COLLOIDAL IRON-OXIDE NANOBEACONS FOR THERANOSTIC USE IN ATHEROSCLEROSIS

纳米医学方法治疗动脉粥样硬化性疾病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，需要开发替代治疗方法。最有可能的第一候选是氧化铁纳米颗粒，它已广泛用于基于高灵敏度T2*成像特性的非靶向和靶向成像应用。不幸的是，这些药物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深色对比体素转换为明亮体素，但成像的延迟、磁化率的显著开花效应以及在成像时血管壁内巨噬细胞对USPIOs的非特异性摄取问题是持续存在的问题。我们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性基质中，比T1更能降低T2效应。CION的这些有利的T1w对比属性取决于合成化学，包括相、磁化率、基质中氧化铁的浓度以及外表面活性剂膜中适度交联的使用。CION新的有益特性包括：

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.