Non-immunogenic dextran-coated superparamagnetic iron oxide nanoparticles: a biocompatible, size-tunable contrast agent for magnetic resonance imaging

Iron oxide-based contrast agents have been in clinical use for magnetic resonance imaging (MRI) of lymph nodes, liver, intestines, and the cardiovascular system. Superparamagnetic iron oxide nanoparticles (SPIONs) have high potential as a contrast agent for MRI, but no intravenous iron oxide-containing agents are currently approved for clinical imaging. The aim of our work was to analyze the hemocompatibility and immuno-safety of a new type of dextran-coated SPIONs (SPIONdex) and to characterize these nanoparticles with ultra-high-field MRI. Key parameters related to nanoparticle hemocompatibility and immuno-safety were investigated in vitro and ex vivo. To address concerns associated with hypersensitivity reactions to injectable nanoparticulate agents, we analyzed complement activation-related pseudoallergy (CARPA) upon intravenous administration of SPIONdex in a pig model. Furthermore, the size-tunability of SPIONdex and the effects of size reduction on their biocompatibility were investigated. In vitro, SPIONdex did not induce hemolysis, complement or platelet activation, plasma coagulation, or leukocyte procoagulant activity, and had no relevant effect on endothelial cell viability or endothelial–monocytic cell interactions. Furthermore, SPIONdex did not induce CARPA even upon intravenous administration of 5 mg Fe/kg in pigs. Upon SPIONdex administration in mice, decreased liver signal intensity was observed after 15 minutes and was still detectable 24 h later. In addition, by changing synthesis parameters, a reduction in particle size <30 nm was achieved, without affecting their hemo- and biocompatibility. Our findings suggest that due to their excellent biocompatibility, safety upon intravenous administration and size-tunability, SPIONdex particles may represent a suitable candidate for a new-generation MRI contrast agent.

[1]  Jiadi Xu,et al.  Real-time MRI for precise and predictable intra-arterial stem cell delivery to the central nervous system , 2017, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[2]  A. Allen,et al.  Nonalcoholic fatty liver: optimizing pretransplant selection and posttransplant care to maximize survival , 2016, Current opinion in organ transplantation.

[3]  C. Alexiou,et al.  Nanoparticles for intravascular applications: physicochemical characterization and cytotoxicity testing. , 2016, Nanomedicine.

[4]  J. Stoker,et al.  Noninvasive Differentiation between Hepatic Steatosis and Steatohepatitis with MR Imaging Enhanced with USPIOs in Patients with Nonalcoholic Fatty Liver Disease: A Proof-of-Concept Study. , 2016, Radiology.

[5]  P. Walczak,et al.  Predicting and optimizing the territory of blood–brain barrier opening by superselective intra-arterial cerebral infusion under dynamic susceptibility contrast MRI guidance , 2016, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[6]  H. Thoeny,et al.  High signal intensity in dentate nucleus and globus pallidus on unenhanced T1‐weighted MR images in three patients with impaired renal function and vascular calcification , 2016, Contrast media & molecular imaging.

[7]  C. Alexiou,et al.  Hypericin-bearing magnetic iron oxide nanoparticles for selective drug delivery in photodynamic therapy , 2015, International journal of nanomedicine.

[8]  C. Diwoky,et al.  Positive contrast of SPIO‐labeled cells by off‐resonant reconstruction of 3D radial half‐echo bSSFP , 2014, NMR in biomedicine.

[9]  Janos Szebeni,et al.  Complement activation-related pseudoallergy: a stress reaction in blood triggered by nanomedicines and biologicals. , 2014, Molecular immunology.

[10]  M. Mahmoudi,et al.  Superparamagnetic iron oxide nanoparticles for delivery of therapeutic agents: opportunities and challenges , 2014, Expert opinion on drug delivery.

[11]  C. Alexiou,et al.  Development and characterization of magnetic iron oxide nanoparticles with a cisplatin-bearing polymer coating for targeted drug delivery , 2014, International journal of nanomedicine.

[12]  J. Gillard,et al.  Sequential imaging of asymptomatic carotid atheroma using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging: a feasibility study. , 2013, Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association.

[13]  Ali Yilmaz,et al.  Imaging of myocardial infarction using ultrasmall superparamagnetic iron oxide nanoparticles: a human study using a multi-parametric cardiovascular magnetic resonance imaging approach. , 2013, European heart journal.

[14]  J. Szebeni,et al.  A porcine model of complement-mediated infusion reactions to drug carrier nanosystems and other medicines. , 2012, Advanced drug delivery reviews.

[15]  Hamidreza Ghandehari,et al.  Size and surface charge significantly influence the toxicity of silica and dendritic nanoparticles , 2012, Nanotoxicology.

[16]  Tom MacGillivray,et al.  Ultrasmall Superparamagnetic Particles of Iron Oxide in Patients With Acute Myocardial Infarction: Early Clinical Experience , 2012, Circulation. Cardiovascular imaging.

