期刊
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
卷 12, 期 6, 页码 1463-1470出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.nano.2016.02.022
关键词
Atherosclerosis; Macrophages; Lipotoxicity; Prednisolone; Liposomal nanoparticles
资金
- European Framework Program 7 grant (ESS) (Nano-Athero) [FP7-Health 309820]
- International Endocrine Scholars Program (IESP) by European Society of Endocrinology (ESE)
- Endocrine Society (ENDO)
- 3E: Exchange in Endocrinology Expertise program by the European Union of Medical Specialists
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. (C) 2016 Elsevier Inc. All rights reserved.
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