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.

Sample storage conditions induce post-collection biases in microbiome profiles

“…Hypoxic conditions were created by storing the sample in purged airtight glass syringes (Restek 2.5MDR-VLL-GT) in an anaerobe chamber (Forma Scientific Inc.) with a gas mix (5% H 2 , 5% CO 2 and 90% N 2 ) generating hypoxic conditions, as defined as oxygen concentrations below 10 mmHg pO 2 or 1% O 2 [14, 15].…”

Galectin-1 Inhibitor OTX008 Induces Tumor Vessel Normalization and Tumor Growth Inhibition in Human Head and Neck Squamous Cell Carcinoma Models

“…injection of 60 mg/kg pimonidazole was given to each mouse prior to euthanasia. Pimonidazole, a substituted 2-nitroimidazole, is preferentially reduced in hypoxic viable cells and forms irreversible protein adducts, which have been optimized for detection with immunohistochemistry [ 42 ]. At 1 h post-injection, the mice were euthanized, then the tumor dissected and immediately either fixed in 10% formalin or snap frozen.…”

Galectins as Molecular Targets for Therapeutic Intervention

“…Aside from Gal-1 overexpression in most cancers, this galectin is also upregulated by radiation [ 165 , 169 , 170 ] and hypoxia [ 171 , 172 ]. General hypoxia and local areas of hypoxia (<10 mmHg pO 2 ) are prevalent in solid tumors and are negatively associated with cancer therapy success, compromising radiotherapy, and driving malignant progression [ 173 , 174 ]. Radiation requires oxygen to induce DNA damage through the generation of hydroxyl radicals and H 2 O 2 [ 175 ] and hypoxic conditions can require up to three times the amount of radiation to generate the same effects (oxygen enhancement ratio) [ 176 ].…”