Evaluating the Effect of Drug Loading on the Acoustic Response of Nanobubbles in Stable and Inertial Cavitation Regimes

Nanobubbles (NBs) have been investigated as ultrasound contrast agents and drug delivery carriers in medical applications. Previous studies have reported the efficacy of NBs in imaging and therapy. However, ultrasound (US) exposure parameters for stable and inertial cavitation of NBs need to be investigated. This study examines passive cavitation detection of ultrasound signatures from two types of NBs across three pressure ranges using passive cavitation detection (PCD), aiming to investigate their cavitation behaviour with and without the inclusion of the chemotherapeutic drug, Doxorubicin (HDox). We compared the power spectral density (PSD) of non-drug loaded Propylene-Glycol Glycerol (PGG) NBs and HDox NBs under 300 kPa, 600 kPa, and 900 kPa pressures at 1 MHz fundamental frequency and 1% duty cycle. Our results indicate that NBs exhibit stable cavitation at 300 kPa, while a mix of inertial and stable cavitation occur at 600 and 900 kPa. The loading of NBs with HDox affects their acoustic activity. HDox NBs exhibit higher acoustic activity at 300 kPa, but their PCD signal profile becomes similar to PGG NBs at 600 kPa and 900 kPa. A numerical model was used to gain additional insight into some of the characteristics of the NB power spectra observed. Our simulations indicate that nonlinear bubble oscillations are characterized by distinctly pronounced harmonics, particularly the third harmonic, with this effect being even more prominent in smaller bubbles and lower ultrasound amplitudes. These findings will help determine ultrasound pulse parameters in imaging and therapeutic applications.