Metallo-fluorocarbon nanoemulsion for PET detection of cancer inflammation

金属氟碳纳米乳用于PET检测癌症炎症

• 批准号: 10737153
• 负责人: ERIC T. AHRENS
• 金额: $ 65.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737153
• 关键词: 3-Dimensional; Animals; Antitumor Response; Autoimmune Diseases; Biological; Biological Assay; Blood; Breast; Cancer Detection; Cancer Model; Cations; Cells; Cellular Assay; Clinical Trials; Complex; Data; Detection; Diagnostic; Diagnostic Imaging; Disease; Disease Progression; Dissociation; Dose; Effectiveness; Encapsulated; Exclusion; Flow Cytometry; Fluorocarbons; Formulation; Future; Growth; Half-Life; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Hydrophobicity; Image; Immune checkpoint inhibitor; Immunooncology; Immunosuppression; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence Study; Inflammation; Inflammatory; Intervention; Intravenous; Label; Laboratories; Lipids; Macrophage; Malignant Neoplasms; Measurement; Metals; Methods; Modeling; Molecular Probes; Mus; Nature; Neoplasm Metastasis; Non-Invasive Detection; Oils; Phagocytes; Phase; Phenotype; Play; Positron-Emission Tomography; Prediction of Response to Therapy; Prognosis; Proteins; Radiochemistry; Radiopharmaceuticals; Reproducibility; Residual state; Reticuloendothelial System; Rodent; Rodent Model; Role; Signal Transduction; Site; Solid Neoplasm; Surface; Suspensions; Technology; Therapeutic; Toxic effect; Treatment Efficacy; Tumor Markers; Tumor-associated macrophages; Vesicle; Water; Zirconium; acute infection; angiogenesis; anti-cancer therapeutic; bioluminescence imaging; cancer clinical trial; cancer imaging; chelation; clinical translation; detection sensitivity; diagnostic biomarker; dosimetry; imaging biomarker; imaging probe; imaging study; improved; in vivo; intravenous injection; mouse model; nanoemulsion; non-invasive imaging; novel; novel diagnostics; patient stratification; personalized medicine; pre-clinical; preclinical study; predicting response; predictive marker; response; scale up; targeted treatment; therapy resistant; translational potential; treatment response; tumor; tumor microenvironment

In cancer, macrophages play a multifaceted role in disease progression and response to therapies. Tumor- associated macrophages (TAMs) serve several pro-tumoral functions including the expression of factors promoting growth, immune suppression and angiogenesis. A high TAM burden in the tumor microenvironment is often associated with poor prognosis and therapeutic resistance to certain immunotherapies. Moreover, TAMs are emerging as a target for anti-cancer therapeutics. Overall, an imaging probe that can non-invasively detect TAM burden could help stratify patients and personalize treatments to improve response rates. Recently, our laboratory has developed novel molecular probes enabling sensitive and precise imaging of inflammatory foci in vivo. We synthesized functionalized fluorocarbon nanoemulsions incorporating a fluorous-encapsulated radiometal chelate (FERM). Pre-formed FERM nanoemulsion rapidly captures zirconium-89 into the fluorous phase. The highly hydrophobic nature of fluorocarbons helps exclude competition from water, cations, lipids and proteins that contribute to the dissociation of 89Zr from the carrier. By encapsulating the radiometal inside the volume of nanoemulsion droplet one can achieve a high payload and cell detection sensitivity, with low background. Following an intravenous injection of FERM, nanoemulsion droplets are scavenged by phagocytic macrophages. The labeled cells accumulate at inflammatory sites resulting in sensitive and quantifiable positron emission tomography (PET) signals reflecting predominantly macrophage burden. Preliminary PET results from our lab demonstrate excellent sensitivity and versatility of the FERM probe in a diversity of inflammation rodent models, including solid tumor, acute infection and autoimmune disease. Building on these results, our project has three Aims: Aim 1. 89Zr FERM formulation. We will perform FERM nanoemulsion formulation optimization and scale-up. We will also develop optimal radiopharmacy methods to maximize labeling efficiency of FERM and product yield. Aim 2. Biological characterizations. Cell-based assays will be performed to evaluate potential toxicity of 89Zr FERM. Moreover, we will characterize the in vivo blood half-life, probe stability, and preliminary dosimetry. Aim 3. In vivo immuno-oncology studies. We will characterize the effectiveness of FERM for TAM detection and quantification, responsiveness to treatments that deplete TAM burden, and the probe’s potential for predicting response to immunotherapeutic interventions in multiple murine solid tumor models. Parallel phenotypic profiling of FERM-labeled cells in the tumor will be performed. The proposed studies will generate essential data needed to drive potential clinical translation of the FERM imaging biomarker for use in future immuno-oncology clinical trials.

在癌症中，巨噬细胞在疾病进度和对疗法的反应中起着多方面的作用。 相关的巨噬细胞（TAM）发挥了Severv-tumoral功能，包括因素的表达 促进生长，免疫抑制和血管生成。 通常，预后不良和对某些免疫疗法的治疗性。 正在成为抗癌治疗剂的靶标。 TAM的负担可以帮助分层患者并个性化她务，以提高我们的反应率 实验室已经开发了新的分子探针，从而实现了对炎症焦点的敏感和精确成像 Vivo。 放射线螯合物（FERM）。 阶段。 通过封装在载体内部的蛋白质，导致89ZR的脱剖分。 纳米调味液的体积可以达到高有效载荷和细胞检测灵敏度，而较低 背景。 巨噬细胞。 明天（宠物）信号反映了巨噬细胞负担。 我们的实验室在多种炎症啮齿动物中表现出极好的灵敏度和多功能性 模型，包括实体瘤，急性感染和自身免疫性疾病。 有三个目的：目标1。89ZRfermulation。 和扩展。我们还将开发最佳的放射性药物 和产品2。 潜在的tomeover，我们将表征体内血液半衰期，探针稳定性和 初步剂量学。 用于TAM检测和量化的FERM，对耗尽TAM负担的治疗的反应能力以及您 探针预测多种鼠实体瘤中免疫治疗干预措施的呼吸的潜力 模型 将生成所需的基本数据，以驱动FERM Imaging Biomarker使用的潜在清洁仪 在未来的免疫NCology临床试验中。