High throughput nanoplasmonic exosome testing (NEXT) of immunotherapies in bladder cancer

膀胱癌免疫疗法的高通量纳米等离子体外泌体测试（NEXT）

• 批准号: 10686016
• 负责人: Cesar M Castro
• 金额: $ 43.35万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-06 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686016
• 关键词: Acceleration; Anatomy; Bioinformatics; Biological Assay; Biological Markers; Biological Specimen Banks; Biology; Biomedical Engineering; Bladder; Bladder Urothelium; Cancer Detection; Cancer Patient; Cancer cell line; Cells; Charge; Clinical; Clinical Oncology; Clinical Trials; Collection; Consensus; Correlative Study; Coupled; Coupling; Decision Making; Detection; Devices; Diagnostic; Generations; Genitourinary system; Glean; Graft Rejection; Guidelines; Human; Image; Image Analysis; Immune checkpoint inhibitor; Immunotherapy; Investigation; Kidney; Kidney Transplantation; Laboratories; Light; Location; Magnetism; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measures; Membrane; Messenger RNA; Molecular; Molecular Profiling; Monitor; Nanotechnology; Neoplasm Metastasis; Nucleic Acids; Oncologist; Patients; Performance; Pharmacodynamics; Physics; Prostate; Proteins; Protocols documentation; Reaction; Regimen; Regression Analysis; Research Personnel; Sampling; Signal Transduction; Source; Surface; System; Systems Biology; Testing; Time; Traction; Tumor Immunity; Urine; Urogenital Cancer; X-Ray Computed Tomography; biomarker panel; cancer therapy; cell bank; clinical imaging; clinical investigation; commercialization; effective therapy; exosome; expectation; experience; extracellular vesicles; imaging modality; improved; innovation; insight; instrumentation; liquid biopsy; multidisciplinary; nanoGold; nanometer; nanoplasmonic; novel; novel marker; peripheral blood; personalized immunotherapy; plasmonics; pre-clinical; pressure; prospective; repository; response; sensor; tool; translational study; treatment strategy; tumor; tumor microenvironment; tumor-immune system interactions; urinary

Challenges. Once metastatic, only 5 out of 100 patients are alive at five years. Immune checkpoint inhibitors have demonstrated increasing clinical traction yet conventional imaging such as CT scans struggle to accurately assess tumor response in this treatment context. Serially accessible sources of tumor and host biomarkers could add earlier insights into response this informing timely go / no-go decision making to render precision immunotherapy. Innovation: In light of needed pre-competitive nanotechnology tools for EV investigation to fill temporal and scientific gaps precluding accurate immunotherapy-based treatment monitoring, our group developed and validated a magneto- electrochemical platform without need for EV purification and capable of 96 parallel readouts within 45 minutes. This proposal exploits the bladder's intimate anatomical location within the genitourinary system; urine would thus provide us with rich repositories of bladder cancer EVs. We previously demonstrated feasibility of urine EV testing in kidney transplant rejection. Through increased excited charges generated by inducing plasmonic resonance in gold nanoparticles, we recently accelerated electrochemical reactions within our most current and scalable platform to achieve 12-fold signal increase from EV surface markers. We hypothesize that advancing our nanoplasmonic EV sensor for human urine and optimizing assay protocols to measure intra-EV and surface markers, could identify high value bladder cancer and host biomarkers (protein and mRNA) to better examine their interplay over time and under treatment pressures. We propose three specific aim: AIM 1: To optimize our nanoplasmonic sensor (NEXT) assay and instrumentation for high-throughput urine-based analyses and comprehensive profiling of both surface and intra-EV markers. AIM 2: To employ pre-clinical and banked biospecimens for NEXT analyses to examine profiling performance and inform optimal biomarker panel. AIM 3: Use NEXT to prospectively monitor and profile urinary EVs from patients undergoing immunotherapy-based therapies for bladder cancer. Impact: Our highly complementary group of accomplished investigators bring to bear longstanding expertise and translational experience in EV biology, bioengineering, systems biology, bioinformatics, and clinical oncology. If successful, our urinary nanoplasmonic EV platform would add critical actionable insights into immunotherapy-based treatments of advanced bladder cancers with promise in other prevalent genitourinary cancers such as kidney and prostate.

挑战。一旦发生转移，100 名患者中只有 5 人能活五年。免疫检查点 抑制剂已显示出增加的临床牵引力，但传统成像（如 CT 扫描） 很难准确评估这种治疗背景下的肿瘤反应。可串行访问的源 肿瘤和宿主生物标志物可以增加对反应的早期洞察，从而及时通知是否进行 做出精准免疫治疗的决策。创新：根据竞争前的需要 用于电动汽车研究的纳米技术工具填补了时间和科学空白，妨碍了准确的研究 基于免疫疗法的治疗监测，我们的小组开发并验证了磁力 电化学平台无需 EV 纯化，并且能够在内部进行 96 个并行读数 45分钟。该提案利用了膀胱在泌尿生殖系统中的亲密解剖位置 系统;因此，尿液将为我们提供丰富的膀胱癌 EV 储存库。我们之前 证明了尿液 EV 检测在肾移植排斥反应中的可行性。通过增加兴奋 通过在金纳米粒子中诱导等离子体共振产生的电荷，我们最近加速了 我们最新且可扩展的平台中的电化学反应可实现 12 倍信号 来自 EV 表面标记的增加。我们假设改进我们的纳米等离子体电动传感器 人类尿液和优化检测方案来测量 EV 内和表面标记物，可以识别 高价值膀胱癌和宿主生物标志物（蛋白质和 mRNA），以更好地检查它们之间的相互作用 随着时间的推移和治疗压力。我们提出三个具体目标： AIM 1：优化我们的 用于基于尿液的高通量分析的纳米等离子体传感器 (NEXT) 测定和仪器 以及表面和 EV 内部标记的综合分析。目标 2：采用临床前和 储存生物样本用于 NEXT 分析，以检查分析性能并提供最佳信息 生物标志物面板。目标 3：使用 NEXT 前瞻性监测和分析患者的尿液 EV 接受基于免疫疗法的膀胱癌治疗。影响：我们的高度互补 一群卓有成就的研究人员带来了长期的专业知识和转化经验 EV生物学、生物工程、系统生物学、生物信息学和临床肿瘤学。如果成功的话，我们的 尿液纳米等离激元 EV 平台将为基于免疫疗法的药物添加关键的可操作见解 晚期膀胱癌的治疗有望治疗其他常见的泌尿生殖系统癌症，例如 如肾脏和前列腺。