Novel ¹H MR Probes To Interrogate The Tumor Microenvironment

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Novel ¹H MR Probes To Interrogate The Tumor Microenvironment

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Title: Novel ¹H MR Probes To Interrogate The Tumor Microenvironment
Author: Gulaka, Praveen Kumar
Abstract: The term "tumor microenvironment" usually refers to the description of the physiological and metabolic conditions within solid tumors (primary or metastatic), and is significantly different from that of normal tissues. Assessment of factors like pH, tissue oxygen tension (pO2) and gene expression in the tumor microenvironment and the ability to image them in vivo can provide useful prognostic information. For example, hypoxia (low pO2), typically distributed heterogeneously in solid tumors, is known to affect both radiation sensitivity and the development of metastases thereby influencing the response to treatment. This dissertation research focuses on the evaluation of novel probes to interrogate the tumor microenvironment using proton (1H) magnetic resonance imaging (MRI), specifically hypoxia and gene expression. For the assessment of hypoxia, hexamethyldisiloxane (HMDSO) has been reported as a 1H MR based pO2 reporter molecule by in vivo spectroscopy and imaging using Proton Imaging of Siloxanes to Map Tissue Oxygenation Levels (PISTOL) technique. In further improvement of the technique, I evaluated HMDSO based nanoemulsions and various other siloxanes as quantitative 1H MR pO2 reporter molecules (Chapter 2). These reporter molecules demonstrated a linear dependence of the spin lattice relaxation rate (R1) on pO2. HMDSO based nanoemulsions were further used in an in vivo feasibility study showing dynamic changes in rat thigh tissue oxygenation in response to hyperoxic gas (normobaric and hyperbaric oxygen) breathing following an intramuscular injection, thus showing the feasibility for use of these nanoemulsions as pO2 nanoprobes for systemic delivery. Another strategy for hypoxia imaging has been the use of 2-nitroimidazole based agents which selectively accumulated in hypoxic regions. In this dissertation, I report the in vitro and in vivo evaluation of GdDOTA monoamide conjugate of 2-nitroimidazole, GdDO3NI, as a novel hypoxia targeting MRI T1 contrast agent (Chapter 3). A higher uptake of GdDO3NI was observed in cells incubated under hypoxic conditions as well as hypoxic regions of Dunning R3327 AT1 prostate tumors. The MR observations were validated through inductively coupled plasma mass spectroscopic analysis. Further, I demonstrated the ability of GdDO3NI in monitoring the effect of hyperoxic (100% oxygen) gas breathing on modifying hypoxia in AT1 and HI tumors. Thus, GdDO3NI shows promise as a hypoxia targeting small molecular contrast agent, enabling the assessment of hypoxia at very high spatial resolution.For the assessment of gene expression, development of noninvasive imaging based reporter molecules has been an active area of study. In this dissertation, I evaluated a novel platform with enhanced T1 and T2 relaxation properties, for detecting β-gal activity in lacZ transfected cells using novel analogs of the product of cleavage of commercially available substrate S-Gal® (Chapter 4). The synthesized mono and di- galactopyranosides (MGD and GD respectively) showed differential relaxation enhancements in vitro and the molecule C3-GD was identified as the optimal candidate for in vivo studies. Following intra-tumoral injection of C3-GD and ferric ammonium citrate solution in the lacZ transfected tumors, a pronounced shortening of T1 & T2 values was observed when compared to baseline, and persisted over 2 hours. This is attributed to the formation of an iron complex following chelation of aglycones produced by β-gal activity. Thus C3-GD shows great promise as a 1H MR gene reporter molecule.
Date: 2011-10-11

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