COLLOIDAL IRON-OXIDE NANOBEACONS FOR THERANOSTIC USE IN ATHEROSCLEROSIS

动脉粥样硬化疾病的纳米医学方法可能对心血管医学的实践和结果产生重大影响。随着最近对钆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诊断方法。最有可能的第一候选者是氧化铁纳米颗粒，其已被广泛用于基于高度灵敏的T2* 成像特性的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的对比效果，由于持续的血池干扰，只能在24小时或更长时间后成像。尽管最近的成像序列和处理进展可以将这些暗对比度体素转换为亮体素，但成像延迟、磁化率的突出晕染效应以及在可以进行成像时血管壁内的巨噬细胞非特异性摄取USPIO的问题是持续存在的问题。我们已经开发了一种新型的胶体氧化铁纳米颗粒平台CION，它将氧化铁封装在疏水基质中，并且比T1更能降低T2效应。CION的这些有利的T1 w对比度属性取决于合成化学，包括基质中氧化铁的相、磁化率和浓度以及在外部表面活性剂膜中使用适度交联。CION新的有益特性包括： 1)T1 w分子成像，无典型偶极诱导的布卢姆伪影， 2)在1小时（vs.24）后无血池干扰的体内分子成像， 3)提供抗血管生成药物的治疗诊断能力， 4)限制血池分布以增加血管内病变的特异性靶向，例如破裂斑块内的纤维蛋白或由新血管系统表达的整合素。 在这项修改后的提案中，我们将开发CION技术和/或锰纳米乳液替代品（备用），具有两个广泛的临床相关具体目标。 合成、表征并在体内（物理、化学、磁性和药物）展示用于血栓和动脉粥样硬化新生血管T1 W MR成像的配体靶向非钆纳米平台。 证明图像引导的药物输送的抗血管生成治疗潜力与配体靶向非钆纳米平台在体内。

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.