Metallo-fluorocarbon nanoemulsion for PET detection of cancer inflammation

在癌症中，巨噬细胞在疾病进展和对治疗的反应中发挥着多方面的作用。肿瘤- 相关巨噬细胞(TAMs)具有多种促肿瘤功能，包括表达多种因子 促进生长、免疫抑制和血管生成。在肿瘤微环境中的高负担 往往与预后不良和对某些免疫疗法的治疗抵抗有关。此外，塔姆斯 正在成为抗癌治疗的靶点。总体而言，一种成像探测器可以非侵入性地检测 负担可以帮助患者分层和个性化治疗，以提高缓解率。最近，我们的 实验室开发了新型分子探针，使炎症病灶能够灵敏和精确地成像 活着。我们合成了功能化的氟碳纳米乳液，其中包含了一种氟封装的 放射性金属络合物(FERM)预制的高铁纳米乳状液能迅速将锆-89捕获到氟中。 相位。氟碳化合物的高度疏水性有助于排除来自水、阳离子、脂类和 促进89Zr从载体上解离的蛋白质。通过将放射性金属封装在 体积小的纳米乳液滴可以实现高有效载荷和电池检测灵敏度，具有低 背景资料。静脉注射FERM后，纳米乳液滴被吞噬细胞清除。 巨噬细胞。标记的细胞聚集在炎症部位，从而产生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。初步的PET结果来自 我们的实验室在多种炎症啮齿动物身上展示了FERM探针的卓越灵敏度和多功能性。 模型包括实体瘤、急性感染和自身免疫性疾病。基于这些结果，我们的项目 有三个目标：目标1.89锆铁制剂。我们将进行FERM纳米乳液的配方优化 以及扩大规模。我们还将开发最佳的放射性药物方法，使FERM的标记效率最大化。 和产品产量。目的2.生物学特性。将进行基于细胞的分析以评估 ~(89)Zr酵母的潜在毒性。此外，我们将表征体内血液的半衰期、探针的稳定性和 初步剂量测定。目的3.体内免疫肿瘤学研究。我们将描述以下内容的有效性 检测和量化的FERM，对消耗负担的治疗的响应性，以及 探针预测多发小鼠实体瘤免疫治疗反应的潜力 模特们。将进行肿瘤中FERM标记细胞的平行表型分析。建议进行的研究 将产生用于驱动FERM成像生物标记物的潜在临床翻译所需的基本数据 在未来的免疫肿瘤学临床试验中。

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.