title: (89)Zr-Oxine Complex PET Cell Imaging in Monitoring Cell-based Therapies.
abstract: OBJECTIVE
  To develop a clinically translatable method of cell labeling with zirconium 89 ((89)Zr) and oxine to track cells with positron emission tomography (PET) in mouse models of cell-based therapy.
  
  
  METHODS
  This study was approved by the institutional animal care committee. (89)Zr-oxine complex was synthesized in an aqueous solution. Cell labeling conditions were optimized by using EL4 mouse lymphoma cells, and labeling efficiency was examined by using dendritic cells (DCs) (n = 4), naïve (n = 3) and activated (n = 3) cytotoxic T cells (CTLs), and natural killer (NK) (n = 4), bone marrow (n = 4), and EL4 (n = 4) cells. The effect of (89)Zr labeling on cell survival, proliferation, and function were evaluated by using DCs (n = 3) and CTLs (n = 3). Labeled DCs (444-555 kBq/[5 × 10(6)] cells, n = 5) and CTLs (185 kBq/[5 × 10(6)] cells, n = 3) transferred to mice were tracked with microPET/CT. In a melanoma immunotherapy model, tumor targeting and cytotoxic function of labeled CTLs were evaluated with imaging (248.5 kBq/[7.7 × 10(6)] cells, n = 4) and by measuring the tumor size (n = 6). Two-way analysis of variance was used to compare labeling conditions, the Wilcoxon test was used to assess cell survival and proliferation, and Holm-Sidak multiple tests were used to assess tumor growth and perform biodistribution analyses.
  
  
  RESULTS
  (89)Zr-oxine complex was synthesized at a mean yield of 97.3% ± 2.8 (standard deviation). It readily labeled cells at room temperature or 4°C in phosphate-buffered saline (labeling efficiency range, 13.0%-43.9%) and was stably retained (83.5% ± 1.8 retention on day 5 in DCs). Labeling did not affect the viability of DCs and CTLs when compared with nonlabeled control mice (P > .05), nor did it affect functionality. (89)Zr-oxine complex enabled extended cell tracking for 7 days. Labeled tumor-specific CTLs accumulated in the tumor (4.6% on day 7) and induced tumor regression (P < .05 on day 7).
  
  
  CONCLUSIONS
  We have developed a (89)Zr-oxine complex cell tracking technique for use with PET that is applicable to a broad range of cell types and could be a valuable tool with which to evaluate various cell-based therapies.
authors.affiliation: From the Molecular Imaging Program, National Cancer Institute (N.S., K.O.A., P.L.C.), Imaging Probe Development Center, National Heart, Lung, and Blood Institute (H.W.), and Positron Emission Tomography Department, Warren Grant Magnuson Clinical Center (L.P.S.), U.S. National Institutes of Health, 10 Center Dr, Bethesda, MD 20892; and Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Md (G.L.G.).
authors.forename: Noriko
authors.initials: N
authors.lastname: Sato
authors.forename: Haitao
authors.initials: H
authors.lastname: Wu
authors.forename: Kingsley O
authors.initials: KO
authors.lastname: Asiedu
authors.forename: Lawrence P
authors.initials: LP
authors.lastname: Szajek
authors.forename: Gary L
authors.initials: GL
authors.lastname: Griffiths
authors.forename: Peter L
authors.initials: PL
authors.lastname: Choyke
mesh_terms: D000818:Animals; D058948:Cell Tracking / Q000379:methods*; D017690:Cell Transplantation; D002477:Cells / Q000000981:diagnostic imaging*; D007554:Isotopes; D051379:Mice; D008810:Mice, Inbred C57BL; D008991:Monitoring, Physiologic / Q000379:methods; D015125:Oxyquinoline; D049268:Positron-Emission Tomography / Q000379:methods; D015040:Zirconium
chemical_list: D007554:Isotopes; D015125:Oxyquinoline; D015040:Zirconium