COLLOIDAL IRON-OXIDE NANOBEACONS FOR THERANOSTIC USE IN ATHEROSCLEROSIS

动脉粥样硬化性疾病的纳米医学方法可能会对心血管医学的实践和结果产生重大影响。最近，由于人们对Gd的使用及其与肾源性系统性纤维化(NSF)的关系的关注，需要开发替代的治疗方法。最有可能的候选是氧化铁纳米颗粒，基于高度敏感的T2*成像特性，它已被广泛用于非靶向和靶向成像应用。不幸的是，这些试剂通常会导致负面对比效应，由于持续的血池干扰，只能在24小时或更长时间后才能成像。尽管最近的成像序列和处理进展可以将这些暗对比体素转换成明亮的体素，但成像的延迟、磁化率的显著开花效应以及血管壁内巨噬细胞在成像时对USPIO的非特异性摄取问题是长期存在的问题。我们已经开发了一种新型的胶体氧化铁纳米颗粒平台，CION，它将氧化铁包裹在疏水基质中，比T1更能减少T2效应。Con的这些良好的T1w对比度属性取决于合成化学，包括基质中氧化铁的物相、磁化率和浓度，以及外表面活性剂膜中适度交联剂的使用。Cion新的有益特性包括： 1)T1w分子成像没有典型的偶极诱导的水华伪影， 2)在没有血池干扰的情况下，1小时(与24小时)后的体内分子成像， 3)注射抗血管生成药物的能力和 4)限制血池分布，以增加血管内病理的特异性靶点，如破裂斑块内的纤维蛋白或新生血管表达的整合素。 在这项修改后的提案中，我们将开发CION技术和/或锰纳米乳剂替代品(作为后备)，具有两个广泛的、与临床相关的具体目标。 合成、表征和体内(物理、化学、磁性和药物)靶向非Gd纳米平台，用于血栓和动脉粥样硬化新生血管的T1W磁共振成像。 在体内展示以配体为靶点的非Gd纳米平台的图像引导药物传递抗血管生成治疗的潜力。

Nanomedicine approaches to atherosclerotic disease could have significant impact on the practice and outcomes of cardiovascular medicine. With recent concerns about the use of gadolinium and its relationship to Nephrogenic Systemic Fibrosis (NSF), alternative theranostic approaches need to be developed. The most likely first candidate are iron oxide nanoparticles, which have been extensively used for nontargeted and targeted imaging applications based upon highly sensitive T2* imaging properties. Unfortunately, these agents typically result in a negative contrast effects that can only be imaged 24 or more hours after due to persistent blood pool interference. Although recent imaging sequence and processing advances can convert these dark contrast voxels into bright ones, the delay in imaging, the prominent blooming effects of the magnetic susceptibility, and the issue of nonspecific uptake of USPIOs by macrophages within the vascular wall at the time imaging can be performed are persistent problems. We have developed a novel, colloidal iron oxide nanoparticle platform, CION, which encapsulates iron oxide within a hydrophobic matrix and decreases T2 effects more than T1. These favorable T1w contrast attributes of CION are dependent on the synthesis chemistry, including the phase, magnetic susceptibility, and concentration of iron oxide in the matrix as well as the use of modest cross-linking in the outer surfactant membrane. CION novel beneficial properties include: 1) T1w molecular imaging without the typical dipole induced bloom artifacts, 2) in vivo molecular imaging after 1 hour (vs. 24) without blood pool interference, 3) theranostic capability to deliver an antiangiogenic drug and 4) constrained blood pool distribution to increase specific targeting of intravascular pathology, such as fibrin within ruptured plaques or integrins expressed by the neovasculature. In this modified proposal, we will develop CION technology and or a manganese nanoemulsion alternative (in back-up), with two broad, clinically relevant specific aims. Synthesize, characterize, and demonstrate in vivo (physical, chemical, magnetic, and pharmaceutical) of ligand-targeted non-gadolinium nanoplatform for T1W MR imaging of thrombus and of atherosclerotic neovasculature. Demonstrate image-guided drug delivery of antiangiogenic therapy potential with ligand-targeted non-gadolinium nanoplatform in vivo.