title: A novel gadolinium-based trimetasphere metallofullerene for application as a magnetic resonance imaging contrast agent.
abstract: OBJECTIVE
  Macromolecular contrast agents for magnetic resonance imaging (MRI) are useful blood-pool agents because of their long systemic half-life and have found applications in monitoring tumor vasculature and angiogenesis. Macromolecular contrast agents have been able to overcome some of the disadvantages of the conventional small-molecule contrast agent Magnevist (gadolinium-diethylenetriaminepentaacetic acid), such as rapid extravasation and quick renal clearance, which limits the viable MRI time. There is an urgent need for new MRI contrast agents that increase the sensitivity of detection with a higher relaxivity, longer blood half-life, and reduced toxicity from free Gd3+ ions. Here, we report on the characterization of a novel water-soluble, derivatized, gadolinium-enclosed metallofullerene nanoparticle (Hydrochalarone-1) in development as an MRI contrast agent.
  
  
  METHODS
  The physicochemical properties of Hydrochalarone-1 were characterized by dynamic light scattering (hydrodynamic diameter), atomic force microscopy (particle height), ζ potential analysis (surface charge), and inductively coupled plasma-mass spectrometry (gadolinium concentration). The blood compatibility of Hydrochalarone-1 was also assessed in vitro through analysis of hemolysis, platelet aggregation, and complement activation of human blood. In vitro relaxivities, in vivo pharmacokinetics, and a pilot in vivo acute toxicity study were also performed.
  
  
  RESULTS
  An extensive in vitro and in vivo characterization of Hydrochalarone-1 is described here. The hydrodynamic size of Hydrochalarone-1 was 5 to 7 nm depending on the dispersing media, and it was negatively charged at physiological pH. Hydrochalarone-1 showed compatibility with blood cells in vitro, and no significant hemolysis, platelet aggregation, or complement activation was observed in vitro. In addition, Hydrochalarone-1 had significantly higher r1 and r2 in vitro relaxivities in human plasma in comparison with Magnevist and was not toxic at the doses administered in an in vivo pilot acute-dose toxicity study in mice.In vivo MRI pharmacokinetic analysis after a single intravenous injection of Hydrochalarone-1 (0.2 mmol Gd/kg) showed that the volume of distribution at steady state was approximately 100 mL/kg, suggesting prolonged systemic circulation. Hydrochalarone-1 also had a long blood half-life (88 minutes) and increased relaxivity, suggesting application as a promising blood-pool MRI contrast agent.
  
  
  CONCLUSIONS
  The evidence suggests that Hydrochalarone-1, with its long systemic half-life, may have significant utility as a blood-pool MRI contrast agent.
authors.affiliation: From the *Nanotechnology Characterization Laboratory, Advanced Technology Program, SAIC-Frederick, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD; †Luna nanoWorks, Luna Innovations, Inc, Danville, VA; ‡Department of Nanoscience, Joint School of Nanoscience and Nanoengineering, Greensboro, NC; §Small Animal Imaging Program, Laboratory Animal Sciences Program, SAIC-Frederick, Inc, Frederick National Laboratory for Cancer Research, Frederick; and ∥Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD.
authors.forename: Pavan
authors.initials: P
authors.lastname: Adiseshaiah
authors.forename: Anthony
authors.initials: A
authors.lastname: Dellinger
authors.forename: Darren
authors.initials: D
authors.lastname: MacFarland
authors.forename: Stephan
authors.initials: S
authors.lastname: Stern
authors.forename: Marina
authors.initials: M
authors.lastname: Dobrovolskaia
authors.forename: Lilia
authors.initials: L
authors.lastname: Ileva
authors.forename: Anil K
authors.initials: AK
authors.lastname: Patri
authors.forename: Marcelino
authors.initials: M
authors.lastname: Bernardo
authors.forename: D Bradford
authors.initials: DB
authors.lastname: Brooks
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhou
authors.forename: Scott
authors.initials: S
authors.lastname: McNeil
authors.forename: Christopher
authors.initials: C
authors.lastname: Kepley
mesh_terms: D000818:Animals; D003167:Complement Activation; D003287:Contrast Media / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D037741:Fullerenes / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D005682:Gadolinium / Q000737:chemistry* / Q000493:pharmacokinetics / Q000633:toxicity; D006461:Hemolysis; D006801:Humans; D046911:Macromolecular Substances; D008279:Magnetic Resonance Imaging; D051379:Mice; D018625:Microscopy, Atomic Force; D056004:Molecular Dynamics Simulation; D053758:Nanoparticles; D009942:Organometallic Compounds / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000633:toxicity; D010974:Platelet Aggregation; D013054:Spectrophotometry, Atomic
chemical_list: D003287:Contrast Media; D037741:Fullerenes; D046911:Macromolecular Substances; D009942:Organometallic Compounds; C000588772:hydrochalarone-1; D005682:Gadolinium