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MRI-Monitored Transcatheter Intra-Arterial Delivery of SPIO-Labeled Natural Killer Cells to Hepatocellular Carcinoma: Preclinical Studies in a Rodent Model

Sheu, Alexander Y. BS*; Zhang, Zhuoli MD, PhD*; Omary, Reed A. MD, MS*†; Larson, Andrew C. PhD*†

doi: 10.1097/RLI.0b013e31827994e5
Original Articles

Objectives The objective of this study was to test the hypotheses that intra-arterial infusion allows for targeted natural killer (NK) lymphocyte delivery to hepatocellular carcinoma (HCC) and that iron oxide labeling allows for quantitative visualization of intra-arterial NK delivery with magnetic resonance imaging (MRI).

Materials and Methods Experiments received approval from the institutional animal care and use committee. NK-92MI cells were labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Cell viability, labeling efficacy, and cell phantom imaging studies were performed. Eighteen rats were each implanted with HCC tumors. Catheter was placed in proper hepatic artery for either NK lymphocyte (12 rats) or saline (6 rats) infusion. For the 6 rats, MRI T2* measurements for tumor and normal liver were compared before and after the NK infusion and correlated with histologic measurements. Prussian blue staining was used for labeled NK identification. The remaining rats survived for 8 days after the infusion to compare tumor size changes in the rats that received NK cell (6 rats) or saline (6 rats) infusions. Spearman correlation coefficients and t tests were calculated for statistical analyses.

Results Increasing SPIO incubation concentration decreased cell viability. Labeling efficacy mean (SD) was 88.0% (3.1%) across samples. The spatial extent of T2*-weighted contrast and R2* relaxivity values increased for cell phantom samples incubated with increasing SPIO concentrations. T2* measurements decreased in the tumor and normal liver tissues after the NK infusion (P < 0.001); ΔT2* was greater in the tumors than in the normal liver tissue (P < 0.001). Histologic measurements demonstrated increased NK delivery to the tumor compared with the normal liver (P < 0.001). ΔT2* was well correlated with histologic NK measurements (ρ = 0.70). Changes in tumor diameter 8 days after the infusion were significantly different between those rats that received NK cell infusions (−2.49 [0.86] mm) and those that received sham saline infusion (5.23 [0.66] mm).

Conclusions Intra-arterial infusion permitted selective delivery of NK cells to HCC. Transcatheter delivery of SPIO-labeled NK cells can be quantitatively visualized with MRI. Transcatheter NK cell delivery limited tumor size progression compared with controls.

From the *Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago; and †Department of Biomedical Engineering, Northwestern University McCormick School of Engineering and Applied Science, Evanston, IL.

Received for publication July 6, 2012; and accepted for publication, after revision October 15, 2012.

Conflict of interest and sources of funding: Alexander Sheu is a Howard Hughes Medical Institute medical research fellow.

Supported by the Northwestern University Mouse Histology and Phenotyping Laboratory.

Magnetic resonance imaging was performed at the Northwestern University Center for Translational Imaging.

Microscopy work was performed at the Northwestern University Cell Imaging Facility generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.

Reprints: Andrew C. Larson, PhD, Department of Radiology, Northwestern University Feinberg School of Medicine, 737 N Michigan Ave, Ste 1600, Chicago, IL 60611. E-mail:

© 2013 by Lippincott Williams & Wilkins