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.
Highlights
High-intensity focused ultrasound (HIFU) is a rapidly developing technique for microinvasive ablation of tumors in recent years
Our results showed that the largest coagulation necrosis volume was observed in the pre-targeting (HMME+PFP/PLGA-SA+High intensity focused ultrasound (HIFU)) group, which was significantly different from other groups (P < 0.05), followed by the direct targeting (HMME+PFP/ PLGA-Ab+HIFU) group
The carbodiimide method was used to combine the amino groups on the streptavidin with the carboxyl groups on the PLGA to form stable ester bonds, thereby producing streptavidin-modified nanoparticles (HMME+PFP/PLGA-SA)
Summary
High-intensity focused ultrasound (HIFU) is a rapidly developing technique for microinvasive ablation of tumors in recent years. Liquid fluorocarbon nanoparticles, prepared by encapsulating liquid fluorocarbon with lipid or polymer materials, are considered as potent synergistic agents because their nano-size and liquid-gas phase transition[13] They are liquid at room temperature, when temperature rises or there is ultrasonic irradiation, the liquid fluorocarbon in the nanoparticles would change from liquid to gas and form microbubbles, thereby increasing the cavitation effect of HIFU treatment[14,15,16,17]. Their results showed significantly enhanced HIFU ablation, both in vivo and in vitro This might be caused by the phase transition of PFH induced by the high temperature at the focal point of HIFU, which produces bubbles to change the acoustic environment and increase the energy accumulation.
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