PET/MRI to study nanotherapy in atherosclerosis

描述（由申请人提供）：动脉粥样硬化及其主要临床表现，冠状动脉疾病（CAD），是西方世界的主要死亡原因。目前的预防策略集中在控制危险因素和血脂水平。即使完全达到治疗目标，实质性剩余风险仍然很高。在人类中，浸润斑块的单核细胞分化成炎性巨噬细胞，产生蛋白水解酶，消化细胞外基质，导致斑块破裂。因此，斑块炎症被作为降低动脉粥样硬化血栓事件复发率的治疗靶点。纳米医学通过改善治疗剂的药代动力学和生物分布，同时减少不良反应和不希望的相互作用，为治疗各种病理提供了令人兴奋的新可能性。在动脉粥样硬化领域，纳米医学仍处于起步阶段，但有望为心血管疾病最具挑战性的治疗提供潜在的革命性进展。由于纳米医学仍然相对未开发的动脉粥样硬化，新的成像策略，允许表征这种疾病，但也允许定量可视化的纳米粒子的靶向和疗效需要开发。在这个项目中，我们建议开发和利用PET/MRI技术，用于基于成像的评估动脉粥样硬化斑块炎症治疗的纳米疗法。为此，我们与纪念斯隆-凯特琳癌症中心的放射化学家合作，开发了脂质体纳米颗粒（LNP）和高密度脂蛋白（HDL）的89 Zr放射性同位素标记方法。我们将在兔动脉粥样硬化模型中评估纳米报告技术。将应用广泛的离体成像和组织学技术来评价体内结果并阐明作用机制。具体目标是：目标1：建立脂质体纳米粒的生物分布和斑块靶向，其中只有一小部分用89 Zr标记。定量评价89 Zr标记HDL的噬斑巨噬细胞靶向性和生物分布。目的2、目的3：通过PET/MRI评价~（89）Zr标记和载药LNP对动脉粥样硬化兔的疗效。所有提出的纳米颗粒制剂的单个组分和标记方法都是FDA批准的，这一事实促进了向临床的转化。最后，使用纳米颗粒制剂快速抑制血管壁炎症并开发成像技术来监测其疗效可能对心血管疾病的管理产生深远的影响。

DESCRIPTION (provided by applicant): Atherosclerosis and its major clinical manifestation, coronary artery disease (CAD), is the leading cause of death in the western world. Preventive strategies currently focus on controlling risk factors and lipid levels. Substantial residual risk remains high, even when treatment goals are fully met. In humans, monocytes that infiltrate the plaque differentiate into inflammatory macrophages produce proteolytic enzymes that digest extracellular matrix causing plaque rupture. Plaque inflammation is therefore pursued as a therapeutic target to lower the recurrent rates of atherothrombotic events. Nanomedicine offers exciting new possibilities for the treatment of a variety of pathologies by improving the pharmacokinetics and biodistribution of therapeutic agents, while simultaneously decreasing adverse effects and undesired interactions. In the field of atherosclerosis, nanomedicine is still in its infancy, but is expected to provide potentially revolutionary advances in treatment for the most challenging aspects of cardiovascular diseases. Since nanomedicine remains relatively unexplored for atherosclerosis, novel-imaging strategies that allow characterizing this disease, but also allow the quantitative visualization of nanoparticle targeting and efficacy need to be developed. In this project, we propose to develop and utilize PET/MRI technology for the imaging-based evaluation of nanotherapy for the treatment of atherosclerotic plaque inflammation. To that aim, in collaboration with radiochemists at Memorial Sloan Kettering Cancer Center, we have developed 89Zr radioisotope labeling methods for liposomal nanoparticles (LNPs) and high-density lipoprotein (HDL). We will evaluate the nanoreporter technology in a rabbit model of atherosclerosis. Extensive ex vivo imaging and histological techniques will be applied to evaluate the in vivo findings and to unravel the mechanism of action. The specific aims are: Aim 1: To establish the biodistribution and plaque targeting of liposomal nanoparticles of which only a small fraction is labeled with 89Zr. To quantitatively evaluate plaque macrophage targeting and biodistribution of 89Zr-labeled HDL. : To theranostically evaluate the efficacy Aim 2 Aim 3 of 89Zr-labeled and drug-loaded LNPs in atherosclerotic rabbits by PET/MRI. Translation to the clinic is facilitated by the fact that the individual components of all the proposed nanoparticle formulations and the labeling methods are FDA approved. Finally, using nanoparticle formulations to rapidly inhibit vessel wall inflammation and develop imaging technology to monitor their efficacy may have a profound impact on the management of cardiovascular diseases.