Sonoporation Using Nanoparticle-Loaded Microbubbles Increases Cellular Uptake of Nanoparticles Compared to Co-Incubation of Nanoparticles and Microbubbles

Abstract

Therapeutic agents can benefit from encapsulation in nanoparticles, due to improved pharmacokinetics and biodistribution, protection from degradation, increased cellular uptake and sustained release. Microbubbles in combination with ultrasound have been shown to improve the delivery of nanoparticles and drugs to tumors and across the blood-brain barrier. Here, we evaluate two different microbubbles for enhancing the delivery of polymeric nanoparticles to cells in vitro: a commercially available lipid microbubble (Sonazoid) and a microbubble with a shell composed of protein and nanoparticles. Various ultrasound parameters are applied and confocal microscopy is employed to image cellular uptake. Ultrasound enhanced cellular uptake depending on the pressure and duty cycle. The responsible mechanisms are probably sonoporation and sonoprinting, followed by uptake, and to a smaller degree enhanced endocytosis. The use of commercial Sonazoid microbubbles leads to significantly lower uptake than when using nanoparticle-loaded microbubbles, suggesting that proximity between cells, nanoparticles and microbubbles is important, and that mainly nanoparticles in the shell are taken up, rather than free nanoparticles in solution.

Ultrasound-Mediated Drug Delivery With a Clinical Ultrasound System: In Vitro Evaluation

“…For example, based on previous in vitro results of Lammertink et al future patients receiving chemotherapy or chemoradiation containing cisplatin could benefit from the addition of local USMB therapy ( Lammertink et al, 2016 ). Furthermore, USMB therapy could be used to enhance the effect of therapeutic antibodies or nanoparticles ( Heath et al, 2012 ; Togtema et al, 2012 ; Bellary et al, 2020 ; Snipstad et al, 2021a ; Snipstad et al, 2021b ). Finally, clinical studies evaluating the potential of USMB therapy in addition to radiotherapy in the absence of drugs are ongoing ( Shi et al, 2021 ) ( Clinicaltrials.gov NCT04431674, NCT04431648).…”

Nano-drug delivery system for pancreatic cancer: A visualization and bibliometric analysis

“…A recent bibliometric study showed that the combination of NDDS and ultrasound microbubbles has become a hot spot to improve tumor efficacy ( Wu et al, 2021 ). Ultrasound microbubbles can improve membrane permeability, making therapeutic drugs easy to pass through biological barriers such as vascular endothelium and cell membrane ( Meng et al, 2021 ; Snipstad et al, 2021 ). Compared with higher-frequency ultrasound, low-frequency ultrasound microbubbles are more effective in promoting the accumulation of NPs in PC tissues ( Lin et al, 2018 ).…”

Synergistic enhancement of cell death by triple combination therapy of docetaxel, ultrasound and microbubbles, and radiotherapy on PC3 a prostate cancer cell line

“…The effectiveness of the double combination therapy of TXT and USMB depended on microbubble concentration. It has also been shown that the efficacy of drug delivery depended on the proximity of microbubbles to the plasma membrane and the bubble-to-cell ratio [ 42 , 43 , 44 ]. In addition, the in vivo application of USMB at higher ultrasound pressures (1.65 MPa) with docetaxel demonstrated a significant effect on tumour cell death [ 24 ].…”