Enhancement of HIFU ablation by sonosensitizer-loading liquid fluorocarbon nanoparticles with pre-targeting in a mouse model

Abstract

High intensity focused ultrasound (HIFU) is a noninvasive thermal ablation technique for the treatment of benign and malignant solid masses. To improve the efficacy of HIFU ablation, we developed poly (lactide-co-glycolide) (PLGA) nanoparticles encapsulating perfluoropentane (PFP) and hematoporphyrin monomethyl ether (HMME) as synergistic agents (HMME+PFP/PLGA). Two-step biotin-avidin pre-targeting technique was applied for the HIFU ablation. We further modified the nanoparticles with streptavidin (HMME+PFP/PLGA-SA). HMME+PFP/PLGA-SA were highly dispersed with spherical morphology (477.8 ± 81.8 nm in diameter). The encapsulation efficiency of HMME and PFP were 46.6 ± 3.3% and 40.1 ± 2.6%, respectively. The binding efficiency of nanoparticles to streptavidin was 95.5 ± 2.5%. The targeting ability of the HMME+PFP/PLGA-SA nanoparticles was tested by parallel plate flow chamber in vitro . In the pre-targeting group (HMME+PFP/PLGA-SA), a large number of nanoparticles bound to the peripheral and surface of the cell. In the HIFU ablation experiment in vivo , compared with the other groups, the largest gray-scale changes and coagulation necrosis areas were observed in the pre-targeting (HMME+PFP/PLGA-SA) group, with the lowest energy efficiency factor value. Moreover, the microvessel density and proliferation index declined, while the apoptotic index increased, in the tumor tissue surrounding the coagulation necrosis area in the pre-targeting group. Meanwhile, the survival time of the tumor-bearing nude mice in the pre-targeting group was significantly longer than that in the HIFU treatment group. These results suggest that HMME+PFP/PLGA-SA have high potential to act as synergistic agents in HIFU ablation.

Biomedical Applications of Reactive Oxygen Species Generation by Metal Nanoparticles

“…Particularly, in more recent decades, NPs have been successfully used in the clinic as effective tools for alternative therapy such as photodynamic therapy (PDT) [ 13 , 14 , 15 ], high-intensity focused ultrasound therapy (HIFU) [ 16 ], photothermal therapy (PPT) [ 17 ] and sonodynamic therapy (SDT) [ 18 , 19 , 20 , 21 ]. The ever-increasing success of these therapies is due to their ability to induce the death of prokaryotic and eukaryotic cells through key cellular mechanisms such as that of induction of NP-mediated reactive oxygen species (ROS) generation [ 22 ].…”

The Study of Enhanced High-Intensity Focused Ultrasound Therapy by Sonodynamic N2O Microbubbles

“…Therefore, it is necessary to increase the efficacy of HIFU. Many studies have confirmed that both microbubbles and SDT can improve the efficacy of HIFU [15, 16, 35]. The N 2 O-loaded microbubbles prepared in this study have a smaller particle size, but similar characteristics as ultrasonic microbubble contrast agents.…”

“…In addition, microbubbles as an exogenous cavitation nucleus also reduce the tissue cavitation threshold and enhance the cavitation effect of HIFU as it passes through the blood circulation into the tumor tissue [14]. In recent years, studies have indicated that sonodynamic therapy (SDT) can synergistically enhance HIFU treatment efficacy [15, 16]. The interactions between the sonosensitizers and ultrasound produce reactive oxygen species (ROS), including singlet oxygen and hydroxyl radicals, which kill tumor cells and inhibit tumor growth via apoptosis and necrosis [17].…”

Biotin-streptavidin-guided two-step pretargeting approach using PLGA for molecular ultrasound imaging and chemotherapy for ovarian cancer

“…The concept of pre-targeting originates from radionuclide imaging research and has attracted great attention for tumor treatment and imaging (Karacay et al, 2002;Kraeber-Bodere et al, 2015;Zhu, Jain & Baxter, 1998). Ding et al (2019) reported a pre-targeting strategy using technetium 99m -labeled dibenzocyclooctyne derivatives to achieve the imaging of glucose metabolism with a high tumor/blood ratio and tumor/muscle ratio. Zhang et al, (2019) used a two-step biotin-avidin pre-targeting strategy involving poly lactic-co-glycolic acid (PLGA) nanoparticles encapsulating perfluoro-n-pentane (PFP) for high intensity focused ultrasound (HIFU) ablation.…”

“…Ding et al (2019) reported a pre-targeting strategy using technetium 99m -labeled dibenzocyclooctyne derivatives to achieve the imaging of glucose metabolism with a high tumor/blood ratio and tumor/muscle ratio. Zhang et al, (2019) used a two-step biotin-avidin pre-targeting strategy involving poly lactic-co-glycolic acid (PLGA) nanoparticles encapsulating perfluoro-n-pentane (PFP) for high intensity focused ultrasound (HIFU) ablation. However, this technology is rarely used in ultrasound molecular imaging and synergistic treatment research.…”