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.
Nanomedicine approaches to atherosclerotic disease offer significant impact on the practice and outcomes of cardiovascular medicine. Early detection of symptomatic ruptured plaque in nonstenotic arterial segments, now virtually impossible, will allow the follow-on design, development and placement of intimal sealants to prevent embolism and catastrophic plaque rupture, while medical therapeutic approaches to the unstable plaque are applied to passivate disease progression. Molecular imaging of angiogenesis, an atherosclerotic biomarker closely associated with atherosclerotic plaque instability will provide a quantifiable index of disease burden individuals at risk, due to history, circulating biomarkers, or events. Molecular imaging of these patients, particularly asymptomatic cases, will provide a quantifiable reference assess the effectiveness of medical strategies to stabilize or slow plaque progression. In the high-risk situations, image quantifiable antiangiogenic treatment can be delivered to acutely abate plaque degeneration through intraplaque neovascular hemorrhage and erosion, which can then be maintained with statins. Subsequent molecular imaging can then be used to reassess pathology progression and manage medical strategy, even in patients without clinically evident disease. Indeed, nanomedicine offers a pathway to alter our current symptom reactionary approach to proactive paradigm for detecting and managing atherosclerosis early in its natural history.
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