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Multiplexed analysis of exosomes in cancer nano therapy

癌症纳米疗法中外泌体的多重分析

基本信息

批准号：
9078198
负责人：
RALPH WEISSLEDER, MD, PHD
金额：
$ 39.12万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-15 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9078198
关键词：
Biological Assay Biological Testing Blood Circulation Blood Platelets Cancer Patient Cells Clinic Clinical Core Biopsy Detection Diagnostic Procedure Drug resistance Elements Endothelial Cells Erythrocytes Evaluation Event Film Generations Goals Gold Human Image Immunocompetent Leukocytes Ligands Malignant Neoplasms Malignant neoplasm of ovary Measurement Measures Mesothelial Cell Messenger RNA Methods Modeling Molecular Monitor Mus Nanotechnology Noise Outcome Parents Patients Pharmaceutical Preparations Printing Process Protein Analysis Proteins RNA Reading Research Design Retrieval Sampling Series Serum Signal Transduction Specimen Surface System Systems Biology Techniques Technology Therapeutic Therapeutic Trials Time Tumor-Derived Vesicle anticancer research base cancer cell cancer therapy chemotherapy clinical practice cost cost effective exosome improved innovation insight lithography macrophage method development mouse model nano nanocoating nanoencapsulated nanoparticle nanoplasmonic nanotherapeutic nanotherapy new technology peripheral blood point of care point-of-care diagnostics protein biomarkers protein expression protein profiling public health relevance research study response scale up sensor transmission process tumor tumor initiation tumor progression validation studies

项目摘要

DESCRIPTION (provided by applicant): Detection of reliable markers of therapy response and drug resistance remains a major clinical challenge in ovarian cancer. This is particularly true for a series of nanotherapeutics entering the clinical arena. One little explored opportunity lies in the analysis of exosomes, 50-200 nm sized vesicles continuously shed into the circulation. Importantly such tumor derived exosomes are abundant (1011 vesicles/ml of peripheral blood in cancer patients), are fairly stable over time and contain proteins reflective of those found in parent tumors. A current major challenge and opportunity is the development of methods for rapidly determining the abundance and composition of cMVs from clinical samples. We have recently developed a highly sensitive, nanotechnology-based, point-of-care diagnostic method termed nPLEX (nano Plasmonic Exosome) which comprises periodic nanohole arrays fabricated in an opaque gold film for transmission plasmon imaging (Nat Biotechnol 2014;32, 490-5). We have shown that i) such analyses are exquisitely sensitive, ii) allow profiling of dozens of proteins on and inside exosomes thus allowing cell of origin studies and iii) that nPLEX analysis allows sophisticated therapy assessment. The goal of this application is to advance the nPLEX technology by i) expanding it to allow parallel profiling of protein and RNA, ii) validating it as a therapeutic read-out of nanoparticle therapeutics in mouse models and in the clinic. We hypothesize that the approach will be more sensitive and comprehensive in exosomal analysis than is currently possible and allow treatment evaluation. The proposed integrated profiling method has the potential to transform nano therapeutic trials, cancer research and clinical practice. It will enable objective therapeutic read-outs, events that occur before conventional clinical metrics. It will facilitate extensive profiling of exosome in paucicellular clinical specimens, significantly reduce costs, and can be easily combined with other downstream analyses.

描述（由申请人提供）：检测治疗反应和耐药性的可靠标志物仍然是卵巢癌的主要临床挑战。尤其如此一系列纳米治疗药物进入临床竞技场。一个很少探索的机会在于外来体的分析，50-200 nm大小的囊泡不断脱落到循环中。重要的是，这样的肿瘤来源的外来体是丰富的（在癌症患者中1011个囊泡/ml外周血），随着时间的推移是相当稳定的，并且含有反映在母体肿瘤中发现的那些的蛋白质。当前的主要挑战和机遇是开发用于快速确定来自临床样品的cMV的丰度和组成的方法。我们最近开发了一种称为nPLEX（纳米等离子体外泌体）的高灵敏度、基于纳米技术的即时诊断方法，其包括在用于透射等离子体成像的不透明金膜中制造的周期性纳米孔阵列（Nat Biotechnol 2014;32，490-5）。我们已经表明，i）这种分析非常敏感，ii）允许对外来体上和外来体内的数十种蛋白质进行分析，从而允许细胞起源研究，以及iii）nPLEX分析允许复杂的治疗评估。本申请的目标是通过i）扩展nPLEX技术以允许蛋白质和RNA的平行谱分析，ii）验证其作为小鼠模型和小鼠模型中的纳米颗粒治疗剂的治疗性读出，以及ii）验证其作为小鼠模型和小鼠模型中的纳米颗粒治疗剂的治疗性读出，来推进nPLEX技术。诊所我们假设该方法在外泌体分析中比目前可能的方法更敏感和全面，并允许治疗评估。所提出的综合分析方法有可能改变纳米治疗试验，癌症研究和临床实践。它将实现客观的治疗读数，即在常规临床指标之前发生的事件。它将有助于在少细胞临床标本中广泛分析外泌体，显着降低成本，并可以很容易地与其他下游分析相结合。