Enhanced HIFU Theranostics with Dual-Frequency-Ring Focused Ultrasound and Activatable Perfluoropentane-Loaded Polymer Nanoparticles

Abstract

High-intensity focused ultrasound (HIFU) has been widely used in tumor ablation in clinical settings. Meanwhile, there is great potential to increase the therapeutic efficiency of temporary cavitation due to enhanced thermal effects and combined mechanical effects from nonlinear vibration and collapse of the microbubbles. In this study, dual-frequency (1.1 and 5 MHz) HIFU was used to produce acoustic droplet vaporization (ADV) microbubbles from activatable perfluoropentane-loaded polymer nanoparticles (PFP@Polymer NPs), which increased the therapeutic outcome of the HIFU and helped realize tumor theranostics with ultrasound contrast imaging. Combined with PFP@Polymer NPs, dual-frequency HIFU changed the shape of the damage lesion and reduced the acoustic intensity threshold of thermal damage significantly, from 216.86 to 62.38 W/cm2. It produced a nearly 20 °C temperature increase in half the irradiation time and exhibited a higher tumor inhibition rate (84.5% ± 3.4%) at a low acoustic intensity (1.1 MHz: 23.77 W/cm2; 5 MHz: 0.35 W/cm2) in vitro than the single-frequency HIFU (60.2% ± 11.9%). Moreover, compared with the traditional PFP@BSA NDs, PFP@Polymer NPs showed higher anti-tumor efficacy (81.13% vs. 69.34%; * p < 0.05) and better contrast-enhanced ultrasound (CEUS) imaging ability (gray value of 57.53 vs. 30.67; **** p < 0.0001), probably benefitting from its uniform and stable structure. It showed potential as a highly efficient tumor theranostics approach based on dual-frequency HIFU and activatable PFP@Polymer NPs.

On-demand regulation and enhancement of the nucleation in acoustic droplet vaporization using dual-frequency focused ultrasound

“…1 illustrates the dual-frequency focused ultrasound system used for the PFP nanodroplets ADV nucleation simulation. The ultrasound transducer consisted of two confocal spherical annular elements, which had a similar geometry as used in previous experimental studies [32] , [33] . The inner ring had a radius r 1 (25 mm) and was stimulated at a high frequency, while the outer ring had a radius r 2 (47 mm) and was stimulated at a lower frequency.…”

“…This was shown to reduce the ADV threshold, manipulate the ADV volume and increase the cavitation efficacy [32] . The dual-frequency HIFU was also shown to effectively activate the phase transition of perfluoropentane (PFP) nanoparticles into microbubbles, while significantly reducing the HIFU threshold for thermal ablation lesion in phantoms, enhancing the antitumor efficacy, and realizing ultrasound monitoring imaging in vitro and in vivo [33] . It indicated a short pulsed high-frequency ultrasound was the main source for ADV, and the long pulsed low-frequency ultrasound increased cavitation-induced bioeffects.…”

Nanomedicines for high‑intensity focused ultrasound cancer treatment and theranostics (Review)

“…Furthermore, it has been indicated that the adoption of NPs can effectively change the acoustic environment (tissue structure, density, blood supply and functional state on ultrasonic transmission and energy deposition during HIFU treatment) of tumour tissues (30), making them more sensitive to HIFU, resulting in greater ablative efficacy with the same or lower HIFU irradiation doses. Additionally, since the first report on the combination of HIFU with nanotechnology in 2000 (31), it has been recognized that HIFU induces target drug release from platforms such as NPs and liposomes to enhance the ablative efficacy of HIFU and improve safety (32); since then, studies have attempted to design nanomedicines to improve the efficacy of HIFU (33)(34)(35)(36) however, progress has not seen clinical translation. Additionally, the promotion of theranostics also highlights novel opportunities in this field.…”

“…The incorporation of PFP also allows ultrasound monitoring of the whole procedure, making these nanodroplets another promising HIFU-based theranostic candidate. On the other hand, Chen et al ( 35 ) focused on HIFU and synthesized PFP-loaded polymer NPs (PFP@Polymer NPs) that were responsive to a dual-frequency HIFU pattern. Compared with single-frequency HIIFU, PFP@Polymer NPs under the irradiation of dual-frequency HIFU (1.1 and 5.0 MHz) were reported to significantly decrease the acoustic intensity threshold needed for ablation from 216.86 to 62.38 W/cm 2 , thus effectively decreasing collateral damage.…”

Focused ultrasound-mediated small-molecule delivery to potentiate immune checkpoint blockade in solid tumors

“…To respond to the thermal effects of FUS, the particles that carry small-molecule agents to the specific sites are designed to be temperature-sensitive, with a certain heat or energy threshold for the drug to be released ( Dromi et al, 2007 ; Luo et al, 2017 ). Futhermore, the particles can act as additional nucleation sites and reduce the cavitation threshold during microbubble (MB) formation, which enhances the mechanical effects of FUS and increases drug unloading through acoustic manipulation at the specific positions ( Airan et al, 2017 ; Khirallah et al, 2019 ; Chen et al, 2021 ). These particles can be either organic, such as lipid- or polymer-based, or inorganic, for example, metallic, or a combination of both types ( Mai et al, 2021 ).…”