title: Immune cell screening of a nanoparticle library improves atherosclerosis therapy.
abstract: Immunological complexity in atherosclerosis warrants targeted treatment of specific inflammatory cells that aggravate the disease. With the initiation of large phase III trials investigating immunomodulatory drugs for atherosclerosis, cardiovascular disease treatment enters a new era. We here propose a radically different approach: implementing and evaluating in vivo a combinatorial library of nanoparticles with distinct physiochemical properties and differential immune cell specificities. The library's nanoparticles are based on endogenous high-density lipoprotein, which can preferentially deliver therapeutic compounds to pathological macrophages in atherosclerosis. Using the apolipoprotein E-deficient (Apoe-/-) mouse model of atherosclerosis, we quantitatively evaluated the library's immune cell specificity by combining immunological techniques and in vivo positron emission tomography imaging. Based on this screen, we formulated a liver X receptor agonist (GW3965) and abolished its liver toxicity while still preserving its therapeutic function. Screening the immune cell specificity of nanoparticles can be used to develop tailored therapies for atherosclerosis and other inflammatory diseases.
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.|Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065.
authors: Jun
authors: 0000-0002-8285-5111
authors: J
authors: Tang
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.
authors: Samantha
authors: S
authors: Baxter
authors: Division of Cardiology, Department of Medicine, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors: Arjun
authors: A
authors: Menon
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.|Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE Enschede, The Netherlands.
authors: Amr
authors: A
authors: Alaarg
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.
authors: Brenda L
authors: BL
authors: Sanchez-Gaytan
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.
authors: Francois
authors: F
authors: Fay
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.
authors: Yiming
authors: Y
authors: Zhao
authors: Division of Cardiology, Department of Medicine, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors: Mireille
authors: M
authors: Ouimet
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.
authors: Mounia S
authors: MS
authors: Braza
authors: Small-Animal Imaging Core Facility, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065.
authors: Valerie A
authors: VA
authors: Longo
authors: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065.
authors: Dalya
authors: D
authors: Abdel-Atti
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.
authors: Raphael
authors: R
authors: Duivenvoorden
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.
authors: Claudia
authors: C
authors: Calcagno
authors: Department of Biomaterials Science and Technology, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, 7500 AE Enschede, The Netherlands.|Department of Pharmaceutics, Utrecht Institute of Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands.
authors: Gert
authors: G
authors: Storm
authors: Sulpizio Cardiovascular Center, Department of Medicine, University of California, San Diego, 9434 Medical Center Drive, La Jolla, CA 92037.
authors: Sotirios
authors: S
authors: Tsimikas
authors: Division of Cardiology, Department of Medicine, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors: Kathryn J
authors: KJ
authors: Moore
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114.
authors: Filip K
authors: FK
authors: Swirski
authors: Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Simches Research Building, 185 Cambridge Street, Boston, MA 02114.
authors: Matthias
authors: M
authors: Nahrendorf
authors: Division of Cardiology, Department of Medicine, Marc and Ruti Bell Program in Vascular Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016.
authors: Edward A
authors: EA
authors: Fisher
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.
authors: Carlos
authors: C
authors: Pérez-Medina
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029.
authors: Zahi A
authors: ZA
authors: Fayad
authors: Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065.
authors: Thomas
authors: T
authors: Reiner
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, NY 10029; Willem.mulder@mssm.edu.|Department of Medical Biochemistry, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors: Willem J M
authors: WJ
authors: Mulder
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D001345:Autoradiography; D001565:Benzoates / Q000819:agonists / Q000737:chemistry; D001596:Benzylamines / Q000819:agonists / Q000737:chemistry; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007167:Immunotherapy; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057054:Molecular Imaging; D050997:Nanomedicine; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D001565:Benzoates; D001596:Benzylamines; C473027:GW 3965; D008075:Lipoproteins, HDL; D012333:RNA, Messenger
keywords: atherosclerosis; drug delivery; immunotherapy; molecular imaging; nanomedicine