title: Simultaneous imaging of tumor oxygenation and microvascular permeability using Overhauser enhanced MRI.
abstract: Architectural and functional abnormalities of blood vessels are a common feature in tumors. A consequence of increased vascular permeability and concomitant aberrant blood flow is poor delivery of oxygen and drugs, which is associated with treatment resistance. In the present study, we describe a strategy to simultaneously visualize tissue oxygen concentration and microvascular permeability by using a hyperpolarized (1)H-MRI, known as Overhauser enhanced MRI (OMRI), and an oxygen-sensitive contrast agent OX63. Substantial MRI signal enhancement was induced by dynamic nuclear polarization (DNP). The DNP achieved up to a 7,000% increase in MRI signal at an OX63 concentration of 1.5 mM compared with that under thermal equilibrium state. The extent of hyperpolarization is influenced mainly by the local concentration of OX63 and inversely by the tissue oxygen level. By collecting dynamic OMRI images at different hyperpolarization levels, local oxygen concentration and microvascular permeability of OX63 can be simultaneously determined. Application of this modality to murine tumors revealed that tumor regions with high vascular permeability were spatio-temporally coincident with hypoxia. Quantitative analysis of image data from individual animals showed an inverse correlation between tumor vascular leakage and median oxygen concentration. Immunohistochemical analyses of tumor tissues obtained from the same animals after OMRI experiments demonstrated that lack of integrity in tumor blood vessels was associated with increased tumor microvascular permeability. This dual imaging technique may be useful for the longitudinal assessment of changes in tumor vascular function and oxygenation in response to chemotherapy, radiotherapy, or antiangiogenic treatment.
authors.affiliation: Radiation Biology Branch, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Hironobu
authors.initials: H
authors.lastname: Yasui
authors.forename: Sonny
authors.initials: S
authors.lastname: Batra
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Kinoshita
authors.forename: Marcelino
authors.initials: M
authors.lastname: Bernardo
authors.forename: Jeeva P
authors.initials: JP
authors.lastname: Munasinghe
authors.forename: Hideo
authors.initials: H
authors.lastname: Utsumi
authors.forename: Rajani
authors.initials: R
authors.lastname: Choudhuri
authors.forename: Nallathamby
authors.initials: N
authors.lastname: Devasahayam
authors.forename: Sankaran
authors.initials: S
authors.lastname: Subramanian
authors.forename: James B
authors.initials: JB
authors.lastname: Mitchell
authors.forename: Murali C
authors.initials: MC
authors.lastname: Krishna
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002199:Capillary Permeability; D003287:Contrast Media; D005260:Female; D000860:Hypoxia / Q000378:metabolism; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008809:Mice, Inbred C3H; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism*; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000378:metabolism*; D020286:Pericytes / Q000378:metabolism / Q000473:pathology
chemical_list: D000199:Actins; D003287:Contrast Media; C544013:alpha-smooth muscle actin, mouse; D010100:Oxygen