MRI-guided Focused Ultrasound Application for Targeted Drug Delivery

Thesis (Ph.D.)--University of Washington, 2014Pancreatic cancer is one of the most incurable and lethal human cancers in the United States. Mild hyperthermia (~ 41 °C) has been shown effective as an adjuvant for chemotherapy. An optimal mild hyperthermia treatment is targeted and non-invasive without tissue damage or vascular shutoff. High intensity focused ultrasound (HIFU) can non-invasively heat solid tumors without heating the surrounding organs. Magnetic resonance imaging (MRI) is suitable for therapy planning and monitoring of HIFU therapy due to its high spatial image resolution and ability to measure temperature changes in real time. Magnetic resonance-guided high intensity focused ultrasound (MR-g HIFU) is the novel approach for non-invasive mild hyperthermia applications. Temperature sensitive liposomes (TSL) release their drug cargo at the target temperature and in combination with mild hyperthermia may improve drug delivery to solid tumors. The objectives of this dissertation were to evaluate the ability of conventional and multi-parametric MRI techniques to characterize pancreas tumor in three different animal models. In addition, to develop and implement targeted drug delivery methods using mild hyperthermia induced by HIFU under guidance and monitoring of MRI in combination with TSL for pancreatic cancer. Moreover, to assess the short-term tumoricidal activity against tumor in response to MR-HIFU hyperthermia targeted drug delivery. The characterization of tumor models using conventional and multi-parametric MRI provided valuable information regarding tumor properties that can be use as in vivo markers for targeting and therapy monitoring. The combination of hyperthermia induced by MR-HIFU and TSL loaded with chemotherapy resulted in significantly higher tumor drug concentrations compared to TSL alone and free drug. Finally survival studies indicated combination of MR-HIFU and TSL for targeted drug delivery resulted in greater tumor response to the therapy. This technique has potential for clinical translation as an image guided method to deliver drug to pancreas tumor