title: Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration.
abstract: Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63h (LN-PLP 1.5mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis.
  
  
  BACKGROUND
  In this study, the authors undertook the first clinical trial using long-circulating liposomal nanoparticle encapsulating prednisolone in patients with atherosclerosis, based on previous animal studies. Despite little evidence of anti-inflammatory effect, the results have provided a starting point for future development of nanomedicine in cardiovascular diseases.
authors: Department of Vascular Medicine, AMC, Amsterdam, The Netherlands. Electronic address: f.m.valkvander@amc.nl.
authors: Fleur M
authors: FM
authors: van der Valk
authors: Department of Vascular Medicine, AMC, Amsterdam, The Netherlands. Electronic address: d.f.vanwijk@amc.nl.
authors: Diederik F
authors: DF
authors: van Wijk
authors: Department of Vascular Medicine, AMC, Amsterdam, The Netherlands. Electronic address: m.e.lobatto@gmail.com.
authors: Mark E
authors: ME
authors: Lobatto
authors: Department of Nuclear Medicine, AMC, Amsterdam, The Netherlands. Electronic address: h.j.verberne@amc.nl.
authors: Hein J
authors: HJ
authors: Verberne
authors: Institute for Pharmaceutical Sciences UU, Utrecht, The Netherlands; Department of Targeted Therapeutics, MIRA Institute UT, Enschede, The Netherlands. Electronic address: g.storm@uu.nl.
authors: Gert
authors: G
authors: Storm
authors: Department of Vascular Surgery, AMC, Amsterdam, The Netherlands. Electronic address: w.c.willems@amc.nl.
authors: Martine C M
authors: MC
authors: Willems
authors: Department of Vascular Surgery, AMC, Amsterdam, The Netherlands. Electronic address: d.a.legemate@amc.nl.
authors: Dink A
authors: DA
authors: Legemate
authors: Department of Radiology, AMC, Amsterdam, The Netherlands. Electronic address: a.j.nederveen@amc.nl.
authors: Aart J
authors: AJ
authors: Nederveen
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: claudia.calcagno@mssm.edu.
authors: Claudia
authors: C
authors: Calcagno
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: venkatesh.mani@mssm.edu.
authors: Venkatesh
authors: V
authors: Mani
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: sarayu.ramachandran@mssm.edu.
authors: Sarayu
authors: S
authors: Ramachandran
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: mpmparidaans@gmail.com.
authors: Maarten P M
authors: MP
authors: Paridaans
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: maartenjotten@gmail.com.
authors: Maarten J
authors: MJ
authors: Otten
authors: Department of Vascular Medicine, AMC, Amsterdam, The Netherlands. Electronic address: g.m.dallinga@amc.nl.
authors: Geesje M
authors: GM
authors: Dallinga-Thie
authors: Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: zahi.fayad@mssm.edu.
authors: Zahi A
authors: ZA
authors: Fayad
authors: Department of Vascular Medicine, AMC, Amsterdam, The Netherlands. Electronic address: m.nieuwdorp@amc.nl.
authors: Max
authors: M
authors: Nieuwdorp
authors: Department of Vascular Medicine, AMC, Amsterdam, The Netherlands; Department of Internal Medicine I, UKSH, Kiel, Germany. Electronic address: dominik.schulte@uksh.de.
authors: Dominik M
authors: DM
authors: Schulte
authors: Department of Targeted Therapeutics, MIRA Institute UT, Enschede, The Netherlands. Electronic address: bart@enceladus.nl.
authors: Josbert M
authors: JM
authors: Metselaar
authors: Department of Vascular Medicine, AMC, Amsterdam, The Netherlands; Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Electronic address: wjmmulder@gmail.com.
authors: Willem J M
authors: WJ
authors: Mulder
authors: Department of Vascular Medicine, AMC, Amsterdam, The Netherlands. Electronic address: e.s.stroes@amc.nl.
authors: Erik S
authors: ES
authors: Stroes
mesh_terms: D061605:Administration, Intravenous; D000328:Adult; D000368:Aged; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001158:Arteries / Q000187:drug effects / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005938:Glucocorticoids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D008081:Liposomes; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000473:pathology; D011239:Prednisolone / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D008081:Liposomes; D011239:Prednisolone
keywords: Atherosclerosis; Glucocorticoids; Macrophages; Nanomedicine