TY - JOUR
T1 - Immune cell screening of a nanoparticle library improves atherosclerosis therapy
AU - Tang, Jun
AU - Baxter, Samantha
AU - Menon, Arjun
AU - Alaarg, Amr
AU - Sanchez-Gaytan, Brenda L.
AU - Fay, Francois
AU - Zhao, Yiming
AU - Ouimet, Mireille
AU - Braza, Mounia S.
AU - Longo, Valerie A.
AU - Abdel-Atti, Dalya
AU - Duivenvoorden, Raphael
AU - Calcagno, Claudia
AU - Storm, Gert
AU - Tsimikas, Sotirios
AU - Moore, Kathryn J.
AU - Swirski, Filip K.
AU - Nahrendorf, Matthias
AU - Fisher, Edward A.
AU - Pérez-Medina, Carlos
AU - Fayad, Zahi A.
AU - Reiner, Thomas
AU - Mulder, Willem J. M.
PY - 2016
Y1 - 2016
N2 - 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
AB - 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
U2 - https://doi.org/10.1073/pnas.1609629113
DO - https://doi.org/10.1073/pnas.1609629113
M3 - Article
C2 - 27791119
SN - 0027-8424
VL - 113
SP - E6731-E6740
JO - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
JF - PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
IS - 44
ER -