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。一旦转移，每百名患者中只有5人在fi五年存活。免疫检查点 抑制剂已经显示出临床牵引力的增加，但传统的成像，如CT扫描 在这种治疗背景下，努力准确地评估肿瘤的反应。可连续访问的源代码 肿瘤和宿主生物标记物可以为这种反应提供更早的洞察力，从而及时通知是否进行 提供精确免疫治疗的决策。创新：根据需要的竞争前 用于电动汽车调查的纳米技术工具fiII时间和科学fic缺口排除了准确的 基于免疫疗法的治疗监测，我们小组开发并验证了一种磁电机- 不需要EV Purifi阳离子的电化学平台，能够在 45分钟。这一建议利用了膀胱在泌尿生殖系统中的亲密解剖位置 因此，尿液将为我们提供丰富的膀胱癌EV储存库。我们之前 论证了尿液EV检测在肾移植排斥反应中的可行性。通过增加兴奋度 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 在我们最电流和可扩展的平台内进行电化学反应，以实现12倍的信号 从电动汽车表面标记增加。我们假设，将我们的纳米等离子电动汽车传感器 人类尿液和优化的检测程序来测量肠道病毒内和表面标志物，可以识别 高价值膀胱癌和宿主生物标记物(蛋白质和信使核糖核酸)更好地检测它们的相互作用 随着时间的推移和治疗压力的增加。我们提出三个具体的fic目标：目标1：优化我们的 用于高通量尿液分析的纳米等离子体传感器(NEXT)分析和仪器 以及对EV表面和EV内标志物的综合检测。目标2：采用临床前和 储存的生物样品，用于下一步分析，以检查fi的性能并提供最佳信息 生物标记物面板。目的3：使用NeXT前瞻性监测和预测患者的尿液EVS 正在接受以免疫疗法为基础的膀胱癌治疗。影响：我们的互补性很强 一组经验丰富的调查人员利用了长期的专业知识和翻译经验 电动汽车生物学、生物工程、系统生物学、生物信息学和临床肿瘤学。如果成功，我们的 尿液纳米血浆EV平台将为基于免疫治疗的研究增加关键的可操作见解 晚期膀胱癌的治疗在其他常见的泌尿生殖系癌症中是有希望的 作为肾脏和前列腺。