title: Estimation of tumor microvessel density by MRI using a blood pool contrast agent.
abstract: Recognition of importance of angiogenesis to tumor growth, metastasis, and treatment outcome has led to efforts to develop non-invasive methods for longitudinal monitoring of tumor microvasculature. We describe a steady-state MRI technique to determine absolute blood volume (BV) as a marker of microvascular density with improved spatial and temporal resolution using an ultra small super paramagnetic iron oxide (USPIO). A noise reduction scheme for BV imaging was also proposed based on weighting factors derived by pre-contrast signal level as an adjustable additive constant. Gradient echo sequence was used for BV imaging with MRI at 7T. Optimal imaging conditions (USPIO dose and echo time) were determined by USPIO dose-dependent studies ex vivo and in vivo. Improved analysis strategies were at first applied for cerebral BV estimation in mice, which were found in good agreement with the literature values. These methods were then used to determine tumor BV in mice. The optimal concentration of USPIO for BV estimates was found to range from 3.6 to 4.48 mM (estimated as Fe concentration) in ex vivo experiments corresponding to an in vivo dosage of 215-287 micromol/kg body weight, whereas a USPIO dose of 287 micromol/kg leads to higher cerebral BV estimate in vivo than the reported values. Application of the BV imaging method to evaluation of anti-angiogenic effect of Sunitinib in squamous cell carcinoma (SCC) tumor bearing mice revealed approximately 46% reduction in tumor BV 4 days after start of Sunitinib treatment. The results show that the MRI approach using USPIO yields high-resolution absolute BV images and the method can be conveniently applied to monitor longitudinal tumor microvessel density changes as a function of growth or in response to treatment.
authors.affiliation: Radiation Biology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Hyodo
authors.forename: Gadisetti V R
authors.initials: GV
authors.lastname: Chandramouli
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Ken-Ichiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Murali C
authors.initials: MC
authors.lastname: Krishna
authors.forename: Jeeva P
authors.initials: JP
authors.lastname: Munasinghe
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D016477:Artifacts; D001810:Blood Volume; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000188:drug therapy; D002560:Cerebrovascular Circulation; D003287:Contrast Media / Q000008:administration & dosage; D003911:Dextrans / Q000008:administration & dosage; D005260:Female; D052203:Ferrosoferric Oxide / Q000008:administration & dosage; D007211:Indoles / Q000494:pharmacology; D007275:Injections, Intravenous; D018810:Magnetic Resonance Angiography / Q000295:instrumentation / Q000379:methods*; D058185:Magnetite Nanoparticles; D051379:Mice; D008809:Mice, Inbred C3H; D055806:Microvessels / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000175:diagnosis* / Q000188:drug therapy / Q000503:physiopathology; D019047:Phantoms, Imaging; D011237:Predictive Value of Tests; D011758:Pyrroles / Q000494:pharmacology; D012983:Soft Tissue Neoplasms / Q000098:blood supply* / Q000188:drug therapy; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D003911:Dextrans; D007211:Indoles; D058185:Magnetite Nanoparticles; D011758:Pyrroles; C097921:ferumoxtran-10; D000077210:Sunitinib; D052203:Ferrosoferric Oxide