Enhancement of Small Molecule Delivery by Pulsed High-Intensity Focused Ultrasound: A Parameter Exploration

Abstract

Chemotherapeutic drug delivery is often ineffective within solid tumors, but increasing the drug dose would result in systemic toxicity. The use of high-intensity focused ultrasound (HIFU) has the potential to enhance penetration of small molecules. However, operation parameters need to be optimized before the use of chemotherapeutic drug in vivo and translation to clinical trial. In this study, the effects of pulsed-HIFU (pHIFU) parameters (spatial-average pulse-average intensity, duty factor, and pulse repetition frequency) to the penetration as well as content of small molecules were evaluated in ex vivo porcine kidneys. Specific HIFU parameters resulted in over 40 times greater Evans blue content and 3.5 times the penetration depth compared to untreated samples. When selected parameters were applied to porcine kidneys in vivo, a 2.3-fold increase in concentration was obtained after a 2-minute pHIFU exposure. Altogether, pHIFU has shown to be an effective modality to enhance both the concentration and penetration depth of small molecules into tissue using the optimized HIFU parameters. Although, performed in normal tissue, this study has the promise of translation into tumor tissue.

Dependence of inertial cavitation induced by high intensity focused ultrasound on transducer F-number and nonlinear waveform distortion

“…However, the experiments also clearly indicate that pis not the only parameter that governs cavitation activity: the metrics of cavitation appear to be highly dependent on the transducer F-number. These observations are consistent with recent reports by us and others (Li et al, 2015;Zhou et al, 2016;ter Haar et al, 2014;Maxwell et al, 2011). Several different mechanisms may be contributing to (or solely responsible for) this effect, and we will consider these mechanisms separately below.…”

“…The induction of de novo cavitation throughout the tumor using pulsed high intensity focused ultrasound (pHIFU) exposures, especially in the dense interstitial structures, may thus circumvent the limitations of UCAs. The effectiveness of this approach has been confirmed in a series of studies harnessing pHIFU-induced inertial cavitation to increase the concentration of doxorubicin or Evans Blue Dye (EBD) in murine pancreatic tumors and porcine kidneys, respectively (Li et al, 2015, Zhou et al, 2016. An important observation from these studies included the presence of a substantial discrepancy in peak negative pressure levels required for inducing inertial cavitation activity.…”

“…Specifically, in the study by Li et al (2015), two highly focused pHIFU transducers (F-numbers 0.75 and 1, frequencies 1.5 and 1.1 MHz, correspondingly) were used, and the treatment was only successful under high peak negative focal pressures correspondingly). In the study by Zhou et al (2016), a less focused 1.1 MHz transducer (F-number 1.4) was used, and the peak negative focal pressure necessary for successful treatment was found to be much lower À6.8 MPa. Similar discrepancies in cavitation threshold across transducers with different form-factors have been reported by another group during continuous high intensity focused ultrasound (HIFU) exposures (ter Haar et al, 2014).…”

“…Importantly, although not consistently reported in the aforementioned studies, the pHIFU output level required for generating a therapeutic effect coincided with the formation of shocks in the in situ focal waveform. The therapeutic effect, as defined qualitatively (fluorescence imaging, Li et al, 2015) or quantitatively (fluorimetric analysis, Zhou et al, 2016) by the enhancement of a delivered substance concentration in the treated areas, exhibited a threshold-like behavior within the range of outputs that corresponded to shock formation at the focus. For example, Fig.…”

Laser ray bundle: a thermometry method for HIFU heating

“…It was driven by a waveform ). This mimicked recent HIFU treatment protocols [11,[52][53][54][55][56][57], and it was a more challenging irradiation protocol to test the RB method. A higher PRF protocol can reduce the total treatment time.…”