Development and evaluation of an ultrasound-triggered microbubble combined transarterial chemoembolization (TACE) formulation on rabbit VX2 liver cancer model.

Transarterial chemoembolization (TACE) is an image-guided locoregional therapy used for the treatment of patients with primary or secondary liver cancer. However, conventional TACE formulations are rapidly dissociated due to the instability of the emulsion, resulting in insufficient local drug concentrations in the target tumor. Methods: To overcome these limitations, a doxorubicin-loaded albumin nanoparticle-conjugated microbubble complex in an iodized oil emulsion (DOX-NPs-MB complex in Lipiodol) has been developed as a new ultrasound-triggered TACE formulation. Results: (1) Microbubbles enhanced therapeutic efficacy by effectively delivering doxorubicin- loaded nanoparticles into liver tumors via sonoporation under ultrasound irradiation (US+). (2) Microbubbles constituting the complex retained their function as an ultrasound contrast agent in Lipiodol. In a rabbit VX2 liver cancer model, the in vivo study of DOX-NPs-MB complex in Lipiodol (US+) decreased the viability of tumor more than the conventional TACE formulation, and in particular, effectively killed cancer cells in the tumor periphery. Conclusion: Incorporation of doxorubicin-loaded microbubble in the TACE formulation facilitated drug delivery to the tumor with real-time monitoring and enhanced the therapeutic efficacy of TACE. Thus, the enhanced TACE formulation may represent a new treatment strategy against liver cancer.

Overcoming anticancer resistance by photodynamic therapy-related efflux pump deactivation and ultrasound-mediated improved drug delivery efficiency.

One of the major obstacles to successful chemotherapy is multi-drug resistance (MDR). A multi-drug resistant cancerous cell abnormally overexpresses membrane transporters that pump anticancer drugs out of the cell, resulting in low anticancer drug delivery efficiency. To overcome the limitation, many attempts have been performed to inhibit the abilities of efflux receptors chemically or genetically or to increase the delivery efficiency of anticancer drugs. However, the results have not yet been satisfactory. In this study, we developed nanoparticle-microbubble complexes (DOX-NPs/Ce6-MBs) by conjugating doxorubicin loaded human serum albumin nanoparticles (DOX-NPs) onto the surface of Chlorin e6 encapsulated microbubbles (Ce6-MBs) in order to maximize anticancer efficiency by overcoming MDR. Under the ultrasound irradiation, DOX-NPs and Ce6 encapsulating self-assembled liposomes or micelles were effectively delivered into the cells due to the sonoporation effect caused by the microbubble cavitation. At the same time, reactive oxygen (ROS) generated from intracellularly delivered Ce6 by laser irradiation arrested the activity of ABCG2 efflux receptor overexpressed in doxorubicin-resistant breast cancer cells (MCF-7/ADR), resulting in increased the chemotherapy efficacy. In addition, the total number of side population cells that exhibit the properties of cancer stem-like cells were also reduced by the combination of photodynamic therapy and chemotherapy. In conclusion, DOX-NPs/Ce6-MBs will provide a platform for simultaneously overcoming MDR and increasing drug delivery and therefore, treatment efficiency, under ultrasound irradiation.

Microbubbles used for contrast enhanced ultrasound and theragnosis: a review of principles to applications.

Ultrasound was developed several decades ago as a useful imaging modality, and it became the second most popular diagnostic tool due to its non-invasiveness, real-time capabilities, and safety. Additionally, ultrasound has been used as a therapeutic tool with several therapeutic agents and in nanomedicine. Ultrasound imaging is often used to diagnose many types of cancers, including breast, stomach, and thyroid cancers. In addition, ultrasound-mediated therapy is used in cases of joint inflammation, rheumatoid arthritis, and osteoarthritis. Microbubbles, when used as ultrasound contrast agents, can act as echo-enhancers and therapeutic agents, and they can play an essential role in ultrasound imaging and ultrasound-mediated therapy. Recently, various types of ultrasound contrast agents made of lipid, polymer, and protein shells have been used. Air, nitrogen, and perfluorocarbon are usually included in the core of the microbubbles to enhance ultrasound imaging, and therapeutic drugs are conjugated and loaded onto the surface or into the core of the microbubbles, depending on the purpose and properties of the substance. Many research groups have utilized ultrasound contrast agents to enhance the imaging signal in blood vessels or tissues and to overcome the blood-brain barrier or blood-retina barrier. These agents are also used to help treat diseases in various regions or systems of the body, such as the cardiovascular system, or as a cancer treatment. In addition, with the introduction of targeted moiety and multiple functional groups, ultrasound contrast agents are expected to have a potential future in ultrasound imaging and therapy. In this paper, we briefly review the principles of ultrasound and introduce the underlying theory, applications, limitations, and future perspectives of ultrasound contrast agents.