[17]  J. Gillard,et al.  Evaluation of Ultrasmall Superparamagnetic Iron Oxide-Enhanced MRI of Carotid Atherosclerosis to Assess Risk of Cerebrovascular and Cardiovascular Events: Follow-Up of the ATHEROMA Trial , 2012, Cerebrovascular Diseases.

[18]  C. A. Shaw,et al.  In Vivo Mononuclear Cell Tracking Using Superparamagnetic Particles of Iron Oxide: Feasibility and Safety in Humans , 2012, Circulation. Cardiovascular imaging.

[19]  T. Ueno,et al.  CD14 expression and Kupffer cell dysfunction in non‐alcoholic steatohepatitis: Superparamagnetic iron oxide‐magnetic resonance image and pathologic correlation , 2012, Journal of gastroenterology and hepatology.

[20]  Toshiro Hirai,et al.  Amorphous nanosilicas induce consumptive coagulopathy after systemic exposure , 2012, Nanotechnology.

[21]  Calum Gray,et al.  Abdominal Aortic Aneurysm Growth Predicted by Uptake of Ultrasmall Superparamagnetic Particles of Iron Oxide: A Pilot Study , 2011, Circulation. Cardiovascular imaging.

[22]  T. Saibara,et al.  Super paramagnetic iron oxide MRI shows defective Kupffer cell uptake function in non-alcoholic fatty liver disease , 2009, Gut.

[23]  Bejoy Thomas,et al.  Principles, techniques, and applications of T2*-based MR imaging and its special applications. , 2009, Radiographics : a review publication of the Radiological Society of North America, Inc.

[24]  Ji-Ho Park,et al.  Differential proteomics analysis of the surface heterogeneity of dextran iron oxide nanoparticles and the implications for their in vivo clearance. , 2009, Biomaterials.

[25]  J. Gillard,et al.  Iron oxide particles for atheroma imaging. , 2009, Arteriosclerosis, thrombosis, and vascular biology.

[26]  J. Gillard,et al.  Utility of USPIO-enhanced MR imaging to identify inflammation and the fibrous cap: a comparison of symptomatic and asymptomatic individuals. , 2009, European journal of radiology.

[27]  Sophie Gaillard,et al.  Safety and Tolerability of Ultrasmall Superparamagnetic Iron Oxide Contrast Agent: Comprehensive Analysis of a Clinical Development Program , 2009, Investigative radiology.

[28]  A. Tanimoto,et al.  Evaluating the severity of nonalcoholic steatohepatitis with superparamagnetic iron oxide‐enhanced magnetic resonance imaging , 2008, Journal of magnetic resonance imaging : JMRI.

[29]  H. Hartung,et al.  Iron Oxide Particle-Enhanced MRI Suggests Variability of Brain Inflammation at Early Stages After Ischemic Stroke , 2007, Stroke.

[30]  J. Gillard,et al.  Identifying Inflamed Carotid Plaques Using In Vivo USPIO-Enhanced MR Imaging to Label Plaque Macrophages , 2006, Arteriosclerosis, thrombosis, and vascular biology.

[31]  H. Shinmoto,et al.  Questionnaire survey of acute and delayed adverse reactions to ferumoxides. , 2005, Radiation medicine.

[32]  Jeff W M Bulte,et al.  Monitoring cell therapy using iron oxide MR contrast agents. , 2004, Current pharmaceutical biotechnology.

[33]  M. E. Kooi,et al.  Accumulation of Ultrasmall Superparamagnetic Particles of Iron Oxide in Human Atherosclerotic Plaques Can Be Detected by In Vivo Magnetic Resonance Imaging , 2003, Circulation.

[34]  H. Shinmoto,et al.  Superparamagnetic iron oxide-mediated hepatic signal intensity change in patients with and without cirrhosis: pulse sequence effects and Kupffer cell function. , 2002, Radiology.

[35]  S. Hussain,et al.  Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging , 2001, European Radiology.

[36]  M. Failla,et al.  Accumulation and metabolism of iron-dextran by hepatocytes, Kupffer cells and endothelial cells in the neonatal pig liver. , 1987, The Journal of nutrition.

[37]  C. Alexiou,et al.  Shell matters: Magnetic targeting of SPIONs and in vitro effects on endothelial and monocytic cell function. , 2015, Clinical hemorheology and microcirculation.

[38]  Ying S. Chao,et al.  Role of carbohydrate receptors in the macrophage uptake of dextran-coated iron oxide nanoparticles. , 2012, Advances in experimental medicine and biology.

[39]  W. Daniel,et al.  Resveratrol inhibits monocytic cell chemotaxis to MCP-1 and prevents spontaneous endothelial cell migration through Rho kinase-dependent mechanism. , 2011, Journal of atherosclerosis and thrombosis.

[40]  A. Tsourkas,et al.  Imaging circulating cells and lymphoid tissues with iron oxide nanoparticles. , 2009, Hematology. American Society of Hematology. Education Program.

[41]  T. Iancu.  Ultrastructural pathology of iron overload. , 1989, Bailliere's clinical haematology.