One-pot synthesis of carboxymethyl-dextran coated iron oxide nanoparticles (CION) for preclinical fMRI and MRA applications
Manasmita Das,
Esteban A. Oyarzabal,
Lars Chen,
Sung-Ho Lee,
Neal Shah,
Gabby Gerlach,
Weiting Zhang,
Tzu-Hao Harry Chao,
Nathalie Van Den Berge,
Carolyn Liu,
Carrie Donley,
Stephanie A. Montgomery,
Yen-Yu Ian Shih
Affiliations
Manasmita Das
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA; Corresponding authors at: Center for Animal MRI, 125 Mason Farm Road, CB# 7513, University of North Carolina, Chapel Hill, NC 27599, USA.
Esteban A. Oyarzabal
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA; Curriculum in Neurobiology, University of North Carolina, Chapel Hill, NC, USA
Lars Chen
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA
Sung-Ho Lee
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA
Neal Shah
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA
Gabby Gerlach
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA
Weiting Zhang
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA
Tzu-Hao Harry Chao
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA
Nathalie Van Den Berge
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA; Medical Image and Signal Processing Group, Ghent University, Ghent, Belgium
Carolyn Liu
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA
Carrie Donley
Center for Nanotechnology in Drug Delivery, University of North Carolina, Chapel Hill, NC, USA
Stephanie A. Montgomery
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
Yen-Yu Ian Shih
Center for Animal MRI, University of North Carolina, Center for Animal MRI, 125 Mason Farm Road, CB# 7513, Chapel Hill, NC 27599, USA; Biomedical Research Imaging Center, University of North Carolina, Chapel Hill, NC, USA; Department of Neurology, University of North Carolina, Chapel Hill, NC, USA; Corresponding authors at: Center for Animal MRI, 125 Mason Farm Road, CB# 7513, University of North Carolina, Chapel Hill, NC 27599, USA.
Superparamagnetic iron-oxide nanoparticles are robust contrast agents for magnetic resonance imaging (MRI) used for sensitive structural and functional mapping of the cerebral blood volume (CBV) when administered intravenously. To date, many CBV-MRI studies are conducted with Feraheme, manufactured for the clinical treatment of iron-deficiency. Unfortunately, Feraheme is currently not available outside the United States due to commercial and regulatory constraints, making CBV-MRI methods either inaccessible or very costly to achieve. To address this barrier, we developed a simple, one-pot recipe to synthesize Carboxymethyl-dextran coated Iron Oxide Nanoparticles, namely, “CION”, suitable for preclinical CBV-MRI applications. Here we disseminate a step-by-step instruction of our one-pot synthesis protocol, which allows CION to be produced in laboratories with minimal cost. We also characterized different CION-conjugations by manipulating polymer to metal stoichiometric ratio in terms of their size, surface chemistry, and chemical composition, and shifts in MR relaxivity and pharmacokinetics. We performed several proof-of-concept experiments in vivo, demonstrating the utility of CION for functional and structural MRI applications, including hypercapnic CO2 challenge, visual stimulation, targeted optogenetic stimulation, and microangiography. We also present evidence that CION can serve as a cross-modality research platform by showing concurrent in vivo optical and MRI measurement of CBV using fluorescent-labeled CION. The simplicity and cost-effectiveness of our one-pot synthesis method should allow researchers to reproduce CION and tailor the relaxivity and pharmacokinetics according to their imaging needs. It is our hope that this work makes CBV-MRI more openly available and affordable for a variety of research applications.
