title: Nanotemplate-engineered nanoparticles containing gadolinium for magnetic resonance imaging of tumors.
abstract: OBJECTIVE
  To design nanoparticles containing accessible gadolinium atoms (Gd-NPs) as a contrast agent for magnetic resonance imaging of tumors.
  
  
  METHODS
  Nanoparticles containing phospholipid-chelates (phosphoethanolamine diethylenetriaminepentaacetate) and DSPE-PEG (MW5000) were prepared from Brij 78 and stearyl alcohol using the nanotemplate engineering approach. After addition of GdCl3, the presence of gadolinium on the surface of nanoparticles was quantified using inductively coupled plasma atomic emission spectroscopy. The in vitro relaxivities of the Gd-NPs in phosphate buffered saline were assessed at 4.7 T. The conditional binding constants of nanoparticle formulations were determined spectrophotometrically by competitive titration. Transmetallation kinetics of Gd from nanoparticles with Cu2+ and Zn2+ as the competing ions was measured in acetate buffer. The biodistribution profiles, pharmacokinetics, and contrast enhancement in tumor region was studied after administration of Gd-NPs to nude mice bearing A549 lung carcinoma xenografts.
  
  
  RESULTS
  Gd-NPs with an average diameter of 138 nm possessing surface chelating functions were prepared from GRAS (generally regarded as safe) materials. The longitudinal relaxivity (r1) and transverse relaxivity (r2) of Gd-NPs in 10% fetal bovine serum at 4.7 T were 7.1 (+/-0.2) and 13.0 (+/-0.7) 1/mM/s, respectively. These pegylated Gd-NPs had enhanced relaxivities and exhibited particle size stability, sufficient binding affinity, and kinetic inertness under physiologic conditions. The contrast enhancement in tumors was demonstrated 40, 120, and 360 minutes after intravenous injection of Gd-NPs at a dose of 0.1 mmol Gd/kg. The Gd plasma concentration of Gd-NPs over a period of 24 hours fit a two-compartmental model with Cl sys = 0.89 mL/h and MRT = 5.93 h. The amount of Gd that accumulated in the tumor region was consistent with the estimated value obtained by T1 measurements using MR imaging.
  
  
  CONCLUSIONS
  Pegylated nanoparticles composed of biocompatible, biodegradable materials and possessing accessible Gd ions on their surface induce relaxivities in the bulk water signal and accumulated sufficiently in tumors, demonstrating their utility as potential magnetic resonance imaging tumor contrast enhancement agents.
authors.affiliation: Department of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
authors.forename: Donghua
authors.initials: D
authors.lastname: Zhu
authors.forename: Xiuling
authors.initials: X
authors.lastname: Lu
authors.forename: Peter A
authors.initials: PA
authors.lastname: Hardy
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
authors.forename: Michael
authors.initials: M
authors.lastname: Jay
mesh_terms: D000818:Animals; D005260:Female; D005682:Gadolinium / Q000493:pharmacokinetics*; D006801:Humans; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000175:diagnosis* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D051379:Mice; D050997:Nanomedicine; D053758:Nanoparticles; D014183:Transplantation, Heterologous
chemical_list: D005682:Gadolinium