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: Jun Tang, Samantha Baxter, Arjun Menon, Amr Alaarg, Brenda L Sanchez-Gaytan, Francois Fay, Yiming Zhao, Mireille Ouimet, Mounia S Braza, Valerie A Longo, Dalya Abdel-Atti, Raphael Duivenvoorden, Claudia Calcagno, Gert Storm, Sotirios Tsimikas, Kathryn J Moore, Filip K Swirski, Matthias Nahrendorf, Edward A Fisher, Carlos Pérez-Medina, Zahi A Fayad, Thomas Reiner, Willem J M Mulder
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 113 Issue 44 Pg. E6731-E6740 (11 01 2016) ISSN: 1091-6490 [Electronic] United States
• PMID: 27791119 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents
• Apolipoproteins E
• Benzoates
• Benzylamines
• GW 3965
• Lipoproteins, HDL
• RNA, Messenger

Topics

• Animals
• Anti-Inflammatory Agents
• Apolipoproteins E (deficiency)
• Atherosclerosis (drug therapy, immunology, pathology)
• Autoradiography
• Benzoates (agonists, chemistry)
• Benzylamines (agonists, chemistry)
• Disease Models, Animal
• Drug Delivery Systems (methods)
• Female
• Gene Expression Regulation (drug effects)
• Immunotherapy
• Lipoproteins, HDL (chemistry, pharmacology)
• Macrophages (drug effects, immunology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Imaging
• Nanomedicine
• Nanoparticles (chemistry, metabolism)
• Positron-Emission Tomography (methods)
• RNA, Messenger (metabolism)