Multifunctional Theranostic Contrast Agent for US/NIRF-Based Tumor Diagnosis and US-Triggered Combined Photothermal and Gene Therapy

Abstract

Purpose: Encapsulated microbubbles (MBs) have been reported asnew theranostic carriers for simultaneous imaging and ultrasound (US)-triggered therapy. Here, we designed a dual-modality US/NIRF contrastagent and extended its applications from image contrast enhancement tocombined diagnosis and therapy with US-directed and site-specifictargeting. Methods: Gold nanorods (AuNRs) resonant at 880 nm together with theNIR797 dye were first encapsulated in lipid-shelled MBs to constructfluorescent gold microbubbles (NIR797/AuMBs) via thin film hydration andmechanical shaking in the presence of sulfur hexafluoride (SF6) gas.Then, polyethylenimine (PEI)-DNA complexes were electrostaticallyconjugated onto the surface of the NIR797/AuMBs, forming theranosticencapsulated MBs (PEI-DNA/NIR797/AuMBs). The potential of the PEIDNA/NIR797/AuMBs for use as a dual-modality contrast enhancement agentwas evaluated in vitro and in vivo. The antitumor effect of US/NIR laserirradiation mediating double-fusion suicide gene and photothermal therapywas also investigated using Bel-7402 cells and xenografts. Results: The developed theranostic AuMB complexes could not only provideexcellent US and NIRF imaging to detect tumors but also serve as anefficient US-triggered carrier for gene delivery and photothermalablation of tumors in xenografted nude mice. And US + laser exposuregroup showed a much higher rate of cell inhibition, apoptosis andnecrosis as well as a higher Bel-7402 xenograft inhibition rate than thesingle gene therapy or single exposure (US or laser) group. Conclusions: PEI-DNA/NIR797/AuMBs would be of great value for providingmore comprehensive diagnostic information and to guide more accurate andeffective synergistic cancer therapy.