Atherosclerosis is an inflammatory disease of the arterial wall whose consequence is risks of myocardial infraction or stroke. It often becomes manifest at a late stage, resulting in fatal consequences and high mortality and morbidity. Therefore, there is a clinical need for improved diagnosis and treatment before the complications arise. Usually current treatment options rely on invasive procedures such as percutaneous coronary intervention, risk factor reduction, and oral statins treatment, which, although lowers circulating low density lipoprotein (LDL) levels, do not eliminate risk of an adverse cardiovascular event. Atherosclerotic plaque at risk of rupture is typically rich in macrophages of the M1 phenotype. We propose to develop sophisticated translational technology based on drug and or diagnostic material loaded (i.e., payloads) high density lipoprotein (HDL) nanoparticles, as payload carriers, for atherosclerotic plaque inflammation and diagnostic therapy of atherosclerosis. The nanoparticle formulation allows for the integration of apoA1 for targeting the inflammatory macrophages of the atherosclerotic plaques, a payload of a drug (e.g., statins) to be directly delivered to the plaque, and imaging modalities such as iron oxide (FeO) nanocrystals or paramagnetic (Gd-DTPA) lipids for non-invasive magnetic resonance imaging (MRI). The FeO and Gd-DTPA components of the nanoparticle provide the "theranostic" approach. The nanoparticles containing all components will be formed using microfluidics, a high throughput technique that swiftly allows the creation of nanoparticle libraries. In our preliminary studies we demonstrated the suitability of this method to produce HDL nanoparticles, obtaining for the first time the reconstitution of HDL nanoparticles in vitro in a single step process, the results of which have been followed with a patent application. Using this setting we can vary the nanoparticle composition with respect to coating and apoA1 content, drug loading, imaging labels, size variations, etc. and will evaluate the formulations in vitro with different monocyte and macrophage subpopulations, all aimed at selecting the most optimal candidate for in vivo testing with highest M1 macrophage targeting potential, therapeutic efficacy, and excellent imaging capabilities. The therapeutic outcomes of theranostic HDL nanoparticles will be evaluated in two clinically relevant settings: 1) acute setting treated with high dose for a short duration for plaque regression and 2) chronic settings with low dose and long treatment regimen in atherosclerosis combined with kidney disease/diabetes for the inhibition of plaque progression. Collectively, the proposed work will form basis for clinical translation of the platform. This application will build upon expertise and strong collaboration between Prof. Zahi Fayad (MSSM), a world leader in the development and use of multimodality cardiovascular imaging, Prof. Robert Langer (MIT), a pioneer in nanoparticle therapeutics development, and Prof. Edward Fisher (NYU), a widely-recognized researcher in lipoprotein metabolism and atherosclerosis.

Public Health Relevance

Atherosclerosis, the progressive process of lipid-rich plaque build-up within the artery wall, is the leading cause of cardiovascular disease and high mortality rates in the USA. In this proposal we will investigate the application of high-density lipoprotein (HDL) nanoparticles for targeted plaque therapy and imaging, by forming drug-loaded and/or diagnostically active HDL nanoparticle libraries with high throughput technology. The nanoparticles will be extensively studied and evaluated for therapeutic efficacy and non- invasive imaging applications in clinically relevant settings.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB009638-10
Application #
8702168
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Liu, Christina
Project Start
2004-09-22
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
$408,585
Indirect Cost
$116,101
Name
Icahn School of Medicine at Mount Sinai
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Mulder, Willem J M; Jaffer, Farouc A; Fayad, Zahi A et al. (2014) Imaging and nanomedicine in inflammatory atherosclerosis. Sci Transl Med 6:239sr1
Garcia-Garcia, Hector M; Jang, Ik-Kyung; Serruys, Patrick W et al. (2014) Imaging plaques to predict and better manage patients with acute coronary events. Circ Res 114:1904-17
Duivenvoorden, Raphaƫl; Tang, Jun; Cormode, David P et al. (2014) A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation. Nat Commun 5:3065
Cormode, David P; Naha, Pratap C; Fayad, Zahi A (2014) Nanoparticle contrast agents for computed tomography: a focus on micelles. Contrast Media Mol Imaging 9:37-52
Gadde, Suresh; Even-Or, Orli; Kamaly, Nazila et al. (2014) Development of therapeutic polymeric nanoparticles for the resolution of inflammation. Adv Healthc Mater 3:1448-56
Kim, Yongtae; Lobatto, Mark E; Kawahara, Tomohiro et al. (2014) Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis. Proc Natl Acad Sci U S A 111:1078-83
Allijn, Iris E; Leong, Wei; Tang, Jun et al. (2013) Gold nanocrystal labeling allows low-density lipoprotein imaging from the subcellular to macroscopic level. ACS Nano 7:9761-70
Fay, Francois; Sanchez-Gaytan, Brenda L; Cormode, David P et al. (2013) Nanocrystal Core Lipoprotein Biomimetics for Imaging of Lipoproteins and Associated Diseases. Curr Cardiovasc Imaging Rep 6:45-54
Gianella, Anita; Mieszawska, Aneta J; Hoeben, Freek J M et al. (2013) Synthesis and in vitro evaluation of a multifunctional and surface-switchable nanoemulsion platform. Chem Commun (Camb) 49:9392-4
Barazza, Alessandra; Blachford, Courtney; Even-Or, Orli et al. (2013) The complex fate in plasma of gadolinium incorporated into high-density lipoproteins used for magnetic imaging of atherosclerotic plaques. Bioconjug Chem 24:1039-48

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