title: In vitro and in vivo imaging studies of a new endohedral metallofullerene nanoparticle.
abstract: OBJECTIVE
  To evaluate the effectiveness of a functionalized trimetallic nitride endohedral metallofullerene nanoparticle as a magnetic resonance (MR) imaging proton relaxation agent and to follow its distribution for in vitro agarose gel infusions and in vivo infusions in rat brain.
  
  
  METHODS
  The animal study was approved by the animal care and use committee. Gd(3)N@C(80) was functionalized with poly(ethylene glycol) units, and the carbon cage was hydroxylated to provide improved water solubility and biodistribution. Relaxation rate measurements (R1 = 1/T1 and R2 = 1/T2) of water solutions of this contrast agent were conducted at 0.35-, 2.4-, and 9.4-T MR imaging. Images of contrast agent distributions were produced following infusions in six agarose gel samples at 2.4 T and from direct brain infusions into normal and tumor-bearing rat brain at 2.4 T. The relaxivity of a control functionalized lutetium agent, Lu(3)N@C(80), was also determined.
  
  
  RESULTS
  Water hydrogen MR imaging relaxivity (r1) for this metallofullerene nanoparticle was markedly higher than that for commercial agents (eg, gadodiamide); r1 values of 102, 143, and 32 L . mmol(-1) . sec(-1) were measured at 0.35, 2.4, and 9.4 T, respectively. In studies of in vitro agarose gel infusion, the use of functionalized Gd(3)N@C(80) at concentrations an order of magnitude lower resulted in equivalent visualization in comparison with commercial agents. Comparable contrast enhancement was obtained with direct infusions of 0.013 mmol/L of Gd(3)N@C(80) and 0.50 mmol/L of gadodiamide in live normal rat brain. Elapsed-time studies demonstrated lower diffusion rates for Gd(3)N@C(80) relative to gadodiamide in live normal rat brain tissue. Functionalized metallofullerenes directly infused into a tumor-bearing brain provided an improved tumor delineation in comparison with the intravenously injected conventional Gd(3+) chelate. A control lutetium functionalized Lu(3)N@C(80) nanoparticle exhibited very low MR imaging relaxivity.
  
  
  CONCLUSIONS
  The new functionalized trimetallic nitride endohedral metallofullerene species Gd(3)N@C(80)[DiPEG5000(OH)(x)] is an effective proton relaxation agent, as demonstrated with in vitro relaxivity and MR imaging studies, in infusion experiments with agarose gel and in vivo rat brain studies simulating clinical conditions of direct intraparenchymal drug delivery for the treatment of brain tumors.
authors.affiliation: Department of Radiology, Virginia Commonwealth University, Sanger Hall, B3-021, 1101 E Marshall St, PO Box 980072, Richmond, VA 23298-0072, USA. ppfatouros@vcu.edu
authors.forename: Panos P
authors.initials: PP
authors.lastname: Fatouros
authors.forename: Frank D
authors.initials: FD
authors.lastname: Corwin
authors.forename: Zhi-Jian
authors.initials: ZJ
authors.lastname: Chen
authors.forename: William C
authors.initials: WC
authors.lastname: Broaddus
authors.forename: James L
authors.initials: JL
authors.lastname: Tatum
authors.forename: Birgit
authors.initials: B
authors.lastname: Kettenmann
authors.forename: Zhongxin
authors.initials: Z
authors.lastname: Ge
authors.forename: Harry W
authors.initials: HW
authors.lastname: Gibson
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Russ
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Leonard
authors.forename: James C
authors.initials: JC
authors.lastname: Duchamp
authors.forename: Harry C
authors.initials: HC
authors.lastname: Dorn
mesh_terms: D000818:Animals; D001921:Brain / Q000033:anatomy & histology*; D005260:Female; D037741:Fullerenes; D008279:Magnetic Resonance Imaging; D049329:Nanostructures; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D037741:Fullerenes