Tissue Hyperthermia Using MR-HIFU
Hyperthermia refers to mild heating, in the range of 40 to 43 degrees Celsius, in the body. At these temperatures thermal damage is not immediate, and can often take hours to occur. During this time, multiple complex intracellular and physiological processes are triggered by the presence of elevated temperatures, many of which can be therapeutic. Blood flow increases in the area of heating, vessel permeability increases, and heat-shock proteins are produced within cells. These responses can sensitize tissues to radiation, and can improve the delivery of drugs to poorly perfused tissues such as tumors.
The challenge with hyperthermia is delivering it safely and consistently in the body. Too low a temperature has no therapeutic effect, and too high a temperature causes thermal damage. The target range is between 41 and 43 degrees Celsius, which is challenging to achieve and maintain. Once heating starts, increases in blood flow tend to counter this effect, requiring more power to maintain a consistent temperature. Furthermore, heating is heterogeneous due to the spatial variations in blood flow and energy absorption.
Clinical hyperthermia delivery systems need the ability to modulate energy spatially to react to dynamic changes in temperature during heating. MR-HIFU is an excellent candidate technology for generating hyperthermia in the body because it can incorporate real-time temperature monitoring in the region of heating to achieve a region of uniform mild heating. Recently, the capability to perform hyperthermia has been integrated into the clinical MR-HIFU system that resides in our department. We are currently evaluating the precision of heating and safety of these algorithms prior to commencing human studies with the technology. An example from one of our preclinical studies is shown below, where we achieve uniform heating in a large animal subject over a period of 30 minutes.
Targeted Drug Delivery Using MR-HIFU and Thermosensitive Liposomes (TSLs)
Our group is evaluating the potential to combine hyperthermia generated with MR-HIFU, with thermosensitive liposomes (TSLs) containing doxorubicin, for localized delivery of this drug in the body. The concept of this approach is shown above. A specific region in the body is heated using MR-HIFU and TSLs are injected systemically.
When the TSL’s pass through the heated region of tissue through the bloodstream, they release their contents rapidly, resulting in local release of the drug. Our initial studies are evaluating this concept in preclinical studies using an investigational drug called Thermodox® manufactured by Celsion Inc. which contains Doxorubicin inside a thermosensitive liposome.
Targeted Delivery of Compounds Into the Brain
Transcranial drug delivery into the brain has a wide application in oncology, functional neuroscience, and physiology. When low-power ultrasound exposures are transmitted into the brain the presence of intravenous micro-bubbles, the blood-brain barrier can be temporarily disrupted, enabling passage of drugs and other therapeutic agents into the brain. The blood-brain barrier is an obstacle to drug delivery, and ultrasound is the only noninvasive method known currently to remove this obstacle without causing damage to surrounding brain cells.
Our group is exploring the applications of this noninvasive method for drug delivery in the brain through collaborative projects with scientists at UT Southwestern developing novel therapeutic agents, such as Dr. Ian Corbin and Dr. Dawen Zhao. These studies are all in the preclinical phase, and we hope to learn more about the activity of these compounds in the brain by removing this physiological barrier.