title: Difference in the intratumoral distributions of extracellular-fluid and intravascular MR contrast agents in glioblastoma growth.
abstract: Contrast enhancement by an extracellular-fluid contrast agent (CA) (Gd-DOTA) depends primarily on the blood-brain-barrier permeability (bp), and transverse-relaxation change caused by intravascular T2CA (superparamagnetic iron oxide nanoparticles, SPIONs) is closely associated with the blood volume (BV). Pharmacokinetic (PK) vascular characterization based on single-CA-using dynamic contrast-enhanced MRI (DCE-MRI) has shown significant measurement variation according to the molecular size of the CA. Based on this recognition, this study used a dual injection of Gd-DOTA and SPIONs for tracing the changes of bp and BV in C6 glioma growth (Days 1 and 7 after the tumor volume reached 2 mL). bp was quantified according to the non-PK parameters of Gd-DOTA-using DCE-MRI (wash-in rate, maximum enhancement ratio and initial area under the enhancement curve (IAUC)). BV was estimated by SPION-induced ΔR2* and ΔR2. With validated measurement reliability of all the parameters (coefficients of variation ≤10%), dual-contrast MRI demonstrated a different region-oriented distribution between Gd-DOTA and SPIONs within a tumor as follows: (a) the BV increased stepwise from the tumor center to the periphery; (b) the tumor periphery maintained the augmented BV to support continuous tumor expansion from Day 1 to Day 7; (c) the internal tumor area underwent significant vascular shrinkage (i.e. decreased ΔR2and ΔR2) as the tumor increased in size; (d) the tumor center showed greater bp-indicating parameters, i.e. wash-in rate, maximum enhancement ratio and IAUC, than the periphery on both Days 1 and 7 and (e) the tumor center showed a greater increase of bp than the tumor periphery in tumor growth, as suggested to support tumor viability when there is insufficient blood supply. In the MRI-histologic correlation, a prominent BV increase in the tumor periphery seen in MRI was verified with increased fluorescein isothiocyanate-dextran signals and up-regulated immunoreactivity of CD31-VEGFR. In conclusion, the spatiotemporal alterations of BV and bp in glioblastoma growth, i.e. augmented BV in the tumor periphery and increased bp in the center, can be sufficiently evaluated by MRI with dual injection of extracellular-fluid Gd chelates and intravascular SPION.
authors.affiliation: Department of Radiology, Research Institute of Radiology, Bioimaging Infrastructure, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Radiology, Research Institute of Radiology, Bioimaging Infrastructure, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.|Center for Bioimaging of New Drug Development, Asan Institute for life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Suh
authors.affiliation: Department of Radiology, Research Institute of Radiology, Bioimaging Infrastructure, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.|Center for Bioimaging of New Drug Development, Asan Institute for life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Dong-Cheol
authors.initials: DC
authors.lastname: Woo
authors.affiliation: Department of Radiology, Research Institute of Radiology, Bioimaging Infrastructure, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.|Center for Bioimaging of New Drug Development, Asan Institute for life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Yu Sub
authors.initials: YS
authors.lastname: Sung
authors.affiliation: Center for Bioimaging of New Drug Development, Asan Institute for life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Woo-Chan
authors.identifier: 0000-0002-4052-8745
authors.initials: WC
authors.lastname: Son
authors.affiliation: Center for Bioimaging of New Drug Development, Asan Institute for life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Yoon Seok
authors.initials: YS
authors.lastname: Choi
authors.affiliation: Department of Surgery, National Health Insurance Service, Ilsan, South Korea.
authors.forename: Sang Joon
authors.initials: SJ
authors.lastname: Pae
authors.affiliation: Department of Radiology, Research Institute of Radiology, Bioimaging Infrastructure, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.|Center for Bioimaging of New Drug Development, Asan Institute for life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
authors.forename: Jeong Kon
authors.initials: JK
authors.lastname: Kim
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000737:chemistry* / Q000473:pathology / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002536:Cerebral Arteries / Q000737:chemistry* / Q000473:pathology / Q000503:physiopathology; D003287:Contrast Media / Q000737:chemistry*; D003911:Dextrans / Q000737:chemistry; D045604:Extracellular Fluid / Q000737:chemistry*; D005909:Glioblastoma / Q000737:chemistry* / Q000473:pathology / Q000503:physiopathology; D006571:Heterocyclic Compounds / Q000737:chemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D003287:Contrast Media; D003911:Dextrans; D006571:Heterocyclic Compounds; D058185:Magnetite Nanoparticles; D009942:Organometallic Compounds; C097921:ferumoxtran-10; C050823:gadolinium 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetate
keywords: MRI; blood volume; glioblastoma; superparamagnetic iron oxide nanoparticles; transvascular leakiness