title: [(18)]F FDG PET/CT imaging to monitor the therapeutic effect of liposome-encapsulated prednisolone in experimental rheumatoid arthritis.
abstract: Current treatment of rheumatoid arthritis includes systemic administration of glucocorticoids. To improve joint targeting and anti-inflammatory efficacy these glucocorticoids are encapsulated in long-circulating liposomes. The present study aimed to monitor therapeutic effects of prednisolone (PLP)-containing PEG-liposomes in murine antigen-induced arthritis (AIA) using [(18)F]FDG PET/CT. Mono-articular arthritis was induced in male C57Bl6/J mice. At 0, 3, 7 and 12 days after arthritis induction, inflamed joints were macroscopically scored (0 = unaffected to 4 = immobile) and [(18)F]FDG PET/CT images were acquired. In a second experiment, to study the feasibility to monitor therapeutic effects of PLP encapsulating PEG-liposomes, mice were treated with a single i.v. injection of PLP-containing PEG-liposomes (10 mg/kg) or empty PEG-liposomes 3 days after arthritis induction. Inflamed joints were macroscopically scored and images were acquired at -3, 0, 4 and 9 days after treatment. PET images were analyzed quantitatively, and mice were dissected to allow histological analysis of the joints. With progression of arthritis, [(18)F]FDG uptake in inflamed joints increased significantly (day 0: 2.5 ± 0.9%ID/ml, day 7: 4.4 ± 0.4%ID/ml, p = 0.0159), while no changes were observed in unaffected paws (day 0: 2.5 ± 1.1%ID/ml, day 7: 2.7 ± 0.8%ID/ml, p = 0.3466). In the second experiment, macroscopic scoring revealed suppression of joint swelling after treatment with PLP-containing PEG-liposomes. In line with that, [(18)F]FDG uptake did not change in the treated mice (day -3: 1.9 ± 0.3%ID/ml, day 4: 2.2 ± 0.2%ID/ml, p = 0.3466), while it increased in mice that developed arthritis (day -3: 2.0 ± 0.2%ID/ml, day 4: 3.1 ± 0.6%ID/ml, p = 0.0225). Histological analysis confirmed therapeutic efficacy, which showed less inflammation (p = 0.0354) and bone erosion (p = 0.0298) in treated mice. These data show that [(18)F]FDG PET/CT could be used to monitor the progression of AIA and confirmed rapid and profound anti-inflammatory effects of PLP-containing PEG-liposomes that were also observed macroscopically and microscopically.
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein zuid 10, 6525 GA Nijmegen, The Netherlands. Electronic address: Tessa.vanderGeest@radboudumc.nl.
authors.forename: Tessa
authors.initials: T
authors.lastname: van der Geest
authors.affiliation: Department of Targeted Therapeutics, MIRA Institute, University of Twente, Zuidhorst, 7500 AE Enschede, The Netherlands; Department of Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH-Aachen University, Pauwelstrasse 30, 52074 Aachen, Germany. Electronic address: j.m.metselaar@utwente.nl.
authors.forename: Josbert M
authors.initials: JM
authors.lastname: Metselaar
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein zuid 10, 6525 GA Nijmegen, The Netherlands. Electronic address: Danny.Gerrits@radboudumc.nl.
authors.forename: Danny
authors.initials: D
authors.lastname: Gerrits
authors.affiliation: Department of Experimental Rheumatology, Radboud university medical center, Geert Grooteplein 28, 6525 GA Nijmegen, The Netherlands. Electronic address: Peter.vanLent@radboudumc.nl.
authors.forename: Peter L
authors.initials: PL
authors.lastname: van Lent
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands. Electronic address: g.storm@uu.nl.
authors.forename: Gert
authors.initials: G
authors.lastname: Storm
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein zuid 10, 6525 GA Nijmegen, The Netherlands. Electronic address: Peter.Laverman@radboudumc.nl.
authors.forename: Peter
authors.initials: P
authors.lastname: Laverman
authors.affiliation: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein zuid 10, 6525 GA Nijmegen, The Netherlands. Electronic address: Otto.Boerman@radboudumc.nl.
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001886:Bordetella pertussis; D018450:Disease Progression; D019788:Fluorodeoxyglucose F18 / Q000008:administration & dosage / Q000493:pharmacokinetics; D005620:Freund's Adjuvant; D007719:Knee Joint / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008081:Liposomes; D008297:Male; D008810:Mice, Inbred C57BL; D049268:Positron-Emission Tomography; D011239:Prednisolone / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics; D014057:Tomography, X-Ray Computed
chemical_list: D000276:Adjuvants, Immunologic; D000893:Anti-Inflammatory Agents; D008081:Liposomes; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D005620:Freund's Adjuvant; D011239:Prednisolone
keywords: 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] (CID 406952); Antigen-induced arthritis; Cholesterol (PubChem CID: 5997); Dipalmitoylphosphatidylcholine (PubChem CID: 452110); Fluorodeoxy glucose (PubChem CID: 450503); Glucocoticoids; Liposomes; PET/CT; Prednisolone Phosphate (PubChem CID:5736945); Therapy monitoring; [(18)F]FDG