Compositions and methods for enhanced fluorine-19 magnetic resonance imaging cell tracking

用于增强氟19磁共振成像细胞追踪的组合物和方法

• 批准号: 9893716
• 负责人: ERIC T. AHRENS
• 金额: $ 53.75万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893716
• 关键词: Adoption; Animal Model; Biological; Cancer Model; Cancer Patient; Cell Count; Cell Therapy; Cell physiology; Cells; Cellular immunotherapy; Chelating Agents; Clinical; Clinical Investigator; Clinical Trials; Dendritic Cells; Detection; Disease; Dose; Elements; Eye; Feedback; Fluorine; Fluorocarbons; Formulation; Future; Growth; Hot Spot; Image; Imaging technology; Immune; Immunotherapeutic agent; Inflammation; Injections; Ions; Iron; Label; Laboratories; Leukocytes; Life; Magnetic Resonance Imaging; Magnetism; Malignant Neoplasms; Measures; Metals; Methods; Modeling; Molecular; Nature; Noise; Oils; Patients; Peptides; Phase; Physiologic pulse; Population; Preclinical Testing; Property; Relaxation; Research Personnel; Route; Sampling; Scheme; Science; Scientist; Signal Transduction; Site; Solid Neoplasm; Speed; T-Lymphocyte; Technology; Therapeutic; Time; Work; base; cancer immunotherapeutics; cancer immunotherapy; cell behavior; cell motility; cell type; cellular imaging; chelation; chimeric antigen receptor; clinical translation; cytotoxicity; data acquisition; design; experience; imaging detection; imaging modality; imaging probe; imaging properties; improved; in vivo; in vivo imaging; innovation; interest; intravenous injection; macrophage; magnetic field; manufacturing scale-up; molecular imaging; nanoemulsion; new technology; novel; novel therapeutics; pre-clinical; prevent; stem cells; surfactant; trafficking; tumor; uptake

A common need for clinical developers of cell therapies, such as immunotherapeutic and stem cells, is a non- invasive means to visualize the fate of cells following injection. Imaging of cell trafficking can provide critical feedback regarding the persistence, motility, optimal routes of delivery and therapeutic doses. This project aims to synthesize and biologically evaluate innovative new imaging probes for sensitive in vivo cell tracking using fluorine-19 (19F) magnetic resonance imaging (MRI). We will advance the formulation science of a compelling new class of ‘metallo-perfluorocarbon’ (MPFC) nanoemulsion imaging probes. These agents will be a key element to a multi-pronged strategy to advance cell detection sensitivity by an order of magnitude over current 19F MRI cell detection technologies. Overall, in 19F cell tracking, cell populations of interest are initially labeled in culture using perfluorocarbon nanoemulsions. Following transfer to the subject, cells are tracked in vivo using 19F MRI. The fluorine inside the cells yields cell-specific images, with no background signal. One of the bottlenecks preventing the broader adoption of 19F based cell tracking is sensitivity limits to sparse cell numbers. The sensitivity of this technology can be improved by a three-pronged approach: (1) molecular design and synthesis to improve the intrinsic sensitivity of the molecular signal generator and (2) nanoemulsion probe formulation with cell targeting to enhance intracellular delivery and uptake, and (3) employing MRI data acquisition schemes that have a more efficient signal-to-noise ratio per acquisition time (SNR/t). Recent results have demonstrated dramatically-enhanced sensitivity of fluorine MRI by molecular design. We have created a new class of molecules that combine highly fluorinated nanoemulsions with the magnetic properties of metals that are solubilized into the fluorous phase. Solubilized paramagnetic metal ions provide a dramatic reduction in the 19F spin-lattice relaxation time thereby enhancing SNR/t and cell detection sensitivity. It was discovered that iron is most effective metal at enhancing the fluorine MRI signal. Building on these preliminary results, the proposal has four Specific Aims: Aim 1. Chelation strategies for MPFCs. We will evaluate a range of suitable chelate molecules and synthesis strategies to stably incorporate metal ions into PFC. Aim 2. Enhanced cell delivery of MPFC nanoemulsion using cell penetrating peptides (CPPs). Successful MRI detection of cells critically requires optimal intracellular delivery of emulsified MPFC ex vivo. We will develop novel MPFC nanoemulsion formulations incorporating CPPs attached to the nanoemulsion surfactant to rapidly and optimally label cells for cell tracking. Aim 3. “Smart” in vivo targeted nanoemulsions. As an exploratory extension of this work, we devise MPFC nanoemulsions that target tumors in vivo. Aim 4. In vivo imaging methods to track immunotherapeutic T cells in cancer. To evaluate new MPFC nanoemulsion probes, we will label T cells and deliver these to immunotherapeutic cancer models. To image these models, sparse sampling MRI acquisition methods (e.g., compressed sensing) will be implemented and optimized for MPFC agents to maximize SNR/t.

对细胞疗法的临床开发者的普遍需求，例如不明治疗和干细胞，是一种非 - 侵入性的手段可视化细胞贩运成像后细胞的命运。 关于持久性，运动性，最佳分娩途径和治疗剂量的反馈 合成和生物学评估创新的新成像探针，用于使用敏感的体内细胞跟踪 Fluorine-19（19F）磁共振成像（MRI）。 新的“金属杂志”类别 多管齐下策略的元素，以通过过电流的数量级来提高细胞检测敏感性 19F MRI细胞检测技术。 在转移到受试者后，培养氟化合物纳米乳液。 19F MRI。内部的氟产生特定的图像，没有背景信号 阻止更广泛采用19F的细胞跟踪的瓶颈是稀疏细胞数的敏感性限制。 技术的敏感性可以通过 合成以提高分子信号基和（2）纳米乳液探针的固有灵敏度 用细胞靶向制定，以增强细胞内的故意和吸收，（3）使用MRI数据 每次收购时间具有更有效的收购计划（SNR/T） 通过分子设计，已经证明了氟的氟氟。 将高度氟化的纳米乳液与金属的磁性结合的新分子 被溶解到荧光阶段。 19f自旋晶格松弛时间，从而增强了SNR/T和细胞检测灵敏度。 铁是增强氟MRI信号的最有效金属。 提案有四个特定的目标：目标1。MPFC的螯合策略。 螯合分子和合成策略可稳定地融入PFC。 使用细胞穿透性肽（CPP）递送MPFC纳米感应。 至关重要的是，我们将发展新型MPFC的乳化MPFC的最佳细胞内递送。 纳米乳液配方合并了连接到纳米乳液表面活性剂的CPP 标签细胞跟踪3。 工作，我们设计了MPFC纳米乳液的靶向体内肿瘤。 癌症中的免疫治疗t细胞。 将这些输送到免疫治疗癌模型。 对于MPFC代理，将使方法（例如，压缩传感）受到最大化SNR/T的限制。