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.
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.
| Roberts, Sheryl; Andreou, Chrysafis; Choi, Crystal et al. (2018) Sonophore-enhanced nanoemulsions for optoacoustic imaging of cancer. Chem Sci 9:5646-5657 |
| Braza, Mounia S; van Leent, Mandy M T; Lameijer, Marnix et al. (2018) Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance. Immunity 49:819-828.e6 |
| Braza, Mounia S; Conde, Patricia; Garcia, Mercedes et al. (2018) Neutrophil derived CSF1 induces macrophage polarization and promotes transplantation tolerance. Am J Transplant 18:1247-1255 |
| Duivenvoorden, Raphaël; Mulder, Willem J M (2018) Imaging Tropoelastin in Atherosclerosis. Circ Cardiovasc Imaging 11:e008147 |
| Srimathveeravalli, Govindarajan; Abdel-Atti, Dalya; Pérez-Medina, Carlos et al. (2018) Reversible Electroporation-Mediated Liposomal Doxorubicin Delivery to Tumors Can Be Monitored With 89Zr-Labeled Reporter Nanoparticles. Mol Imaging 17:1536012117749726 |
| Senders, Max L; Hernot, Sophie; Carlucci, Giuseppe et al. (2018) Nanobody-Facilitated Multiparametric PET/MRI Phenotyping of Atherosclerosis. JACC Cardiovasc Imaging : |
| Teunissen, Abraham J P; Pérez-Medina, Carlos; Meijerink, Andries et al. (2018) Investigating supramolecular systems using Förster resonance energy transfer. Chem Soc Rev 47:7027-7044 |
| Senders, Max L; Que, Xuchu; Cho, Young Seok et al. (2018) PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis. J Am Coll Cardiol 71:321-335 |
| 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 |
| 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 |
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