An efficient noninvasive method for in vivo imaging of tumor oxygenation by using a low-field magnetic resonance scanner and a paramagnetic contrast agent is described. The methodology is based on Overhauser enhanced magnetic resonance imaging (OMRI), a functional imaging technique. OMRI experiments were performed on tumor-bearing mice (squamous cell carcinoma) by i.v. administration of the contrast agent Oxo63 (a highly derivatized triarylmethyl radical) at nontoxic doses in the range of 2-7 mmol/kg either as a bolus or as a continuous infusion. Spatially resolved pO 2 (oxygen concentration) images from OMRI experiments of tumor-bearing mice exhibited heterogeneous oxygenation profiles and revealed regions of hypoxia in tumors (<10 mmHg; 1 mmHg ‫؍‬ 133 Pa). Oxygenation of tumors was enhanced on carbogen (95% O 2͞5% CO2) inhalation. The pO2 measurements from OMRI were found to be in agreement with those obtained by independent polarographic measurements using a pO 2 Eppendorf electrode. This work illustrates that anatomically coregistered pO 2 maps of tumors can be readily obtained by combining the good anatomical resolution of water proton-based MRI, and the superior pO 2 sensitivity of EPR. OMRI affords the opportunity to perform noninvasive and repeated pO 2 measurements of the same animal with useful spatial (Ϸ1 mm) and temporal (2 min) resolution, making this method a powerful imaging modality for small animal research to understand tumor physiology and potentially for human applications.A bnormal values of pO 2 (the partial pressure of O 2 ) are linked to many pathophysiological conditions (e.g., ischemic diseases, reperfusion injury, and oxygen toxicity). Approximately one-third of human tumors evaluated for oxygen status have shown significant oxygen deficiency, and oxygen deficiency increases the tumor's resistance toward cancer treatment modalities, including radiation and chemotherapy (1, 2). Additionally, hypoxic microenvironments in tumors are known to promote processes driving malignant progression, such as angiogenesis, elimination of p53 tumor suppressor activity, genetic instability, and metastasis (3-5). Understanding of tumor hypoxia could lead to the discovery of diagnostic and prognostic markers for malignant progression, discovery of novel therapeutic targets, and the development of new constructs for gene therapy applications in human cancer. Hence, a noninvasive technique that could accurately and repetitively measure tissue oxygenation would find broad application in clinical and basic research. Unfortunately, the currently used electrochemical method (6) for in vivo oxygen measurement is an invasive technique applicable only to accessible tumors. Further, the technique is hampered by measurements of only a small part of the total tumor, which cannot be re-evaluated. Several magnetic resonance techniques (7, 8) have been developed for in vivo oximetry, including spin label oximetry (9), MRI (10), and electron paramagnetic resonance imaging (EPRI) (11,12). The blood oxygen level-dependent...

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Small SAAs (≤25 mm) are not prone to significant expansion and do not require frequent surveillance imaging. Imaging every 3 years for small SAAs is adequate. Aneurysms of the pancreaticoduodenal arcade and gastroduodenal aneurysms are more likely to rupture and therefore warrant a more aggressive interventional approach.

The paramagnetic spin probe Oxo63 is used in oximetric imaging studies based on electron paramagnetic resonance (EPR) methods by monitoring the oxygen-dependent linewidth while minimizing the contributions from self-broadening seen at high probe concentrations. Therefore, it is necessary to determine a suitable dose of Oxo63 for EPR-based oxygen mapping where the self-broadening effects are minimized while signal intensity adequate for imaging can be realized. A constant tissue concentration of spin probe would be useful to image a subject and assess changes in pO 2 over time; accumulation or elimination of the compound in specific anatomical regions could translate to and be mistaken for changes in local pO 2 , especially in OMRI-based oximetry. The in vivo pharmacokinetics of the spin probe, Oxo63, after bolus and/or continuous intravenous infusion was investigated in mice using a novel approach with X-band EPR spectroscopy. The results show that the half-life in blood was 17-21 min and the clearance by excretion was 0. A number of techniques currently have the capability to assess tissue oxygen tension or are under development (1,2). Clarke-type oxygen electrodes are widely used experimentally and clinically to estimate pO 2 levels, although only a small portion of the tissue is sampled (3,4). However, results from such measurements over the past several years have shown a strong correlation between tumor pO 2 and treatment outcome, suggesting that tumor oxygenation status is a useful prognostic factor (5). Ideally, a method of oxygen measurement in tissue, e.g., a tumor, should be noninvasive, quantitative, and global with respect to the volume of interest. In addition, such techniques should allow for measurement in tissue before, during, and after treatment. Noninvasive imaging techniques such as blood oxygen level-dependent MRI (BOLD-MRI), single photon emission computed tomography (SPECT), and positron-emission tomography (PET) (6 -9) are now used to assess tumor oxygenation.BOLD-MRI examines differences in T 2 contrast between two images, based on the ratio of diamagnetic oxy-hemoglobin and paramagnetic deoxy-hemoglobin in the blood, and provides qualitative assessment of pO 2 (10,11). PET uses positron-emitting radioisotope-labeled molecular probes such as 18 F-fluoromisonidazole ( 18 F-MISO) (12-14) or 64 Cu-diacetyl-bis(N 4 -methylthiosemicarbazone) ( 64 Cu-ATSM) (15-17), which have high affinity for the hypoxic atmosphere and obtain spatial maps of hypoxic regions in a patient and/or experimental animals. Measurement of oxygen metabolism was clinically carried out by PET using 15 O gas as the probe (18 -22). SPECT is also a radiological imaging technique which has been used for measurement of blood perfusion volume in the brain employing a ␥-ray emitting radioisotope such as N-isopropyl-p- Noninvasive imaging techniques based on electron paramagnetic resonance (EPR) such as continuous wave (CW) and time-domain electron paramagnetic resonance imaging (EPRI) (11,33,34), or Overhauser-enhanced MRI (OMR...

