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

Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system

© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Purpose: High intensity focussed ultrasound (HIFU) can non-invasively treat tumours with minimal or no damage to intervening tissues. While continuous-wave HIFU thermally ablates target tissue, the effect of hundreds of microsecond-long pulsed sonications is examined in this work. The objective of this study was to characterise sonication parameter-dependent thermomechanical bioeffects to provide the foundation for future preclinical studies and facilitate clinical translation. Methods and materials: Acoustic power, number of cycles/pulse, sonication time and pulse repetition frequency (PRF) were varied on a clinical magnetic resonance imaging (MRI)-guided HIFU (MR-HIFU) system. Ex vivo porcine liver, kidney and cardiac muscle tissue samples were sonicated (3 × 3 grid pattern, 1 mm spacing). Temperature, thermal dose and T2 relaxation times were quantified using MRI. Lesions were histologically analysed using H&E and vimentin stains for lesion structure and viability. Results: Thermomechanical HIFU bioeffects produced distinct types of fractionated tissue lesions: solid/thermal, paste-like and vacuolated. Sonications at 20 or 60 Hz PRF generated substantial tissue damage beyond the focal region, with reduced viability on vimentin staining, whereas H&E staining indicated intact tissue. Same sonication parameters produced dissimilar lesions in different tissue types, while significant differences in temperature, thermal dose and T2 were observed between the parameter sets. Conclusion: Clinical MR-HIFU system was utilised to generate distinct types of lesions and to produce targeted thermomechanical bioeffects in ex vivo tissues. The results guide HIFU research on thermomechanical tissue bioeffects, inform future studies and advice sonication parameter selection for direct tumour ablation or immunomodulation using a clinical MR-HIFU system

Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system

© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Purpose: High intensity focussed ultrasound (HIFU) can non-invasively treat tumours with minimal or no damage to intervening tissues. While continuous-wave HIFU thermally ablates target tissue, the effect of hundreds of microsecond-long pulsed sonications is examined in this work. The objective of this study was to characterise sonication parameter-dependent thermomechanical bioeffects to provide the foundation for future preclinical studies and facilitate clinical translation. Methods and materials: Acoustic power, number of cycles/pulse, sonication time and pulse repetition frequency (PRF) were varied on a clinical magnetic resonance imaging (MRI)-guided HIFU (MR-HIFU) system. Ex vivo porcine liver, kidney and cardiac muscle tissue samples were sonicated (3 × 3 grid pattern, 1 mm spacing). Temperature, thermal dose and T2 relaxation times were quantified using MRI. Lesions were histologically analysed using H&E and vimentin stains for lesion structure and viability. Results: Thermomechanical HIFU bioeffects produced distinct types of fractionated tissue lesions: solid/thermal, paste-like and vacuolated. Sonications at 20 or 60 Hz PRF generated substantial tissue damage beyond the focal region, with reduced viability on vimentin staining, whereas H&E staining indicated intact tissue. Same sonication parameters produced dissimilar lesions in different tissue types, while significant differences in temperature, thermal dose and T2 were observed between the parameter sets. Conclusion: Clinical MR-HIFU system was utilised to generate distinct types of lesions and to produce targeted thermomechanical bioeffects in ex vivo tissues. The results guide HIFU research on thermomechanical tissue bioeffects, inform future studies and advice sonication parameter selection for direct tumour ablation or immunomodulation using a clinical MR-HIFU system

Mechanical fractionation of tissues using microsecond-long HIFU pulses on a clinical MR-HIFU system.

© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Purpose: High intensity focussed ultrasound (HIFU) can non-invasively treat tumours with minimal or no damage to intervening tissues. While continuous-wave HIFU thermally ablates target tissue, the effect of hundreds of microsecond-long pulsed sonications is examined in this work. The objective of this study was to characterise sonication parameter-dependent thermomechanical bioeffects to provide the foundation for future preclinical studies and facilitate clinical translation. Methods and materials: Acoustic power, number of cycles/pulse, sonication time and pulse repetition frequency (PRF) were varied on a clinical magnetic resonance imaging (MRI)-guided HIFU (MR-HIFU) system. Ex vivo porcine liver, kidney and cardiac muscle tissue samples were sonicated (3 × 3 grid pattern, 1 mm spacing). Temperature, thermal dose and T2 relaxation times were quantified using MRI. Lesions were histologically analysed using H&E and vimentin stains for lesion structure and viability. Results: Thermomechanical HIFU bioeffects produced distinct types of fractionated tissue lesions: solid/thermal, paste-like and vacuolated. Sonications at 20 or 60 Hz PRF generated substantial tissue damage beyond the focal region, with reduced viability on vimentin staining, whereas H&E staining indicated intact tissue. Same sonication parameters produced dissimilar lesions in different tissue types, while significant differences in temperature, thermal dose and T2 were observed between the parameter sets. Conclusion: Clinical MR-HIFU system was utilised to generate distinct types of lesions and to produce targeted thermomechanical bioeffects in ex vivo tissues. The results guide HIFU research on thermomechanical tissue bioeffects, inform future studies and advice sonication parameter selection for direct tumour ablation or immunomodulation using a clinical MR-HIFU system

Boiling histotripsy lesion characterization on a clinical magnetic resonance imaging-guided high intensity focused ultrasound system - Fig 12

<p><b>a</b>. T1W imaging of porcine liver using fast field echo 3D used for planning HIFU sonications <b>b</b>. T1W imaging of the liver tissue post sonication shows a hypointense signal of a tadpole-shaped lesion created using BH (red dotted circle) <b>c</b>. Subtraction of pre-sonication from post-sonication (Fig 12b minus Fig 12a) images highlights the BH lesion. <b>d</b>. T2W imaging using turbo spin echo 3D were also performed <b>e</b>. T2W imaging post sonication showing the BH lesion along the coronal plane <b>f</b>. Subtraction of pre-sonication from post-sonication images (Fig 12e minus Fig 12d) highlighting the lesion (blue box) and surrounding blood vessels (blue arrowhead).</p