Multimodal nanoagents for the detection and treatment of atherosclerosis

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DESCRIPTION (provided by applicant): A variety of novel nanomaterials have recently been developed with primary in vivo distribution to macrophages and macrophage subtypes. These materials have been used for the diagnosis of diseases where macrophages play a critical role in pathogenesis. For example, we have developed fluorescently labeled dextran-based superparamagnetic iron oxide (magnetofluorescent) nanoparticles detectable by magnetic resonance and optical imaging and have used them for macrophage targeting in lymph nodes, atherosclerosis, rheumatoid arthritis, diabetes and other diseases. Clinical trials with some of these materials are currently ongoing. Macrophages, in particular activated macrophages, are a key component of atherosclerotic vessels and can constitute up to 10-20% of the cells present within the culprit lesions. Macrophages secrete proteolytic enzymes which cause degradation of fibrous caps, promote atherothrombosis, and/or play other key roles in the progressive inflammatory cascade. We originally hypothesized that selective "silencing" of activated macrophages could lead to long lasting therapeutic effects. Thus, we have conjugated light-activatable therapeutic moieties to the nanoparticles. In one specific design we conjugated a novel, highly phototoxic chlorin (& = 0.6), and a near-infrared fluorophore (AlexaFluor 750, ex/em 749/775 nm) to the nanoparticle. When activated by laser irradiation at 650 nm, the nanoagent displays exquisite phototoxicity, with an LC50 of 14 nM. Preliminary results demonstrate superb accumulation and therapeutic efficacy of this nanoparticle in atherosclerotic lesions in apolipoprotein E knockout (ApoE-/-) mice following systemic injection and light treatment. The challenge now is to develop a clinically viable, next-generation nanoplatform and ascertain its potential utility in the detection and treatment of atherosclerotic vascular disease. Prior screens have identified polyvinyl alcohol (PVA) as a highly promising coating material, and results in nanoparticle preparations that are both biostable and biocompatible. The overall goal of the proposed research is to synthesize and fully characterize a novel theranostic (therapeutic and diagnostic) nanomaterial based upon PVA coated iron oxide nanoparticles. The in vitro and in vivo efficacy of the nanomaterial will be elucidated with respect to both the imaging and therapeutic functionalities. Within these studies, we will also explore the role of focal macrophage ablation on the stasis of the atherosclerotic lesions at the cellular level, and possible modulatory effects on circulating monocytes. The impetus for these studies is the belief that the combination of diagnostic and therapeutic functionalities within one multifunctional nanoparticle has the potential to revolutionize the prevention of coronary syndromes. PUBLIC HEALTH RELEVANCE: The overall goal of this research is to build upon our preliminary data with respect to the therapeutic efficacy of a theranostic agent in the diagnosis and treatment of atherosclerotic vasculature. In particular, we will: 1) synthesize and characterize a novel therapeutic nanoagent, 2) determine its in vivo efficacy in a murine model of atherosclerosis, and 3) investigate the local and systemic effects of focal macrophage ablation.