The viability of a drug delivery system which encapsulates chemotherapeutic drugs (Doxorubicin) in the hydrophobic core of polymeric micelles and triggers release by ultrasound application was investigated at an applied frequency of 500 kHz. The investigation also included elucidating the mechanism of drug release at 70 kHz, a frequency which had previously been shown to induce drug release. A fluorescence detection chamber was used to measure in vitro drug release from both Pluronic and stabilized micelles and a hydrophone was used to monitor bubble activity during the experiments. A threshold for release between 0.35 and 0.40 in mechanical index was found at 70 kHz and shown to correspond with the appearance of the subharmonic signal in the acoustic spectrum. Additionally, drug release was found to correlate with increase in subharmonic emission. No evidence of drug release or of the subharmonic signal was detected at 500 kHz. These findings confirmed the role of cavitation in ultrasonic drug release from micelles. A mathematical model of a bubble oscillator was solved to explore the differences in the behavior of a single 10 um bubble under 70 and 500 kHz ultrasound. The dynamics were found to be fundamentally different; the bubble follows a period-doubling route to chaos at 500 kHz and an intermittent route to chaos at 70 kHz. It was concluded that this type of "intermittent subharmonic" oscillation is associated with the apparent drug release. This research confirmed the central role of cavitation in ultrasonically-triggered drug delivery from micelles, established the importance of subharmonic bubble oscillations as an indicator, and expounded the key dynamic differences between 70 and 500 kHz ultrasonic cavitation.



College and Department

Ira A. Fulton College of Engineering and Technology; Chemical Engineering



Date Submitted


Document Type





drug delivery, doxorubicin, cavitation, pluronic micelles, ultrasound, bubble dynamics, chaos, bifurcation, fluorescence, acoustic spectroscopy