title: Liposomal Treatment of Experimental Arthritis Can Be Monitored Noninvasively with a Radiolabeled Anti-Fibroblast Activation Protein Antibody.
abstract: Rheumatoid arthritis is a chronic autoimmune disorder resulting in synovial inflammation. Fibroblast activation protein (FAP) is overexpressed by fibroblastlike synoviocytes in arthritic joints. Radioimmunoimaging with an anti-FAP antibody might be used to monitor the response to therapy, thus enabling tailored therapy strategies and therapeutic outcomes. The aim of this study was to assess whether a radiolabeled anti-FAP antibody could be used to monitor the efficacy of treatment with long-circulating liposomes (LCL) containing prednisolone phosphate (PLP-LCL) in a mouse model of arthritis.
  
  
  METHODS
  Collagen-induced arthritis (CIA) was induced in male DBA/1J mice. Mice were treated with a single injection (10 mg/kg) of PLP-LCL or empty LCL as a control. SPECT and CT images were acquired 24 h after injection of99mTc-labeled succinimidyl-hydrazinonicotinamide (99mTc-S-HYNIC)-conjugated anti-FAP antibody 28H1 at 2, 5, and 9 d after treatment. The uptake of99mTc-S-HYNIC-28H1 in all joints was quantified and correlated with macroscopic arthritis scores.
  
  
  RESULTS
  Treatment of CIA with PLP-LCL significantly suppressed joint swelling. At just 1 d after treatment, the macroscopic arthritis scores had decreased by 50%. Scores decreased further, to only 10% of the initial scores, at 5 and 9 d after treatment. In contrast, macroscopic arthritis scores had increased up to 600% in untreated mice at 9 d after the injection of empty LCL.99mTc-S-HYNIC-28H1 uptake ranged from 1.5 percentage injected dose per gram in noninflamed joints to 22.6 percentage injected dose per gram in severely inflamed joints. The uptake of radiolabeled 28H1 in inflamed joints (percentage injected dose) correlated with the arthritis score (Spearman ρ, 0.77; P < 0.0001). Moreover, the uptake of99mTc-S-HYNIC-28H1 was slightly increased at 9 d after therapy but was not seen macroscopically, indicating that SPECT/CT imaging might be more sensitive than the macroscopic arthritis scoring method.
  
  
  CONCLUSIONS
  SPECT/CT imaging with99mTc-S-HYNIC-28H1 specifically monitored the response to therapy, and tracer accumulation correlated with the severity of inflammation. In addition, SPECT/CT imaging was potentially more sensitive than the macroscopic arthritis scoring method. This study showed that SPECT/CT with99mTc-S-HYNIC-28H1 could be used to noninvasively monitor the course of CIA in mice.
authors: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands Tessa.vanderGeest@radboudumc.nl.
authors: Tessa
authors: T
authors: van der Geest
authors: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Peter
authors: P
authors: Laverman
authors: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Danny
authors: D
authors: Gerrits
authors: Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Birgitte
authors: B
authors: Walgreen
authors: Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Monique M
authors: MM
authors: Helsen
authors: Roche Pharmaceutical Research and Early Development, Innovation Center Zurich, Schlieren, Switzerland.
authors: Christian
authors: C
authors: Klein
authors: Roche Pharmaceutical Research and Early Development, Innovation Center Basel, Basel, Switzerland.
authors: Tapan K
authors: TK
authors: Nayak
authors: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.|Department of Targeted Therapeutics, MIRA Institute, University of Twente, Zuidhorst, The Netherlands; and.
authors: Gert
authors: G
authors: Storm
authors: Department of Targeted Therapeutics, MIRA Institute, University of Twente, Zuidhorst, The Netherlands; and.|Department of Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.
authors: Josbert M
authors: JM
authors: Metselaar
authors: Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Marije I
authors: MI
authors: Koenders
authors: Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Otto C
authors: OC
authors: Boerman
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging* / Q000188:drug therapy* / Q000276:immunology; D003692:Delayed-Action Preparations / Q000008:administration & dosage; D016903:Drug Monitoring / Q000379:methods*; D010450:Endopeptidases; D018093:Gelatinases / Q000276:immunology*; D005938:Glucocorticoids / Q000008:administration & dosage; D007553:Isotope Labeling / Q000379:methods; D008081:Liposomes / Q000008:administration & dosage; D008297:Male; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008811:Mice, Inbred DBA; D057054:Molecular Imaging / Q000379:methods; D011239:Prednisolone / Q000008:administration & dosage / Q000031:analogs & derivatives; D019275:Radiopharmaceuticals / Q000276:immunology; D012697:Serine Endopeptidases / Q000276:immunology*; D000072098:Single Photon Emission Computed Tomography Computed Tomography / Q000379:methods*; D013667:Technetium / Q000276:immunology; D016896:Treatment Outcome; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D000911:Antibodies, Monoclonal; D003692:Delayed-Action Preparations; D010450:Endopeptidases; D018093:Gelatinases; D005938:Glucocorticoids; D008081:Liposomes; D008565:Membrane Proteins; D011239:Prednisolone; D019275:Radiopharmaceuticals; D012697:Serine Endopeptidases; D013667:Technetium; D000099167:Fibroblast Activation Protein Alpha; C009022:prednisolone phosphate
keywords: SPECT/CT imaging; collagen-induced arthritis; fibroblast activation protein; prednisolone phosphate–encapsulating PEG liposomes; therapy monitoring