Immune cell screening of a nanoparticle library improves atherosclerosis therapy

J. Tang, S. Baxter, A. Menon, Amr Muhmed Sabry Abdelhakeem Alaarg, B.L. Sanchez-Gaytan, F. Fay, Yiming Zhao, M. Quimet, M.S. Braza, V.A. Longo, D. Abdel-Atti, R. Duivenvoorden, Claudia Calcagno, Gerrit Storm, S. Tsimikas, Kathryn Moore, F.K. Swirski, M. Nahrendorf, E.A. Fisher, C. Pérez-MedinaZ.A. Fayad, T. Reiner, W.J.M. Mulder

Research output: Contribution to journalArticleAcademicpeer-review

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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.
Original languageEnglish
Pages (from-to)E6731-E6740
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number44
DOIs
Publication statusPublished - 2016

Keywords

  • METIS-320738
  • IR-103740

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