Time Domian Electron Paramagnetic Resonance Imaging

Division Of Basic Sciences - Nci

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Abstract

a) A multimodal molecular imaging study evaluates pharmacological alteration of the tumor microenvironment to improve radiation response. Hypoxic zones in solid tumors contribute to radio-resistance. Pharmacological agents including anti-angiogenic drugs increasing tumor oxygenation prior to radiation can enhance treatment response to radiotherapy. However, imaging assessments of tumor oxygenation to identify a time window for radiotherapy using such strategies have not been fully explored. In this study, we investigated the effects of alpha-sulfoquinovosylacyl-1,3-propanediol (SQAP) a synthetic derivative of an anti-angiogenic agent in altering the tumor microenvironment in terms of oxygen partial pressure (pO2), oxyhemoglobin saturation (sO2), blood perfusion and microvessel density using electron Paramagnetic Resonance (EPR) imaging, photoacoustic (PA) imaging, dynamic contrast-enhanced MRI with Gd-DTPA injection, and T2*-weighted imaging with USPIO injection, respectively. SCCVII and A549 tumors were grown by injecting tumor cells into the hind legs of mice. The 5-days of daily radiation (2 Gy) combined with intravenous injection of SQAP (2 mg/kg) 30 min prior to irradiation significantly delayed growth of tumor xenografts. The 3-days of daily treatment improved tumor oxygenation and decreased tumor microvascular density from T2*-weighted images with USPIO explained by vascular normalization. Acute effects of SQAP on tumor oxygenation were examined by pO2 imaging, sO2 imaging, and Gd-DTPA contrast-enhanced imaging. SQAP treatment resulted in improved perfusion and tumor pO2 (pO2: 3.1mmHg) accompanied with decreased sO2 (20-30% decrease) in SCCVII implants 20-30 min after SQAP administration. These results provide evidence that SQAP enhanced tumor oxygenation transiently by facilitating oxygen dissociation from oxyhemoglobin and improved tumor perfusion. SQAP mediated in vivo radiation sensitization was attributed to increased tumor oxygenation caused by SQAP. b) Spin-lattice relaxation time, T1-based Quantitative High Resolution Single Point EPR imaging and oximetry in vivo by inter-pulse delay (TR) variation: We report what is likely to be the ultimate method of time-domain small animal EPR oximetry that uses rapid signal averaging and renders the signals spin lattice relaxation time (T1) weighted. Using the Single Point Imaging modality, high resolution T1-weighted imaging and oximetry were carried out that promises the lowest energy absorption compared to echo-based approaches besides yielding spin-concentration independent oximetry. An added advantage, especially in time-domain globally phase-encoded imaging strategy is the more effective coverage of the large bandwidth compared to frequency encoding approach, especially in the context of FT-EPR imaging. The T1 dependence of a triarylmethyl probe Oxo71 on pO2 was assessed by saturation by fast repetition sequence at repetition times from 2.1 - 40 us. The pO2 maps of a phantom containing three glass tubes containing 2mM Oxo71 solutions equilibrated at 0%, 2% and 5% of oxygen were determined by T1 and apparent spin-spin relaxation time T2* separately. Both the pO2 maps derived from T1 and T2* agreed well with the pO2 levels of the solutions in the phantom. However, the histograms of pO2 maps indicated that T1 offers better pO2 resolution than T2*. Recent studies indicated that the self-broadening of spin probe contributes much higher to T2* than T1 prompting that T1 based oximetry does not require concentration correction. Besides, the concentrations of the spin probe cannot be assessed accurately in vivo because, a bolus of spin probe injected at one location is gradually distributes in to various body tissues. Nevertheless, T1 mapping by standard pulse sequences is unsuitable to in vivo studies due to high energy absorption and long scan times. In this report, we present oximetry in vivo by fast T1 mapping using 90 pules suitable to in vivo work at low absorption. The scan time of T1 mapping can be brought down to routine T2* based oximetry times using three repetition times ranging from 4 - 12 us.