title: Multiple pathway assessment to predict anti-atherogenic efficacy of drugs targeting macrophages in atherosclerotic plaques.
abstract: Macrophages play a central role in atherosclerosis development and progression, hence, targeting macrophage activity is considered an attractive therapeutic. Recently, we documented nanomedicinal delivery of the anti-inflammatory compound prednisolone to atherosclerotic plaque macrophages in patients, which did however not translate into therapeutic efficacy. This unanticipated finding calls for in-depth screening of drugs intended for targeting plaque macrophages.
  
  
  
  We evaluated the effect of several candidate drugs on macrophage activity, rating overall performance with respect to changes in cytokine release, oxidative stress, lipid handling, endoplasmic reticulum (ER) stress, and proliferation of macrophages. Using this in vitro approach, we observed that the anti-inflammatory effect of prednisolone was counterbalanced by multiple adverse effects on other key pathways. Conversely, pterostilbene, T0901317 and simvastatin had an overall anti-atherogenic effect on multiple pathways, suggesting their potential for liposomal delivery.
  
  
  
  This dedicated assay setup provides a framework for high-throughput assessment. Further in vivo studies are warranted to determine the predictive value of this macrophage-based screening approach and its potential value in nanomedicinal drug development for cardiovascular patients.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands; Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Enschede, The Netherlands. Electronic address: a.m.s.a.alaarg@uu.nl.
authors.forename: Amr
authors.initials: A
authors.lastname: Alaarg
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: k.h.zheng@amc.nl.
authors.forename: Kang He
authors.initials: KH
authors.lastname: Zheng
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: f.m.valkvander@amc.nl.
authors.forename: Fleur M
authors.initials: FM
authors.lastname: van der Valk
authors.affiliation: Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Enschede, The Netherlands. Electronic address: acariliasilva@gmail.com.
authors.forename: Acarilia Eduardo
authors.initials: AE
authors.lastname: da Silva
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: m.versloot@amc.nl.
authors.forename: Miranda
authors.initials: M
authors.lastname: Versloot
authors.affiliation: Medicinal Chemistry & Chemical Biology - Biomolecular Analysis, Department of Pharmaceutical Sciences, Utrecht University, The Netherlands. Electronic address: h.c.quarlesvanufford@uu.nl.
authors.forename: Linda C Quarles
authors.initials: LC
authors.lastname: van Ufford
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine I, UKSH, 24105 Kiel, Germany. Electronic address: dominik.schulte@uksh.de.
authors.forename: Dominik M
authors.initials: DM
authors.lastname: Schulte
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, The Netherlands; Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Enschede, The Netherlands.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Enschede, The Netherlands; Department of Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH-Aachen University, Aachen, Germany. Electronic address: bart@enceladus.nl.
authors.forename: Josbert M
authors.initials: JM
authors.lastname: Metselaar
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: e.s.stroes@amc.nl.
authors.forename: Erik S G
authors.initials: ES
authors.lastname: Stroes
authors.affiliation: Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: a.a.hamers@amc.nl.
authors.forename: Anouk A J
authors.initials: AA
authors.lastname: Hamers
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D057166:High-Throughput Screening Assays; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D058226:Plaque, Atherosclerotic; D011239:Prednisolone / Q000494:pharmacology; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019821:Simvastatin / Q000494:pharmacology; D013267:Stilbenes / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014162:Transfection; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D006845:Hydrocarbons, Fluorinated; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011239:Prednisolone; D017382:Reactive Oxygen Species; D019821:Simvastatin; D013267:Stilbenes; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C107773:pterostilbene
keywords: Atherosclerosis; Drug screening; Inflammation; Macrophages; Nanomedicine