|Title:||Microbubbles and nanodroplets based theranostic platform for dual-mode ultrasound and photoacoustic imaging and therapeutics|
|Advisors:||Yang, Mo (BME)|
|Subject:||Hong Kong Polytechnic University -- Dissertations|
Contrast media (Diagnostic imaging)
|Department:||Department of Biomedical Engineering|
|Pages:||xix, 121 pages : color illustrations|
|Abstract:||Biomedical imaging has always been a very important existence, both for clinical diagnosis and basic research. There are many types of biomedical imaging, such as computed tomography (CT) based on X-ray, ultrasound (US) imaging based on ultrasound reflection and scattering, magnetic resonance imaging (MRI) based on magnetic resonance principle, or various optical imaging modalities. Each imaging mode has different imaging mechanism and therefore has its own advantages and disadvantages. Therefore, there is now a trend to combine two or more imaging methods to compensate for each other's advantages and disadvantages to achieve better imaging quality and obtain more imaging information. Contrast agents are essential in biomedical imaging. It can provide a stronger contrast effect, and can even specifically image certain tissues or certain metabolic processes. The contrast agent can be a small molecule, such as Fludeoxyglucose (18F), which is applied to positron emission tomography-computed tomography (PET-CT) to achieve imaging of metabolically active tumor sites. The contrast agent can also be a nanomaterial or a micron material, such as gold nanoparticles, or lipid microbubbles. In this thesis, we are focusing on the multi-functional contrast agents which are used in dual-mode ultrasound and photoacoustic imaging. Ultrasound (US) imaging and photoacoustic (PA) imaging have similar principles. Ultrasound imaging is produced by reflecting the transmitted ultrasound at different interfaces in the tissue. However, the excitation signal of photoacoustic imaging is a laser pulse. The laser energy is absorbed in the tissue and converted into heat, which produces thermal vibrations that are ultimately emitted as broadband ultrasound. The principle of proximity can make the two imaging systems more easily embedded together and achieve a combination of high contrast of optical imaging with the high spatial resolution of ultrasound imaging. The synthesis of dual-mode contrast agents can be achieved by combining ultrasound and photoacoustic contrast agents. First, we designed a contrast agent for dual-mode ultrasound and photoacoustic imaging, which combines polyvinyl alcohol (PVA) microbubbles and molybdenum disulfide (MoS2) nanosheets by electrostatic adsorption. Microbubbles are the most commonly used ultrasound contrast agents, and PVA encapsulated microbubbles provide more stable properties and facilitate subsequent surface modification. The molybdenum disulfide nanosheets have a strong extinction in the near-infrared region, which can convert photon energy into ultrasonic waves and produce photoacoustic contrast. The dual-mode contrast agent has been shown to have good stability and biocompatibility, as well as ultrasound/photoacoustic contrast both in vivo and in vitro.|
In order to enrich the dual-mode contrast agent system based on polyvinyl alcohol microbubbles, we replaced molybdenum disulfide nanosheets with another material with excellent photoacoustic contrast: polydopamine. Polydopamine is oxidized and polymerized by dopamine in an alkaline environment, and has good extinction ability under full-wave illumination, so that photoacoustic contrast can be produced. More importantly, polydopamine has excellent biocompatibility, and the large amount of phenolic hydroxyl groups on the surface makes surface modification easy. We first demonstrated that the polydopamine doped PVA microbubbles have good stability and biocompatibility, as well as in vitro ultrasound/photoacoustic contrast. Next, we modified the RGD peptides on the surface of polydopamine doped PVA microbubbles, a biomolecule that specifically targets epithelial cells at the tumor site. In vitro experiments have demonstrated that PDA doped PVA microvesicles modified with RGD peptides can specifically target epithelial cells Hy.926 and further achieve photothermal therapy of the cells. Since the size of the microbubbles is too large, it appears to be incapable of imaging the inside of the tumor because microbubbles cannot penetrate the blood vessel wall and enter deep into the tumor. We synthesized a nanoscale ultrasound/photoacoustic contrast agent by coating polydopamine on the surface of low-boiling point perfluorohexane nanodroplets. Without any triggering, the contrast agent will only provide photoacoustic imaging with no ultrasound signals. When externally irradiated with near infrared laser light, the photothermal effect of polydopamine raises the temperature of the perfluorohexane nanodroplets, thereby vaporizing to produce perfluorohexane microbubbles, thus obtaining an ultrasound contrast effect. The size of the polydopamine-coated perfluorohexane nanodroplets can be controlled at around 300 nm, with the ability to pass through the vessel wall of the tumor site and into the tumor for imaging and treatment. By adjusting the pH of the synthesis, as well as the volume of the perfluorohexane liquid, size control from 235 nm to 510 nm could be achieved without any introductions of surfactants. The nanodroplets have been shown to have good biocompatibility, as well as in vitro ultrasound and photoacoustic imaging capabilities, which are able to kill tumor cells by photothermal therapy.
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