The development of advanced contrast agents for ultrasound and photoacoustic imaging
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Light and sound are the ones of major energy sources used in the biomedical field throughout history. Today, these energy sources provide foundation for optical, ultrasound, and hybrid imaging technologies. Even though ultrasound and optical imaging techniques alone have various advantages, their applications are often limited by their disadvantages. For example, optical imaging has a low penetration depth beyond which the spatial resolution is drastically reduced; ultrasound imaging has the extended penetration depth and spatial/temporal resolution, but also low contrast. The combination of light and sound can overcome these limitations because optical and ultrasound imaging have high contrast and a deep penetration depth, respectively. I developed photoacoustic and ultrasound contrast agents to enable and assist combined light and ultrasound multimodal imaging. The developed photoacoustic contrast agents consist of gold nanoparticles, whose surface was modified with a biocompatible polymer, glycol chitosan. Gold nanoparticles absorbed light and generated photoacoustic signals; the surface coating polymer played an important role in the stability and functionality of gold nanoparticles in target sites. These glycol-chitosan-coated gold nanoparticles were applied to cancer cell imaging and lymph node mapping. After the selective accumulation of gold nanoparticles in the cancer cells or lymph nodes, gold nanoparticles produced enhanced photoacoustic signals through the plasmon coupling effect. Both in vitro and in vivo photoacoustic imaging confirmed the feasibility of glycol-chitosan coated gold nanoparticles as a photoacoustic contrast agent. The developed ultrasound contrast agents were composed of gold nanoparticles as a photocatalyst and azide compounds as a gas-generating precursor. If the gold nanoparticles were irradiated by a laser, they produced photo-induced electrons for the photolysis of azide compounds, which released nitrogen gas molecules. By these generated N2 bubbles, the enhanced contrast was achieved in ultrasound imaging. Based on these results, gas-generating gold nanorods were developed for ultrasound and photoacoustic multimodal imaging in in vivo applications. Because of the high absorption coefficient and the tunable surface plasmon resonance peak, gold nanorods have been a promising photoacoustic contrast agent. Moreover, these unique optical properties also enable photocatalytic reduction of azide groups with near IR laser. The developed azide-conjugated gold nanorods successfully generated enhanced photoacoustic and ultrasound signals during in vivo imaging. The developed photoacoustic and ultrasound contrast agents have synergistic effects by the combination of two energy sources into one imaging modality. As a result, both contrast-agent-aided photoacoustic imaging and laser-induced contrast-enhanced ultrasound imaging techniques became possible. These new imaging techniques may overcome the limitations that conventional optical and ultrasound imaging have.