A multifunctional theranostic contrast agent for ultrasound/near infrared fluorescence imaging-based tumor diagnosis and ultrasound-triggered combined photothermal and gene therapy.

Abstract

Encapsulated microbubbles (MBs) have been reported as new theranostic carriers for simultaneous imaging and ultrasound (US)-triggered therapy. Here, we designed a dual-modality US/NIRF contrast agent and extended its applications from image contrast enhancement to combined diagnosis and therapy with US-directed and site-specific targeting. Gold nanorods (AuNRs) resonant at 880 nm together with the NIR797 dye were first encapsulated in lipid-shelled MBs to construct fluorescent gold microbubbles (NIR797/AuMBs) via thin film hydration and mechanical shaking in the presence of sulfur hexafluoride (SF₆) gas. Then, polyethylenimine (PEI)-DNA complexes were electrostatically conjugated onto the surface of the NIR797/AuMBs, forming theranostic encapsulated MBs (PEI-DNA/NIR797/AuMBs). The potential of the PEI-DNA/NIR797/AuMBs for use as a dual-modality contrast enhancement agent was evaluated in vitro and in vivo. The antitumor effect of US/NIR laser irradiation mediating double-fusion suicide gene and photothermal therapy was also investigated using Bel-7402 cells and xenografts. The developed theranostic AuMB complexes could not only provide excellent US and NIRF imaging to detect tumors but also serve as an efficient US-triggered carrier for gene delivery and photothermal ablation of tumors in xenografted nude mice. And US + laser exposure group showed a much higher rate of cell inhibition, apoptosis and necrosis as well as a higher Bel-7402 xenograft inhibition rate than the single gene therapy or single exposure (US or laser) group. PEI-DNA/NIR797/AuMBs would be of great value for providing more comprehensive diagnostic information and to guide more accurate and effective synergistic cancer therapy. This is an original paper focusing on developing a dual-modality US/NIRF contrast agent and extended its applications from image contrast enhancement to combined diagnosis and therapy with US-directed and site-specific targeting. The developed theranostic AuMB complexes could not only provide excellent US and NIRF imaging to detect tumors but also serve as an efficient US-triggered carrier for gene delivery and photothermal ablation of tumors in xenografted nude mice. PEI-DNA/NIR797/AuMBs would be of great value for providing more comprehensive diagnostic information and to guide more accurate and effective synergistic cancer therapy.