PET/MRI to study nanotherapy in atherosclerosis

简介(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)是西方世界主要的死亡原因。预防战略目前侧重于控制危险因素和血脂水平。即使在完全达到治疗目标的情况下，仍有很高的残留风险。在人类中，渗透斑块的单核细胞分化为炎性巨噬细胞，产生蛋白水解酶，消化细胞外基质，导致斑块破裂。因此，斑块炎症被认为是降低动脉粥样硬化血栓形成事件复发率的治疗目标。纳米药物通过改善治疗药物的药代动力学和生物分布，同时减少不良反应和不良相互作用，为各种病理疾病的治疗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，但有望在治疗最具挑战性的心血管疾病方面取得潜在的革命性进展。由于纳米药物在治疗动脉粥样硬化方面仍然相对未被探索，因此需要开发新的成像策略，既可以描述这种疾病的特征，也可以定量显示纳米颗粒的靶向性和有效性。在这个项目中，我们建议开发和利用PET/MRI技术来评估纳米疗法治疗动脉粥样硬化斑块炎症的基于成像的评估。为此，我们与纪念斯隆-凯特琳癌症中心的放射化学家合作，开发了脂质体纳米粒(LNPs)和高密度脂蛋白(HDL)的89Zr放射性同位素标记方法。我们将在动脉粥样硬化的兔模型中评估纳米报告技术。广泛的体外成像和组织学技术将被应用于评估体内的发现并揭示其作用机制。其具体目的是：目的1：建立只有一小部分89Zr标记的脂质体纳米粒的生物分布和斑块靶向性。[目的]定量评价89Zr标记高密度脂蛋白的斑块巨噬细胞靶向性和生物分布。目的：用正电子发射计算机断层扫描(PET/MRI)从理论上评价~(89)Zr标记的载药LNPs在动脉粥样硬化兔体内的疗效。所有建议的纳米颗粒配方和标签方法的单独成分都是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，可能会对心血管疾病的管理产生深远影响。

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.