Atherosclerosis and its major clinical manifestation, coronary artery disease (CAD), is the leading cause of death in the western world. Preventive strategies currently focus on controlling risk factors and lipid levels. Substantial residual risk remains high, even when treatment goals are fully met. In humans, monocytes that infiltrate the plaque differentiate into inflammatory macrophages produce proteolytic enzymes that digest extracellular matrix causing plaque rupture. Plaque inflammation is therefore pursued as a therapeutic target to lower the recurrent rates of atherothrombotic events. Nanomedicine offers exciting new possibilities for the treatment of a variety of pathologies by improving the pharmacokinetics and biodistribution of therapeutic agents, while simultaneously decreasing adverse effects and undesired interactions. In the field of atherosclerosis, nanomedicine is still in its infancy, but is expected to provide potentially revolutionary advances in treatment for the most challenging aspects of cardiovascular diseases. Since nanomedicine remains relatively unexplored for atherosclerosis, novel-imaging strategies that allow characterizing this disease, but also allow the quantitative visualization of nanoparticle targeting and efficacy need to be developed. In this project, we propose to develop and utilize PET/MRI technology for the imaging-based evaluation of nanotherapy for the treatment of atherosclerotic plaque inflammation. To that aim, in collaboration with radiochemists at Memorial Sloan Kettering Cancer Center, we have developed 89Zr radioisotope labeling methods for liposomal nanoparticles (LNPs) and high-density lipoprotein (HDL). We will evaluate the nanoreporter technology in a rabbit model of atherosclerosis. Extensive ex vivo imaging and histological techniques will be applied to evaluate the in vivo findings and to unravel the mechanism of action.
The specific aims are:
Aim 1 : To establish the biodistribution and plaque targeting of liposomal nanoparticles of which only a small fraction is labeled with 89Zr. To quantitatively evaluate plaque macrophage targeting and biodistribution of 89Zr-labeled HDL. : To theranostically evaluate the efficacy Aim 2 Aim 3 of 89Zr-labeled and drug-loaded LNPs in atherosclerotic rabbits by PET/MRI. Translation to the clinic is facilitated by the fact that the individual components of all the proposed nanoparticle formulations and the labeling methods are FDA approved. Finally, using nanoparticle formulations to rapidly inhibit vessel wall inflammation and develop imaging technology to monitor their efficacy may have a profound impact on the management of cardiovascular diseases.

Public Health Relevance

In this project, we propose to develop novel radioisotope nanoreporter technology, which will be employed for PET/MR imaging-based evaluation of nanotherapy for the treatment of atherosclerotic plaque inflammation in a rabbit model. We expect our approach to have a broad and profound impact on the management of atherosclerotic disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125703-04
Application #
9391708
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Danthi, Narasimhan
Project Start
2014-11-14
Project End
2018-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
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
Zupan?i?, Eva; Fayad, Zahi A; Mulder, Willem J M (2017) Cardiovascular Immunotherapy and the Role of Imaging. Arterioscler Thromb Vasc Biol 37:e167-e171
Zhao, Yiming; Shaffer, Travis M; Das, Sudeep et al. (2017) Near-Infrared Quantum Dot and 89Zr Dual-Labeled Nanoparticles for in Vivo Cerenkov Imaging. Bioconjug Chem 28:600-608
Keliher, Edmund J; Ye, Yu-Xiang; Wojtkiewicz, Gregory R et al. (2017) Polyglucose nanoparticles with renal elimination and macrophage avidity facilitate PET imaging in ischaemic heart disease. Nat Commun 8:14064
Tang, Jun; Pérez-Medina, Carlos; Zhao, Yiming et al. (2017) A Comprehensive Procedure to Evaluate the In Vivo Performance of Cancer Nanomedicines. J Vis Exp :
Alaarg, Amr; Pérez-Medina, Carlos; Metselaar, Josbert M et al. (2017) Applying nanomedicine in maladaptive inflammation and angiogenesis. Adv Drug Deliv Rev 119:143-158
Beldman, Thijs J; Senders, Max L; Alaarg, Amr et al. (2017) Hyaluronan Nanoparticles Selectively Target Plaque-Associated Macrophages and Improve Plaque Stability in Atherosclerosis. ACS Nano 11:5785-5799
Sanchez-Gaytan, Brenda L; Fay, François; Hak, Sjoerd et al. (2017) Real-Time Monitoring of Nanoparticle Formation by FRET Imaging. Angew Chem Int Ed Engl 56:2923-2926
Kossatz, Susanne; Carney, Brandon; Schweitzer, Melanie et al. (2017) Biomarker-Based PET Imaging of Diffuse Intrinsic Pontine Glioma in Mouse Models. Cancer Res 77:2112-2123
Fay, Francois; Hansen, Line; Hectors, Stefanie J C G et al. (2017) Investigating the Cellular Specificity in Tumors of a Surface-Converting Nanoparticle by Multimodal Imaging. Bioconjug Chem 28:1413-1421
Pérez-Medina, Carlos; Abdel-Atti, Dalya; Tang, Jun et al. (2016) Nanoreporter PET predicts the efficacy of anti-cancer nanotherapy. Nat Commun 7:11838

Showing the most recent 10 out of 23 publications