title: Molecular MR imaging of neovascular progression in the Vx2 tumor with αvβ3-targeted paramagnetic nanoparticles.
abstract: OBJECTIVE
  To assess the dependence of neovascular molecular magnetic resonance (MR) imaging on relaxivity (r1) of αvβ3-targeted paramagnetic perfluorocarbon (PFC) nanoparticles and to delineate the temporal-spatial consistency of angiogenesis assessments for individual animals.
  
  
  METHODS
  Animal protocols were approved by the Washington University Animal Studies Committee. Proton longitudinal and transverse relaxation rates of αvβ3-targeted and nontargeted PFC nanoparticles incorporating gadolinium diethylenetrianime pentaacedic acid (Gd-DTPA) bisoleate (BOA) or gadolinium tetraazacyclododecane tetraacetic acid (Gd-DOTA) phosphatidylethanolamine (PE) into the surfactant were measured at 3.0 T. These paramagnetic nanoparticles were compared in 30 New Zealand White rabbits (four to six rabbits per group) 14 days after implantation of a Vx2 tumor. Subsequently, serial MR (3.0 T) neovascular maps were developed 8, 14, and 16 days after tumor implantation by using αvβ3-targeted Gd-DOTA-PE nanoparticles (n = 4) or nontargeted Gd-DOTA-PE nanoparticles (n = 4). Data were analyzed with analysis of variance and nonparametric statistics.
  
  
  RESULTS
  At 3.0 T, Gd-DTPA-BOA nanoparticles had an ionic r1 of 10.3 L · mmol(-1) · sec(-1) and a particulate r1 of 927000 L · mmol(-1) · sec(-1). Gd-DOTA-PE nanoparticles had an ionic r1 of 13.3 L · mmol(-1) · sec(-1) and a particulate r1 of 1 197000 L · mmol(-1) · sec(-1). Neovascular contrast enhancement in Vx2 tumors (at 14 days) was 5.4% ± 1.06 of the surface volume with αvβ3-targeted Gd-DOTA-PE nanoparticles and 3.0% ± 0.3 with αvβ3-targeted Gd-DTPA-BOA nanoparticles (P = .03). MR neovascular contrast maps of tumors 8, 14, and 16 days after implantation revealed temporally consistent and progressive surface enhancement (1.0% ± 0.3, 4.5% ± 0.9, and 9.3% ± 1.4, respectively; P = .0008), with similar time-dependent changes observed among individual animals.
  
  
  CONCLUSIONS
  Temporal-spatial patterns of angiogenesis for individual animals were followed to monitor longitudinal tumor progression. Neovasculature enhancement was dependent on the relaxivity of the targeted agent.
authors.affiliation: Department of Medicine, Washington University Medical School, 660 S. Euclid Ave, Campus Box 8215, St Louis, MO 63108, USA. Anne@dom.wustl.edu
authors.forename: Anne H
authors.initials: AH
authors.lastname: Schmieder
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Winter
authors.forename: Todd A
authors.initials: TA
authors.lastname: Williams
authors.forename: John S
authors.initials: JS
authors.lastname: Allen
authors.forename: Grace
authors.initials: G
authors.lastname: Hu
authors.forename: Huiying
authors.initials: H
authors.lastname: Zhang
authors.forename: Shelton D
authors.initials: SD
authors.lastname: Caruthers
authors.forename: Samuel A
authors.initials: SA
authors.lastname: Wickline
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Lanza
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D045744:Cell Line, Tumor; D003287:Contrast Media / Q000138:chemical synthesis; D004195:Disease Models, Animal; D018450:Disease Progression; D019786:Gadolinium DTPA / Q000737:chemistry; D006571:Heterocyclic Compounds / Q000737:chemistry; D006614:Hindlimb; D007091:Image Processing, Computer-Assisted; D021621:Imaging, Three-Dimensional; D016018:Least-Squares Analysis; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D008297:Male; D009389:Neovascularization, Pathologic / Q000473:pathology*; D009942:Organometallic Compounds / Q000737:chemistry; D011817:Rabbits; D018709:Statistics, Nonparametric
chemical_list: D003287:Contrast Media; D006571:Heterocyclic Compounds; D058185:Magnetite Nanoparticles; D009942:Organometallic Compounds; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate; D019786:Gadolinium DTPA