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治疗反应中发挥多方面的作用。 相关巨噬细胞（TAM）具有多种促肿瘤功能，包括因子的表达 促进肿瘤生长、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耐药性有关。 总体而言，一种可以非侵入性检测的成像探针正在成为抗癌治疗的目标。 TAM 负担可以帮助对患者进行分层并个性化治疗，以提高缓解率。 实验室开发了新型分子探针，能够对炎症灶进行灵敏和精确的成像 我们合成了包含氟封装的功能化碳氟纳米乳液。 放射性金属螯合物 (FERM) 预制的 FERM 纳米乳液可快速将 zircium-89 捕获到氟中。 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。 通过将放射性金属封装在载体内，有助于 89Zr 从载体上解离。 纳米乳滴体积小，可实现高有效负载和细胞检测灵敏度，且成本低 背景 静脉注射 FERM 后，纳米乳液液滴被吞噬细胞清除。 标记的细胞在炎症部位积聚，产生敏感且可量化的正电子。 发射断层扫描 (PET) 信号主要反映巨噬细胞负荷的初步 PET 结果。 我们的实验室在多种炎症啮齿动物中展示了 FERM 探针出色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，我们的项目基于这些结果。 有三个目标： 目标 1. 89Zr FERM 配方 我们将进行 FERM 纳米乳液配方优化。 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。 目标 2. 将进行基于细胞的测定来评估。 此外，我们将表征 89Zr FERM 的体内血液半衰期、探针稳定性和特性。 目标 3. 体内免疫肿瘤学研究的有效性。 用于 TAM 检测和量化的 FERM、对消除 TAM 负担的治疗的响应以及 探针预测多种小鼠实体瘤免疫治疗干预反应的潜力 将对肿瘤中 FERM 标记的细胞进行平行表型分析。 将生成推动 FERM 成像生物标志物潜在临床转化所需的基本数据 在未来的免疫肿瘤学临床试验中。