Folate-targeted perfluorohexane nanoparticles carrying bismuth sulfide for use in US/CT dual-mode imaging and synergistic high-intensity focused ultrasound ablation of cervical cancer

Abstract

The integration of multimodal contrast-enhanced diagnostic imaging techniques with noninvasive high-intensity focused ultrasound (HIFU) synergistic therapy could allow the real-time guidance, monitoring, and assessment of cancer therapeutic procedures and effects. Herein, we investigated the use of folate-targeted perfluorohexane nanoparticles carrying bismuth sulfide (Bi₂S₃) (FLBS-PFH-NPs) as a dual-modal contrast agent for ultrasound/computed tomography (US/CT) imaging and aimed to targeted increase the therapeutic efficiency of HIFU for cervical cancer treatment. FLBS-PFH-NPs were fabricated to investigate their potential as theranostic nanoplatforms. Their characteristics, phase-transformation properties, and cytotoxicities were also studied in this work. Sequential modifications with polyethylene glycol (PEG) endowed the FLBS-PFH-NPs with excellent stability and good biocompatibility. Moreover, compared with a non-folate-targeted group, the experimental group that received folate ligands had higher internalization efficiency and specificity. We sequentially investigated the effectiveness of these nanoparticles when used as dual-modal contrast agents in US and CT imaging in vitro and in vivo. The capsulated PFH could undergo a phase transition and form microbubbles upon ultrasonic irradiation, which enhanced the cavitation effects of HIFU in the targeted regions. Then, they were applied to in vitro bovine liver samples; the composite nanoparticles improved the efficiency of HIFU synergistic ablation. Our in vivo results also revealed that the coagulative necrosis volumes of tumors in the folate-targeted groups with HIFU ablation after FLBS-PFH-NP administration were significantly greater than those of the non-folate-targeted groups. Pathological and immunohistochemical examinations were systematically performed to further verify these results. In brief, FLBS-PFH-NPs may serve as a dual-modal contrast agent to enhance US/CT imaging and HIFU synergistic therapy. Novel nanosized multifunctional contrast agents would be of great value and could provide more comprehensive diagnostic information for more accurate and effective cancer therapy.