Ultrasound Microbubbles Enhance the Efficacy of Insulin-Like Growth Factor-1 Therapy for the Treatment of Noise-Induced Hearing Loss

The application of insulin-like growth factor 1 (IGF-1) to the round window membrane (RWM) is an emerging treatment for inner ear diseases. RWM permeability is the key factor for efficient IGF-1 delivery. Ultrasound microbubbles (USMBs) can increase drug permeation through the RWM. In the present study, the enhancing effect of USMBs on the efficacy of IGF-1 application and the treatment effect of USMB-mediated IGF-1 delivery for noise-induced hearing loss (NIHL) were investigated. Forty-seven guinea pigs were assigned to three groups: the USM group, which received local application of recombinant human IGF-1 (rhIGF-1, 10 µg/µL) following application of USMBs to the RWM; the RWS group, which received IGF-1 application alone; and the saline-treated group. The perilymphatic concentration of rhIGF-1 in the USM group was 1.95- and 1.67- fold of that in the RWS group, 2 and 24 h after treatment, respectively. After 5 h of 118 dB SPL noise exposure, the USM group had the lowest threshold shift in auditory brainstem response, least loss of cochlear outer hair cells, and least reduction in the number of synaptic ribbons on postexposure day 28 among the three groups. The combination of USMB and IGF-1 led to a better therapeutic response to NIHL. Two hours after treatment, the USM group had significantly higher levels of Akt1 and Mapk3 gene expression than the other two groups. The most intense immunostaining for phosphor-AKT and phospho-ERK1/2 was detected in the cochlea in the USM group. These results suggested that USMB can be applied to enhance the efficacy of IGF-1 therapy in the treatment of inner ear diseases.

Treatment of pancreatic cancer cells in vitro using ultrasound, microbubbles, and gemicitabine

Ultrasonically stimulated microbubbles can enhance the localized delivery and cytotoxic effects of chemotherapy drugs to cells by transient permeabilization of cell membranes in a process called sonoporation. However, there is insufficient data investigating whether ultrasound and microbubbles (USMB) enhances the delivery and cytotoxicity of the nucleoside analog (NA) gemcitabine. To address this gap in the literature, cancer cells were sonicated using low frequency ultrasound in combination with Definity® microbubbles in the presence of NAs. Viability analyses show that gemcitabine in combination with USMB additively enhanced cell death, suggesting that these two therapies mediate cell death independent of one another. This was confirmed when USMB treatment did not enhance (nor impair) the retention of a radiolabeled NA molecule. Altogether, these data suggest that the laws of diffusion forcing small molecules across a barrier cannot solely describe the efficacy of sonoporation; there are obviously important biological factors specific to the molecule intended to be delivered to consider as well.

Treatment of pancreatic cancer cells in vitro using ultrasound, microbubbles, and gemicitabine

Ultrasonically stimulated microbubbles can enhance the localized delivery and cytotoxic effects of chemotherapy drugs to cells by transient permeabilization of cell membranes in a process called sonoporation. However, there is insufficient data investigating whether ultrasound and microbubbles (USMB) enhances the delivery and cytotoxicity of the nucleoside analog (NA) gemcitabine. To address this gap in the literature, cancer cells were sonicated using low frequency ultrasound in combination with Definity® microbubbles in the presence of NAs. Viability analyses show that gemcitabine in combination with USMB additively enhanced cell death, suggesting that these two therapies mediate cell death independent of one another. This was confirmed when USMB treatment did not enhance (nor impair) the retention of a radiolabeled NA molecule. Altogether, these data suggest that the laws of diffusion forcing small molecules across a barrier cannot solely describe the efficacy of sonoporation; there are obviously important biological factors specific to the molecule intended to be delivered to consider as well.

Enhanced Radiosensitization for Cancer Treatment with Gold Nanoparticles through Sonoporation

We demonstrate the megavoltage (MV) radiosensitization of a human liver cancer line by combining gold-nanoparticle-encapsulated microbubbles (AuMBs) with ultrasound. Microbubbles-mediated sonoporation was administered for 5 min, at 2 h prior to applying radiotherapy. The intracellular concentration of gold nanoparticles (AuNPs) increased with the inertial cavitation of AuMBs in a dose-dependent manner. A higher inertial cavitation dose was also associated with more DNA damage, higher levels of apoptosis markers, and inferior cell surviving fractions after MV X-ray irradiation. The dose-modifying ratio in a clonogenic assay was 1.56 ± 0.45 for a 10% surviving fraction. In a xenograft mouse model, combining vascular endothelial growth factor receptor 2 (VEGFR2)-targeted AuMBs with sonoporation significantly delayed tumor regrowth. A strategy involving the spatially and temporally controlled release of AuNPs followed by clinically utilized MV irradiation shows promising results that make it worthy of further translational investigations.