Multivalent Theranostics for Inflammation

用于血管成像和治疗的多价治疗诊断学 项目摘要 动脉粥样硬化功能评估的非侵入性方法为干预提供了机会 在心血管疾病中。在我们的初步研究中，我们成功地采用了多模态囊泡 （荧光和磁共振成像，MRI），其含有M 使 动脉粥样硬化中这些细胞的优先成像。我们的方法利用巨噬细胞吞噬 的代理，允许在动脉粥样硬化血管壁的MRI信号的延长保留。在本提案中，我们 假设基于这些原理的免疫脂质体含有针对骨髓相关抗体， 蛋白-8/14（MRP），被我们的小组证明是炎症和损伤的关键介质，将促进成像， 修改M 表型，增强抗炎作用，同时最大限度地减少治疗的脱靶副作用 剂.在这项提案中，我们建议在相关炎症模型中进行一系列结构化研究， 动脉粥样硬化（ApoE-/-和ApoE-/-MRP 14-/-）。在目标1中，我们将测试离体和体内治疗诊断 PEG保护的含Gd荧光标记的免疫脂质体抗MRP（抗MRP-CC- L）。空间定位，靶向和优化将在类器官培养和短期线- 伤害模型在目标2中，我们将合成和测试治疗诊断免疫脂质体，并假设 在Aim 1中验证的免疫脂质体，另外含有一种PPAR？试剂（？-antiMRP 8/14-CC-L） 代表了一种有吸引力的方法，该方法将位点特异性递送与协同治疗效果相结合， M上的PPAR？试剂 功能作为这一目标的一部分，我们将研究的生物分布和药代动力学 在ApoE-/-中使用几种剂量的优化的抗MRP-CC-L，并将额外测试体内 在炎症中成像。对M的影响 表型和功能将通过评估M 表面标志物、细胞因子和炎性基因表达。我们提出了精心设计的实验， 允许评估成像性能、治疗效果，包括作用机制， 对MRP的作用和与M的治疗协同作用的独特见解 高亲和力特异性递送 PPAR配体。临床批准的Gd制剂、高Gd-有效载荷/颗粒和同源性的利用 MRP在小鼠和人类中的表达赋予了直接的翻译相关性。我们设想， M 靶向成像探针和疗法具有用于多种炎性疾病的潜力。

Multivalent Theranostics for Vascular Imaging and Therapy Project Summary Non-invasive approaches for functional assessment of atherosclerosis present an opportunity for intervention in cardiovascular disease. In our preliminary studies, we have successfully employed multimodal vesicles (fluorescence and magnetic resonance imaging, MRI) containing key engulfment ligands of M to enable preferential imaging of these cells in atherosclerosis. Our method takes advantage of macrophage engulfment of agents, allowing prolonged retention of MRI signal in the atherosclerotic vessel wall. In this proposal, we hypothesize that immunoliposomes based on these principles containing antibodies against myeloid related protein-8/14 (MRP), shown to be a key mediator of inflammation and injury by our group, will facilitate imaging, alter M phenotype, enhance anti-inflammatory effects, while minimizing off-target side effects of therapeutic agents. In this proposal we suggest a series of structured studies in relevant models of inflammation and atherosclerosis (ApoE-/- and ApoE-/-MRP14-/-). In Aim 1, we will test the ex-vivo and in-vivo theranostic properties of PEG protected Gd-containing fluorescently-tagged immunoliposomes against MRP (antiMRP-CC- L). Spatial localization, targeting and optimization will be carried out in organoid cultures and short-term wire- injury models. In Aim 2, we will synthesize and test theranostic immunoliposomes and hypothesize that immunoliposomes validated in Aim 1 and additionally containing a PPAR¿ agent (¿-antiMRP8/14-CC-L) represents an attractive approach that combines locus specific delivery with synergistic therapeutic effects of PPAR¿ agents on M function. As part of this aim, we will investigate biodistribution and pharmacokinetics of several doses of an optimized ¿-antiMRP-CC-L in ApoE-/- and will additionally test the feasibility of in-vivo imaging in inflammation. The effects on M phenotype and function will be evaluated by assessing M surface markers, cytokines and inflammatory gene expression. We propose well designed experiments that will allow assessment of imaging performance, therapeutic effects including mechanisms of action that will shed unique insights into the roles of MRP and therapeutic synergism with M specific delivery of high-affinity PPAR¿ ligands. The utilization of clinically approved Gd preparations, high Gd-payload/particle and homology of MRP in mice and humans confers immediate translational relevance. We envision that strategies combining M targeted imaging probes and therapies has the potential for use in a variety of inflammatory diseases.