Investigation of Microbubble-enhanced Mild Hyperthermia with Focused Ultrasound for Drug Delivery Enhancement

Abstract

Conventional methods for treating cancer include the use of systemic chemotherapeutic drugs. However, due to the tumor’s low drug uptake, high doses of these drugs are needed for effective treatment, which can result in adverse side effects. Research has shown that elevating the temperature of the tumor by 5-10 ℃, defined as mild hyperthermia, results in increased drug uptake of the tumor. Heating of the tumor can be performed via High Intensity Focused Ultrasound (HIFU) however, HIFU focuses energy onto a millimeter size area. Prior work has shown that adding microbubbles during HIFU can enhance the heating. It was suggested that there exists an optimal microbubble concentration that varies with respect to acoustic pressure amplitude that results in enhanced heating and larger lesion formation for ablative purposes. However, no group has investigated bubble-enhanced heating in the context of inducing mild hyperthermia over a larger area. In this work, we first identified and characterized three media that allowed for uniform dilution of microbubbles, developed a robust technique of thermocouple alignment, measured temperature elevation with and without microbubbles of varying concentrations and varying acoustic pressure amplitudes in the characterized media, and imaged microbubble behavior including destruction during heating treatment. Our results showed that solid gel phantoms were more similar to human tissue in terms of acoustic properties and allowed for more reliable temperature measurements. Despite acoustic streaming of the fluid media, our temperature measurements showed that as the acoustic pressure amplitude increases, the optimal microbubble concentration needed for inducing enhanced temperature elevation at the focus decreases. This is due to acoustic streaming where at higher concentrations, attenuation also increases such that the heating occurs prefocally, resulting in little or no enhancement in temperature rise. We were able to induce focal temperature elevation relevant for mild hyperthermia in the gelatin evaporated milk phantom when heating at a focal pressure of 1.5 MPa and 104-105 MBs/mL. Via imaging, we confirmed that the microbubble destruction path changes as microbubble concentration and pulse length changes, which affects where and how much heating occurs in the media. Real time imaging of the microbubbles allowed us to identify that after the first six heating pulses (1.074 MHz, focal pressures of 1.5-2 MPa, 400K cycles), most of the microbubbles that contribute to bubble-enhanced heating at the focus have been destroyed. Furthermore, as the pulse length increases so does the extent of microbubble destruction. Our findings underscore the importance of having a real-time image guidance during ultrasound treatment and the need to further investigate the effects of microbubble concentration and acoustic pressure amplitude for further optimizing heating relevant for mild hyperthermia.