Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part II. In Vivo Imaging of Bone Marrow Stromal Cells in Swine with PET/CT and MR Imaging

Abstract

4 The complete list of authors and affiliations is at the end of this article.q RSNA, 2016 Purpose:To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods:Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ( 18 F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results:MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R 2 = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 3 10 7 cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R 2 = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R 2 = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 3 10 8 cells. Conclusion:The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling.q RSNA, 2016

Engineering molecular imaging strategies for regenerative medicine

“…70,197 To determine the sensitivity of cell imaging in patients, we recently performed a study of MSC injection in swine hearts, followed by MRI and PET. 82 We found the detection levels in the heart, with the HSV1-tk sr39tk mutant, and 18F-FHBG, to be 2.5 × 10 8 cells. Although other studies did not perform a full, quantitative limit of detection study, reports…”

“…Furthermore, single cell MRI in mouse breast has been reported and validated by a second technique, which demonstrates the ability to optimize multiple MRI parameters, including extended acquisition times and specialized engineered coils. Using a clinical 1.5 T MRI scanner, a swine study with MSC injected in the heart demonstrated ∼1 × 10 6 SPIO‐labeled MSC, and using a 3 T MRI scanner, we recently reported at least 1.51 × 10 7 MSC SPIO‐labeled in the swine heart . Positive contrast MRI imaging approaches have been developed, and a recent study, employing manganese NP, reported serial in vivo imaging of 2.1 × 10 6 MSC in the hips of rats, using 3.0 T MRI scanner .…”

“…Importantly, this sr39tk‐FHBG combination was tested in patients in a trial of gene therapy directed toward liver cancer, and in the setting of T cell therapies expressing HSV1‐tk in patients . To determine the sensitivity of cell imaging in patients, we recently performed a study of MSC injection in swine hearts, followed by MRI and PET . We found the detection levels in the heart, with the HSV1‐tk sr39tk mutant, and 18F‐FHBG, to be ∼2.5 × 10 8 cells.…”

“…Dosing with pharmaceutical can be done based on mass of the patient (or the amount of receptor available), but because molecular targets of cell therapies are complex, it is unclear how to perform exact dosing. In a recent set of publications, we demonstrated experimentally an idea of how molecular imaging in small animals and large animals could be connected, to improve the clinical translation of cell therapies . In this case, multimodality RG, bearing eGFP (enhanced GFP), Fluc2, and hsv1 mutant (sr39tk), for fluorescence, bioluminescence, and PET RG imaging, were transduced into MSC.…”

“…In a recent set of publications, we demonstrated experimentally an idea of how molecular imaging in small animals and large animals could be connected, to improve the clinical translation of cell therapies. 82,180 In this case, multimodality RG, bearing eGFP (enhanced GFP), Fluc2, and hsv1 mutant (sr39tk), for fluorescence, bioluminescence, and PET RG imaging, were transduced into MSC. These MSCs were tested in small animal disease models and Fluc signal was associated with cell…”