Permeability of tumor vasculature can be a major barrier to successful drug delivery, particularly for high molecular weight agents such as monoclonal antibodies and their diagnostic or therapeutic conjugates. In this study, changes in permeability of SCCVII tumor vessels after radiation treatment were evaluated by dynamic magnetic resonance imaging as a function of time after irradiation using a generation-8 polyamidoamine dendrimer (G8-Gd-D)-based magnetic resonance imaging contrast agent shown previously to be confined to tumor blood vessels. Tumor irradiation consisted of either single doses (2-15 Gy) or various daily fractionated doses (5 days). A single radiation dose of 15 Gy resulted in significant transient image enhancement of the tumor tissue with a maximum occurring between 7 and 24 hours after radiation treatment. No observable enhancement was recorded for fractionated radiation doses. Use of dynamic magnetic resonance imaging coupled with G8-Gd-D provides an exquisite methodology capable of defining the timing of enhanced permeability of macromolecules in tumors after irradiation. Such information might be applied to optimize the efficacy of subsequent or concurrent therapies including radiolabeled antibodies or other anticancer agents in combination with external beam therapies.

Using redox-sensitive paramagnetic contrast agents, EPRI can non-invasively discriminate redox status differences between normal tissue and tumors.

Background: The monocyte chemoattractant protein-1/CCR2 (chemokine receptor 2) axis plays an important role in abdominal aortic aneurysm (AAA) pathogenesis, with effects on disease progression and anatomic stability. We assessed the expression of CCR2 in a rodent model and human tissues, using a targeted positron emission tomography radiotracer ( 64 Cu-DOTA-ECL1i). Methods: AAAs were generated in Sprague-Dawley rats by exposing the infrarenal, intraluminal aorta to PPE (porcine pancreatic elastase) under pressure to induce aneurysmal degeneration. Heat-inactivated PPE was used to generate a sham operative control. Rat AAA rupture was stimulated by the administration of β-aminopropionitrile, a lysyl oxidase inhibitor. Biodistribution was performed in wild-type rats at 1 hour post tail vein injection of 64 Cu-DOTA-ECL1i. Dynamic positron emission tomography/computed tomography imaging was performed in rats to determine the in vivo distribution of radiotracer. Results: Biodistribution showed fast renal clearance. The localization of radiotracer uptake in AAA was verified with high-resolution computed tomography. At day 7 post-AAA induction, the radiotracer uptake (standardized uptake value [SUV]=0.91±0.25) was approximately twice that of sham-controls (SUV=0.47±0.10; P <0.01). At 14 days post-AAA induction, radiotracer uptake by either group did not significantly change (AAA SUV=0.86±0.17 and sham-control SUV=0.46±0.10), independent of variations in aortic diameter. Competitive CCR2 receptor blocking significantly decreased AAA uptake (SUV=0.42±0.09). Tracer uptake in AAAs that subsequently ruptured (SUV=1.31±0.14; P <0.005) demonstrated uptake nearly twice that of nonruptured AAAs (SUV=0.73±0.11). Histopathologic characterization of rat and human AAA tissues obtained from surgery revealed increased expression of CCR2 that was co-localized with CD68 + macrophages. Ex vivo autoradiography demonstrated specific binding of 64 Cu-DOTA-ECL1i to CCR2 in both rat and human aortic tissues. Conclusions: CCR2 positron emission tomography is a promising new biomarker for the noninvasive assessment of AAA inflammation that may aid in associated rupture prediction.

[ 64 Cu]Cu(II)-ATSM (64 Cu-ATSM) and [18F]-Fluoromisonidazole (18 F-FMiso) tumor binding as assessed by positron emisson topography (PET) was used to determine the responsiveness of each probe to modulation in tumor oxygenation levels in the SCCVII tumor model. Animals bearing the SCCVII tumor were injected with 64 Cu-ATSM or 18 F-FMiso followed by dynamic small animal PET imaging. Animals were imaged with both agents using different inspired oxygen mixtures (air, 10% oxygen, carbogen) which modulated tumor hypoxia as independently assessed by the hypoxia marker pimonidazole. The extent of hypoxia in the SCCVII tumor as monitored by the pimonidazole hypoxia marker was found to be in the following order: 10% oxygen > air > carbogen. Tumor uptake of 64 Cu-ATSM could not be changed if the tumor was oxygenated using carbogen inhalation 90 min post-injection suggesting irreversible cellular uptake of the 64 Cu-ATSM complex. A small but significant paradoxical increase in 64 Cu-ATSM tumor uptake was observed for animals breathing air or carbogen compared to 10% oxygen. There was a positive trend toward 18 F-FMiso tumor uptake as a function of changing hypoxia levels in agreement with the pimonidazole data. 64 Cu-ATSM tumor uptake was unable to predictably detect changes in varying amounts of hypoxia when oxygenation levels in SCCVII tumors were modulated. 18 F-FMiso tumor uptake was more responsive to changing levels of hypoxia. While the mechanism of nitroimidazole binding to hypoxic cells has been extensively studied, the avid binding of Cu-ATSM to tumors may involve other mechanisms independent of hypoxia that warrant further study.