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，巨噬细胞在疾病进展和对治疗的反应中发挥多方面的作用。肿瘤- 相关巨噬细胞（TAM）具有几种促肿瘤功能，包括表达因子 促进生长、免疫抑制和血管生成。肿瘤微环境中的高TAM负荷 通常与不良预后和对某些免疫疗法的治疗抗性有关。此外， 正在成为抗癌治疗的靶点。总的来说，一个成像探头，可以非侵入性地检测 TAM负荷有助于患者分层和个性化治疗，以提高应答率。最近我们 一个实验室开发了新的分子探针，能够灵敏和精确地成像炎症灶， vivo.我们合成了功能化的氟碳纳米乳液， 放射性金属螯合物（FERM）。预先形成的FERM纳米乳液迅速将锆-89捕获到氟离子中， 相位碳氟化合物的高度疏水性有助于排除来自水、阳离子、脂质和水的竞争。 有助于89 Zr从载体解离的蛋白质。通过将放射性金属封装在 纳米乳液液滴的体积可以实现高的有效载荷和细胞检测灵敏度， 背景静脉注射FERM后，纳米乳液液滴被吞噬细胞清除， 巨噬细胞标记的细胞在炎症部位聚集，导致敏感和可定量的正电子 发射断层扫描（PET）信号主要反映巨噬细胞负荷。初步PET结果来自 我们的实验室证明了FERM探针在多种炎症啮齿动物中具有出色的灵敏度和通用性 模型包括实体瘤、急性感染和自身免疫性疾病。基于这些结果，我们的项目 有三个目标：目标1。89 Zr FERM制剂。我们将进行FERM纳米乳液配方优化 and scale-up放大.我们还将开发最佳的放射性药物方法，以最大限度地提高FERM的标记效率 和产品收率。目标2.生物学特性。将进行基于细胞的试验，以评价 89 Zr FERM的潜在毒性。此外，我们将表征体内血液半衰期，探针稳定性， 初步剂量测定。目标3.体内免疫肿瘤学研究。我们将描述 用于TAM检测和定量的FERM，对消耗TAM负荷的治疗的反应性，以及 探针预测多发性小鼠实体瘤对免疫干预反应的潜力 模型将对肿瘤中的FERM标记细胞进行平行表型分析。拟议的研究 将生成驱动FERM成像生物标志物的潜在临床转化所需的基本数据 在未来的免疫肿瘤临床试验中。