy, with more than 73,000 new cases and 14,000 deaths estimated to occur in 2019 in the United States. Renal cell carcinoma (RCC) is the most prevalent type, accounting for more than 90% of all kidney cancers. Surgical resection is the treatment choice for localized RCC, however, patients with RCC are often deemed unfit for surgery because of multiple comorbidities. Stereotactic body radiotherapy (SBRT), characterized by the delivery of high doses of ionizing radiation in a few fractions, can overcome the radioresistance of RCC and achieve high therapeutic efficiency. Therefore, SBRT is currently considered as an alternative treatment option to manage non-operable patients. Post-treatment surveillance, established on the belief that detecting asymptomatic disease recurrence offers an optimal opportunity for beneficial intervention, is an integral part of RCC care. However, detecting RCC biomarkers by conventional methods requires large sample volumes and tedious work. No molecular biomarkers have been reliably validated or integrated into daily clinical practice to rationally guide kidney cancer therapy after SBRT. Thus, identifying potential RCC post-treatment biomarkers after irradiation with minimum sample preparation and high sensitivity would be invaluable. Recently, ‘liquid biopsy’ relying on detecting circulating tumor cells (CTCs), circulating transcripts, RNAs (miRNAs/mRNAs), and tumor-related genes has been investigated as a potential diagnostic and prognostic biomarker for various cancers. Extracellular vesicles (EVs) such as exosomes are difficult to detect and all current approaches to detect EVs have proven to be tedious, expensive, and time consuming. The primary objective of this R21 proposal is to develop and evaluate a newly developed immune-tethered lipoplex nanoparticle (ILN) technology system for preclinical molecular diagnosis. ILNs are designed to provide a simple, non-invasive, and low-cost method for RCC surveillance after SBRT. To achieve this goal, we have developed a biochip with nanoparticles containing specific molecular beacons (MBs) inside and RCC-specific antibody on the surface. The antibodies can capture EVs with specific RCC surface receptors, and then MBs can bind to the target EV RNAs to produce fluorescence that can be recorded by total internal reflection fluorescence microscope (TIRF). This new biochip allows capturing homogeneous EV subgroups secreted from RCC tumor cells, and measuring both EV RNA and membrane protein targets in a single step. If successfully implemented, this diagnostic and surveillance tool, could be highly transformative for the surveillance of patients with cancer.

项目摘要 肾癌是一种常见且致命的恶性肿瘤，有73,000多例新病例和14,000例死亡 估计在2019年在美国发生。肾细胞癌（RCC）是最普遍的类型， 占所有肾脏癌的90％以上。手术切除是局部RCC的治疗选择， 但是，由于多种合并症，RCC患者通常被认为不适合手术。立体定向 身体放射疗法（SBRT），其特征是在几个部分中输送高剂量的电离辐射， 可以克服RCC的放射线并实现高治疗效率。因此，SBRT当前是 被认为是管理不可依访患者的替代治疗选择。治疗后监视， 基于以下信念，即检测无症状疾病复发为 有益干预是RCC护理的组成部分。但是，通过常规检测RCC生物标志物 方法需要大量样品量和繁琐的工作。尚无分子生物标志物可靠验证 或纳入每日临床实践，以合理地指导SBRT后的肾癌治疗。那，识别 辐照后潜在的RCC后处理生物标志物，并以最小的样品制备和高灵敏度 将是无价的。最近，依赖于检测循环肿瘤细胞（CTC）的“液体活检” 成绩单，RNA（miRNA/mRNA）和与肿瘤相关的基因已被研究为潜在的诊断 以及用于各种癌症的预后生物标志物。细胞外蔬菜（EV），例如外泌体很难 检测和所有当前检测电动汽车的方法已被证明是乏味，昂贵且耗时的。 该R21提案的主要目的是开发和评估新开发的免疫脂肪 用于临床前分子诊断的纳米颗粒（ILN）技术系统。 ILNS旨在提供简单的 SBRT后无创和低成本的RCC监视方法。为了实现这一目标，我们已经发展 带有纳米颗粒的生物芯片，其中含有特定的分子信标（MB）和RCC特异性抗体 表面。抗体可以用特定的RCC表面受体捕获EV，然后MB可以与 目标EV RNA产生荧光，可以通过总内反射荧光记录 显微镜（TIRF）。这种新的生物芯片允许捕获从RCC肿瘤分泌的均质EV子组 细胞，并在一个步骤中测量EV RNA和膜蛋白靶标。如果成功实施， 这种诊断和监视工具对于对癌症患者的监测可能具有很高的变化。