Liposomal prednisolone promotes macrophage lipotoxicity in experimental atherosclerosis

Fleur M. van der Valk, Dominik M. Schulte, Svenja Meiler, Jun Tang, Kang He Zheng, Jan van den Bossche, Tom Seijkens, Matthias Laudes, Menno de Winther, Esther Lutgens, Amr Alaarg, Josbert M. Metselaar, Geesje M. Dallinga-Thie, Willem J. M. Mulder, Erik S. G. Stroes, Anouk A. J. Hamers

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Atherosclerosis is a lipid-driven inflammatory disease, for which nanomedicinal interventions are under evaluation. Previously, we showed that liposomal nanoparticles loaded with prednisolone (LN-PLP) accumulated in plaque macrophages, however, induced proatherogenic effects in patients. Here, we confirmed in low-density lipoprotein receptor knockout (LDLr -/-) mice that LN-PLP accumulates in plaque macrophages. Next, we found that LN-PLP infusions at 10 mg/kg for 2 weeks enhanced monocyte recruitment to plaques. In follow up, after 6 weeks of LN-PLP exposure we observed (i) increased macrophage content, (ii) more advanced plaque stages, and (iii) larger necrotic core sizes. Finally, in vitro studies showed that macrophages become lipotoxic after LN-PLP exposure, exemplified by enhanced lipid loading, ER stress and apoptosis. These findings indicate that liposomal prednisolone may paradoxically accelerate atherosclerosis by promoting macrophage lipotoxicity. Hence, future (nanomedicinal) drug development studies are challenged by the multifactorial nature of atherosclerotic inflammation.
Original languageEnglish
Pages (from-to)1463-1470
Number of pages8
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume12
Issue number6
DOIs
Publication statusPublished - 2016
Externally publishedYes

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