Tumor hypoxia appears to be strongly associated with tumor propagation, malignant progression, and resistance to therapy and it has thus become a central issue in tumor physiology and cancer treatment. The ability to quantitatively measure tumor oxygenation could be of great value to cancer diagnosis and prognosis. The overall objective of the proposed research is to develop HMDSO based nanoemulsions as a proton magnetic resonance imaging based pO2 reporter nanoprobes and to use them to explore the tumor microenviromental response to combination chemotherapy. This innovative concept is suitable for rapid clinical translation.
Specific Aim 1. (months 1-6) To synthesize and characterize pO2 nanoprobes: In months 1-6, HMDSO nanoemulsions will be synthesized for use as pO2 nanoprobes by ultrasonic emulsification method and characterized by dynamic light scattering. A polyethylene glycol derivative surfactant will be used to increase blood pool retention time for extravasation of the nanoprobes into tumors.
Specific Aim 2. (months 7-12) Test nanoprobe stability in plasma over time and under variable pH conditions and obtain pO2 calibration curve as a function of temperature: Next, the stability of the synthesized nanoemulsions will be tested in a variety of pH conditions. pO2 calibration curves will be obtained for different temperatures in the physiologically relevant range by measurement of spin-lattice relaxation rates for samples bubbled with gases with different O2 levels.
Specific Aim 3. (72 mice, months 13-20) To deliver HMDSO nanoprobes intravenously to nude mice bearing human prostate (PC3) and breast (MCF7) tumor xenografts and measure tumor uptake and clearance by MRI: Having obtained calibration curves, tumor uptake and clearance of nanoprobes will be studied by 1H magnetic resonance spectroscopy for different particle sizes to identify particles with optimal uptake and time course in two human tumor xenografts implanted in nude mice. In vivo microdistribution will also be assessed by Nile red staining.
Specific aim 4. (48 mice, months 21-24) To detect the modulation of tumor oxygenation by gas intervention and vascular targeting agent CA4P and assess the efficacy of combination chemotherapy in human prostate (PC3) and breast (MCF7) tumor xenografts in mice: Finally, the pO2 nanoprobes will then be used to study tumor oxygen dynamics and response to hyperoxia in two human tumor xenografts implanted in nude mice. Effect of combination chemotherapy consisting of metronomic cyclophosphamide and will be studied on tumor oxygenation parameters such as baseline pO2, HF5 and response to hyperoxia with the view to identifying early changes that correlate with long- term outcome. Different treatment groups will be statistically compared to controls using ANOVA.
Oxygen is required for efficient function by most tissues and hypoxia leads to rapid cellular dysfunction and damage. This application aims to develop a novel method for measuring tissue oxygen levels using nanoprobes, which can be easily translated to the clinic. Although we study tumors, the technique developed here has potential applications in a wide range of diseased states and can be applied to study basic physiology and oxygen consumption in tissue as well.
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