Ultrasound imaging guided targeted sonodynamic therapy enhanced by magnetophoretically controlled magnetic microbubbles.

Sonodynamic therapy (SDT) utilizes ultrasonic excitation of a sensitizer to generate reactive oxygen species (ROS) to destroy tumor. Two dimensional (2D) black phosphorus (BP) is an emerging sonosensitizer that can promote ROS production to be used in SDT but it alone lacks active targeting effect and showed low therapy efficiency. In this study, a stable dispersion of integrated micro-nanoplatform consisting of BP nanosheets loaded and Fe3O4 nanoparticles (NPs) connected microbubbles was introduced for ultrasound imaging guided and magnetic field directed precision SDT of breast cancer. The targeted ultrasound imaging at 18 MHz and efficient SDT effects at 1 MHz were demonstrated both in-vitro and in-vivo on the breast cancer. The magnetic microbubbles targeted deliver BP nanosheets to the tumor site under magnetic navigation and increased the uptake of BP nanosheets by inducing cavitation effect for increased cell membrane permeability via ultrasound targeted microbubble destruction (UTMD). The mechanism of SDT by magnetic black phosphorus microbubbles was proposed to be originated from the ROS triggered mitochondria mediated apoptosis by up-regulating the pro-apoptotic proteins while down-regulating the anti-apoptotic proteins. In conclusion, the ultrasound theranostic was realized via the magnetic black phosphorus microbubbles, which could realize targeting and catalytic sonodynamic therapy.

Ultrasound image-guided cancer gene therapy using iRGD dual-targeted magnetic cationic microbubbles.

The gene therapy attracted more and more attention for the tumor therapy. To obtain a safe gene therapy system, the new gene vectors beyond the virus were developed for a high gene therapy efficiency. The ultrasound mediated gene therapy was safer and the plasmid DNA could be delivered by the microbubbles and combined with the ultrasound to increase the gene transfection efficiency. In this work, the cationic microbubbles decorated with Cyclo(Cys-Arg-Gly-Asp-Lys-Gly-Pro-AspCys) (iRGD peptides) and magnetic Fe3O4 nanoparticles (MBiM) was designed for targeted ultrasound contrast imaging guided gene therapy of tumors. The ultrasound image intensity was dramatically enhanced at the tumor site that received MBiM with the magnet applied, compared to those administrated the non-targeted microbubbles (MBb) or the microbubbles with only one target material on the surface (MBM and MBbi). The pGPU6/GFP/Neo-shAKT2 was used as a sample gene, which down regulate the AKT2 protein expression for the cancer therapy. It illustrated that MBiM/AKT2 had the highest gene transfection efficiency in the studied microbubbles mediated by the ultrasound, leading to the AKT2 protein expression downregulation and the strongest tumor killing effect in vitro and in vivo. In summary, a novel and biocompatible gene delivery platform via MBiM with both the endogenous and external targeting effects for breast cancer theranostics was developed.

Contrast-enhanced ultrasound imaging using long-circulating cationic magnetic microbubbles in vitro and in vivo validations.

Traditional encapsulated microbubbles are recently used as delivery carriers for drugs and genes, but they have low efficiency. If the local microbubble concentration could be increased, this might be able to improve the therapeutic efficacy of diseases. In this study, we developed novel cationic magnetic microbubbles (MBM), which could simultaneously realize targeted aggregation under a magnetic field as well as ultrasonographic real-time visualization. Their physicochemical properties, biocompatibility, ultrasonography, magnetic response characteristics, and biodistribution were systematically evaluated. Here, the MBM were 2.55 ± 0.14 µm in size with a positive zeta potential, and had a good biocompatibility. They were able to enhance ultrasonographic contrast both in vitro and in vivo. MBM could be attracted by an external magnet for directional movement and aggregation in vitro. We confirmed that MBM also had a great magnetic response in vivo, by means of fluorescence imaging and contrast-enhanced ultrasound imaging. Following intravenous injection into tumor-bearing mice, MBM showed excellent stability in the internal circulation, and could accumulate in the tumor vasculature through magnetic targeting. With the excellent combination of magnetic response and acoustic properties, cationic magnetic microbubbles (MBM) have promising potential for use as a new kind of drug/gene carrier for theranostics in the future.