Research Project
8307121
DESCRIPTION (provided by applicant): Despite advances in cardiovascular care, atherosclerosis remains the leading cause of mortality in the United States and worldwide. A vast majority of cardiovascular events such as stroke or myocardial infarction result from rupture or erosion of vulnerable atherosclerotic plaques. These plaques are characterized by high and active macrophage content. Accurate in vivo tracking of plaque vulnerability and progression using non-invasive imaging approaches allows early identification of high-risk patients as well as facilitates early intervention decision-making process and monitoring of the effectiveness of interventions. However, current imaging modalities including magnetic resonance (MR) imaging characterize anatomic and structural features of the plaque rather than its content. Contrast agents such as gadolinium-based contrast agents (GBCAs) are often used in cardiovascular MR imaging to enhance contrast between tissues. Macrophage-specific delivery of GBCAs will allow early detection of vulnerable plaques and risk stratification of vulnerable patients. This wil also minimize the GBCA dose, thus diminishing the risk of nephrogenic systemic fibrosis, a major adverse consequence of GBCAs that may lead to disability or death. Recently, high density lipoproteins (HDLs) were suggested as delivery nanocarriers for GBCAs. We hypothesize that oxidative modification of apolipoprotein (apo) A-I, the major protein constituent of HDL, can be used to direct GBCA-carrying HDL (GBCA-HDL) to macrophage-rich plaques. This is rationalized by the fact that this modification occurs in vivo and converts HDL into a substrate for macrophages. Thus, it may enhance intraplaque macrophage uptake of HDL. The long-term objective of the proposed project is to develop a novel approach to early detection and evaluation of vulnerable plaques. The major goal of the Phase I study is to demonstrate that modification of apo A-I in HDL-based MR imaging agents increases the detection of intraplaque macrophages in animal model system. Phase I specific aims are: 1) generate and characterize GBCA-HDL nanoformulations that contain modified apo A-I, and 2) test the optimal GBCA-HDL formulation in a mouse model of atherosclerosis. We will synthesize GBCA-HDL particles that contain modified apo A-I, characterize them and assess macrophage uptake in vitro. We will vary the GBCA:lipid:apo A-I ratios and choose the optimal formulation based upon maximum Gd content and highest macrophage uptake. We will use apo E-knockout mouse model to assess MR efficacy of the optimal formulation in plaque imaging in vivo. It is anticipated that the Phase study will identify novel MR contrast agents that will provide a powerful platform for imaging of atherosclerosis. The Phase I data will be used to improve this technology in a Phase II program. Importantly, not only imaging but also therapeutic agents can be incorporated into the proposed platform. Thus, successful completion of Phase I will provide the proof of concept for the development of new multifunctional nanoformulations for targeted delivery of diagnostics and therapeutics. PUBLIC HEALTH RELEVANCE: Atherosclerosis is the major cause of cardiovascular disease, the number one leading cause of death worldwide. The proposed research will result in the development of novel imaging techniques that could substantially improve early diagnosis and treatment of atherosclerosis, allowing for diagnosis before symptoms occur, identification of those individuals with higher risk, and for monitoring response to treatment.
