Orthotopic pleural mesothelioma in mice: SPECT/CT and MR imaging with HER1- and HER2-targeted radiolabeled antibodies

Abstract

Purpose: To evaluate the potential of anti-human epidermal growth factor receptor (HER)1- and anti-HER2-targeted radiolabeled antibodies and magnetic resonance (MR) imaging for imaging of orthotopic malignant pleural mesothelioma (MPM) in mouse models.

Materials and methods: Animal studies with 165 mice were performed in accordance with National Institutes of Health guidelines for the humane use of animals, and all procedures were approved by the institutional Animal Care and Use Committee. Flow cytometry studies were performed to evaluate HER1 and HER2 expression in NCI-H226 and MSTO-211H mesothelioma cells. Biodistribution and single photon emission computed tomography (SPECT)/computed tomography (CT) imaging studies were performed in mice (four or five per group, depending on tumor growth) bearing subcutaneous and orthotopic MPM tumors by using HER1- and HER2-targeted indium 111 ((111)In)- and iodine 125 ((125)I)-labeled panitumumab and trastuzumab, respectively. Longitudinal MR imaging over 5 weeks was performed in three mice bearing orthotopic tumors to monitor tumor growth and metastases. SPECT/CT/MR imaging studies were performed at the final time point in the orthotopic models (n = 3). The standard unpaired Student t test was used to compare groups.

Results: Orthotopic tumors and pleural effusions were clearly visualized at MR imaging 3 weeks after tumor cell inoculation. At 2 days after injection, the mean (111)In-panitumumab uptake of 29.6% injected dose (ID) per gram ± 2.2 (standard error of the mean) was significantly greater than the (111)In-trastuzumab uptake of 13.6% ID/g ± 1.0 and the (125)I-panitumumab uptake of 7.4% ID/g ± 1.2 (P = .0006 and P = .0001, respectively). MR imaging fusion with SPECT/CT provided more accurate information about (111)In-panitumumab localization in the tumor, as the tumor was poorly visualized at CT alone.

Conclusion: This study demonstrates the utility of radiolabeled anti-HER1 antibodies in the imaging of MPM in preclinical models.

Supplemental material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.12121021/-/DC1.

Figure 1:

A, B, Bar graphs show biodistribution of ¹¹¹In-CHX-A″-DTPA–panitumumab in selected organs of female athymic (NCr) nu/nu mice bearing, A, human MSTO-211H and, B, NCI-H226 subcutaneous tumor xenografts. C, D, Bar graphs show biodistribution of ¹¹¹In-CHX-A″-DTPA–trastuzumab in selected organs of female athymic (NCr) nu/nu mice bearing, C, human MSTO-211H and, D, NCI-H226 subcutaneous tumor xenografts. Data are means ± standard errors of the mean from at least four determinations.

Figure 2:

Representative coregistered SPECT/CT maximum intensity projections in female athymic (NCr) nu/nu mice bearing (top) NCI-H226 and (bottom) MSTO-211H subcutaneous tumor xenografts. Mice were given intravenous injections via tail vein of 2.0 MBq of ¹¹¹In-CHX-A″-DTPA–panitumumab, and images were acquired 1 day and 3 days after injection. Scale = percentage of maximum and minimum threshold intensity (80% for 1 day and 70% for 3 days).

Figure 3:

Representative coronal MR imaging sections obtained 3, 4, and 5 weeks after cell inoculation in (top) female athymic (NCr) nu/nu mouse bearing orthotopic NCI-H226 and (bottom) non–tumor-bearing mouse. Arrows = tumors.

Figure 4:

Bar graph shows biodistribution of ¹¹¹In-CHX-A″-DTPA–panitumumab in selected organs of female athymic (NCr) nu/nu mice bearing orthotopic NCI-H226 MPM. Data are means ± standard errors of the mean from at least four determinations.

Figure 5:

Top: Representative CT images in female athymic (NCr) nu/nu mouse bearing orthotopic NCI-H226 MPM. Bottom: Corresponding coregistered SPECT/CT images in same mouse injected intravenously via tail vein with 2.0 MBq of ¹¹¹In-CHX-A″-DTPA–panitumumab. Left-to-right: Maximum intensity projections, sagittal sections, coronal sections, and transverse sections. Images were acquired 2 days after the injection of radiolabeled panitumumab.

Figure 6:

Representative coronal sections in female athymic (NCr) nu/nu mouse bearing orthotopic NCI-H226 MPM injected intravenously via tail vein with 2.0 MBq of ¹¹¹In-CHX-A″-DTPA–panitumumab. Images were acquired 5 days after the injection of radiolabeled panitumumab.