89Zr-Oxine Complex PET Cell Imaging in Monitoring Cell-based Therapies

Purpose: To develop a clinically translatable method of cell labeling with zirconium 89 (Zr-89) and oxine to track cells with positron emission tomography (PET) in mouse models of cell-based therapy. Materials and Methods: This study was approved by the institutional animal care committee. Zr-89-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), naive (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 Zr-89 labeling on cell survival, proliferation, and function were evaluated by using DCs (n = 3) and CTLs (n = 3). Labeled DCs (444-555 kBq/[5 x 10 (6)] cells, n = 5) and CTLs (185 kBq/[5 x 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 x 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: Zr-89-oxine complex was synthesized at a mean yield of 97.3% +/- 2.8 (standard deviation). It readily labeled cells at room temperature or 4 degrees 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. Zr-89-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). Conclusion: We have developed a Zr-89-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. (C)RSNA, 2015