Magnetic Resonance Imaging Tracking of Ferumoxytol‐Labeled Human Neural Stem Cells: Studies Leading to Clinical Use

• Published in: Stem cells translational medicine Vol. 2; no. 10; pp. 766 - 775
• Main Authors: Gutova, Margarita, Frank, Joseph A., D'Apuzzo, Massimo, Khankaldyyan, Vazgen, Gilchrist, Megan M., Annala, Alexander J., Metz, Marianne Z., Abramyants, Yelena, Herrmann, Kelsey A., Ghoda, Lucy Y., Najbauer, Joseph, Brown, Christine E., Blanchard, M. Suzette, Lesniak, Maciej S., Kim, Seung U., Barish, Michael E., Aboody, Karen S., Moats, Rex A.
• Format: Journal Article
• Language: English
• Published: United States AlphaMed Press 01.10.2013; Oxford University Press
• Subjects: Animals; Brain cancer; Brain tumors; Cell adhesion & migration; Cell Tracking - methods; Cell transplantation; Cell viability; Cellular therapy; Clinical trials; Contrast agents; Data analysis; Enabling Technologies for Cell-Based Clinical Translation; Enzymes; FDA approval; Ferrosoferric Oxide; Histopathology; Humans; Immunohistochemistry; In vivo tracking; Iron; Laboratories; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Mice; Nanoparticles; Neural stem cell; Neural stem cells; Neural Stem Cells - transplantation; Neuroimaging; NMR; Nuclear magnetic resonance; Pharmaceuticals; Staining and Labeling - methods; Statistical analysis; Stem cell; Stem cell transplantation; Stem Cell Transplantation - methods; Stem cells; Stockholders; Studies; Tropism; In vivo tracking; Stem cell; Cellular therapy; Neural stem cell; Clinical trials; Stem cell transplantation; Cell transplantation
• DOI: 10.5966/sctm.2013-0049
• ISSN: 2157-6564

These preclinical studies of ferumoxytol‐labeled neural stem cells (NSCs) for magnetic resonance imaging (MRI) cell tracking led to U.S. FDA approval for first‐in‐human use of this labeling method for NSCs transplanted into brain tumor patients. Ferumoxytol labeling of NSCs did not affect cell viability, growth kinetics, or tumor tropism, and enabled MRI visualization of NSC distribution in vivo. These studies support the clinical development of ferumoxytol labeling of cells for post‐transplant MRI visualization and tracking. Numerous stem cell‐based therapies are currently under clinical investigation, including the use of neural stem cells (NSCs) as delivery vehicles to target therapeutic agents to invasive brain tumors. The ability to monitor the time course, migration, and distribution of stem cells following transplantation into patients would provide critical information for optimizing treatment regimens. No effective cell‐tracking methodology has yet garnered clinical acceptance. A highly promising noninvasive method for monitoring NSCs and potentially other cell types in vivo involves preloading them with ultrasmall superparamagnetic iron oxide nanoparticles (USPIOs) to enable cell tracking using magnetic resonance imaging (MRI). We report here the preclinical studies that led to U.S. Food and Drug Administration approval for first‐in‐human investigational use of ferumoxytol to label NSCs prior to transplantation into brain tumor patients, followed by surveillance serial MRI. A combination of heparin, protamine sulfate, and ferumoxytol (HPF) was used to label the NSCs. HPF labeling did not affect cell viability, growth kinetics, or tumor tropism in vitro, and it enabled MRI visualization of NSC distribution within orthotopic glioma xenografts. MRI revealed dynamic in vivo NSC distribution at multiple time points following intracerebral or intravenous injection into glioma‐bearing mice that correlated with histological analysis. Preclinical safety/toxicity studies of intracerebrally administered HPF‐labeled NSCs in mice were also performed, and they showed no significant clinical or behavioral changes, no neuronal or systemic toxicities, and no abnormal accumulation of iron in the liver or spleen. These studies support the clinical use of ferumoxytol labeling of cells for post‐transplant MRI visualization and tracking.