Amr Alaarg1, Kang He Zheng2, Fleur M van der Valk3, Acarilia Eduardo da Silva4, Miranda Versloot5, Linda C Quarles van Ufford6, Dominik M Schulte7, Gert Storm8, Josbert M Metselaar9, Erik S G Stroes10, Anouk A J Hamers11. 1. 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. 2. Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: k.h.zheng@amc.nl. 3. Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: f.m.valkvander@amc.nl. 4. Department of Biomaterials Science and Technology, Targeted Therapeutics section, MIRA Institute, University of Twente, Enschede, The Netherlands. Electronic address: acariliasilva@gmail.com. 5. Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: m.versloot@amc.nl. 6. Medicinal Chemistry & Chemical Biology - Biomolecular Analysis, Department of Pharmaceutical Sciences, Utrecht University, The Netherlands. Electronic address: h.c.quarlesvanufford@uu.nl. 7. 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. 8. 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. 9. 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. 10. Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: e.s.stroes@amc.nl. 11. Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: a.a.hamers@amc.nl.
Abstract
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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.
BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSION: 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: Iwona Cicha; Cédric Chauvierre; Isabelle Texier; Claudia Cabella; Josbert M Metselaar; János Szebeni; László Dézsi; Christoph Alexiou; François Rouzet; Gert Storm; Erik Stroes; Donald Bruce; Neil MacRitchie; Pasquale Maffia; Didier Letourneur Journal: Cardiovasc Res Date: 2018-11-01 Impact factor: 10.787
Authors: Nicholas Don-Doncow; Lotte Vanherle; Frank Matthes; Sine Kragh Petersen; Hana Matuskova; Sara Rattik; Anetta Härtlova; Anja Meissner Journal: NPJ Aging Mech Dis Date: 2021-08-04