Multivalent Theranostics for Inflammation

炎症的多价治疗诊断

• 批准号: 8033013
• 负责人: Sanjay Rajagopalan
• 金额: $ 21.53万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033013
• 关键词: Acute; Adverse effects; Affinity; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Aorta; Apolipoprotein E; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Binding; Biodistribution; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cells; Characteristics; Cholesterol Esters; Confocal Microscopy; Data; Diagnostic; Diet; Disease; Dose; Drug Delivery Systems; Drug Kinetics; Event; Fatty acid glycerol esters; Flow Cytometry; Fluorescein-5-isothiocyanate; Fluorescence; Gene Expression; Human; ITGAM gene; Image; Immunoglobulin G; Immunoliposome; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injury; Intervention; Label; Leukocytes; Ligands; Liposomes; Magnetic Resonance Imaging; Methods; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myocardial Infarction; Organ; Organoids; Pathway interactions; Peptide Hydrolases; Performance; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; Phosphatidylserines; Plasma; Polyethylene Glycols; Preparation; Property; Proteins; Role; S100A9 gene; Safety; Series; Signal Transduction; Sorting - Cell Movement; Specificity; Stroke; Structure; Surface; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Time; Vesicle; base; cellular imaging; cytokine; design; feeding; imaging probe; in vivo; inflammatory marker; insight; macrophage; mortality; novel; particle; research study; synergism; theranostics; uptake; vascular inflammation

DESCRIPTION (provided by applicant): Multivalent 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 macrophages 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 PPAR3 agent (3-antiMRP8/14-CC-L) represents an attractive approach that combines locus specific delivery with synergistic therapeutic effects of PPAR3 agents on M function. As part of this aim, we will investigate biodistribution and pharmacokinetics of several doses of an optimized 3-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 PPAR3 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. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the leading cause of morbidity and mortality worldwide. Plaque build-up within arteries and instability of the plaque result in the cardiovascular events such as heart attacks and stroke. Instability of the plaque is related to progressive accumulation of white blood cells that result in synthesis of substances that are deleterious to the blood vessel. In this proposal, we propose building novel drug delivery systems that will allow imaging using magnetic resonance imaging (MRI) and at the same time accomplish delivery of high concentrations of drugs to specific areas of the plaque where white cells reside. In order to accomplish this, we propose in-vitro and in-vivo studies in susceptible atherosclerosis animal models to assess uptake, efficiency, pathways, therapeutic mechanisms and safety of agents to reduce inflammation and plaque. We envision that the strategies combining targeted imaging probes and therapies in a single platform has the potential to provide unique insights to "plaque vulnerability" and an opportunity for therapeutic intervention.

描述（由申请人提供）：动脉粥样硬化功能评估的多价非侵入性方法为干预心血管疾病提供了机会。在我们的初步研究中，我们成功地采用了含有巨噬细胞的关键吞噬配体的多模式囊泡（荧光和磁共振成像，MRI），以使这些细胞在动脉粥样硬化中的优先成像。我们的方法利用了巨噬细胞吞没药物，从而允许在动脉粥样硬化血管壁上长时间保留MRI信号。在这一提议中，我们假设基于这些原理的免疫脂质体含有针对髓样相关的蛋白质8/14（MRP）的抗体，被证明是我们组的炎症和损伤的关键介体，将促进成像，促进MM表型，增强抗炎性效应，同时提高抗炎性效果，同时最小化更高的副作用的副作用。在此提案中，我们建议在相关炎症和动脉粥样硬化模型中进行一系列结构化研究（APOE-/ - 和APOE-/ - MRP14 - / - ）。在AIM 1中，我们将测试PEG保护的含GD荧光标记的免疫体针对MRP（antiMRP-CC-L）的VIVO和体内疗法。空间定位，靶向和优化将在器官培养物和短期电线损伤模型中进行。在AIM 2中，我们将合成和测试theranostic免疫脂质体，并假设在AIM 1中验证的免疫脂质体以及含有PPAR3剂（3-ANTIMRP8/14-CC-L）的其他有吸引力的方法代表了一种有吸引力的方法，该方法将基因座特异性递送与PPAR3 Agents的Synergistic Tressiation tovily结合在一起。作为此目的的一部分，我们将研究几种优化的3-抗-cc-L的生物分布和药代动力学在APOE-/ - ，并还测试炎症中体内成像的可行性。通过评估M表面标记，细胞因子和炎症基因表达，将评估对M表型和功能的影响。我们提出了精心设计的实验，将允许评估成像性能，治疗效果，包括作用机制，这些机制将使MRP和治疗协同作用具有独特的见解，并通过M特异性地递送高亲和力PPAR3配体。在小鼠和人类中，临床认可的GD制剂，高GD付费/粒子的高付款/粒子的利用均赋予了立即转化相关性。我们设想，结合M的成像探针和疗法的策略有可能在各种炎症性疾病中使用。 公共卫生相关性：动脉粥样硬化是全球发病率和死亡率的主要原因。动脉内的斑块积聚和斑块的不稳定性导致心血管事件，例如心脏病发作和中风。斑块的不稳定性与白细胞的进行性积累有关，这导致综合对血管有害的物质。在此提案中，我们提出了建立新的药物输送系统，该系统将允许使用磁共振成像（MRI）进行成像，同时将高浓度的药物递送到白细胞居住的斑块的特定区域。为了实现这一目标，我们提出了易感动脉粥样硬化动物模型的体外和体内研究，以评估摄取，效率，途径，治疗机制和药物的安全性，以减少炎症和斑块。我们设想，将目标成像探针和疗法结合在单个平台中的策略有可能为“斑块脆弱性”和治疗干预的机会提供独特的见解。