title: Targeting Artificial Tumor Stromal Targets for Molecular Imaging of Tumor Vascular Hypoxia.
abstract: Developed and tested for many years, a variety of tumor hypoxia detection methods have been inconsistent in their ability to predict treatment outcomes or monitor treatment efficacy, limiting their present prognostic capability. These variable results might stem from the fact that these approaches are based on inherently wide-ranging global tumor oxygenation levels based on uncertain influences of necrotic regions present in most solid tumors. Here, we have developed a novel non-invasive and specific method for tumor vessel hypoxia detection, as hypoxemia (vascular hypoxia) has been implicated as a key driver of malignant progression, therapy resistance and metastasis. This method is based on high-frequency ultrasound imaging of α-pimonidazole targeted-microbubbles to the exogenously administered hypoxia marker pimonidazole. The degree of tumor vessel hypoxia was assessed in three mouse models of mammary gland carcinoma (4T1, SCK and MMTV-Wnt-1) and amassed up to 20% of the tumor vasculature. In the 4T1 mammary gland carcinoma model, the signal strength of α-pimonidazole targeted-microbubbles was on average 8-fold fold higher in tumors of pimonidazole-injected mice than in non-pimonidazole injected tumor bearing mice or non-targeted microbubbles in pimonidazole-injected tumor bearing mice. Overall, this provides proof of principle for generating and targeting artificial antigens able to be 'created' on-demand under tumor specific microenvironmental conditions, providing translational diagnostic, therapeutic and treatment planning potential in cancer and other hypoxia-associated diseases or conditions.
authors: Department of Radiation Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors: Nathan A
authors: NA
authors: Koonce
authors: Department of Radiation Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors: Joseph
authors: J
authors: Levy
authors: Department of Radiation Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors: Matthew E
authors: ME
authors: Hardee
authors: Department of Radiation Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors: Azemat
authors: A
authors: Jamshidi-Parsian
authors: Center for Integrative Nanotechnology Sciences, University of Arkansas at Little Rock, Arkansas, United States of America.
authors: Kieng B
authors: KB
authors: Vang
authors: Department of Radiation Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors: Sunil
authors: S
authors: Sharma
authors: Department of Radiation Oncology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America.
authors: James A
authors: JA
authors: Raleigh
authors: Department of Radiation Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors: Ruud P M
authors: RP
authors: Dings
authors: Department of Radiation Oncology, Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors: Robert J
authors: RJ
authors: Griffin
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001808:Blood Vessels / Q000000981:diagnostic imaging / Q000473:pathology*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D003287:Contrast Media; D005260:Female; D021621:Imaging, Three-Dimensional; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology*; D051379:Mice; D045423:Microbubbles; D057054:Molecular Imaging / Q000379:methods*; D009593:Nitroimidazoles / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014463:Ultrasonography
chemical_list: D014408:Biomarkers, Tumor; D003287:Contrast Media; D009593:Nitroimidazoles; C033815:pimonidazole