Investigation of Photoacoustic Imaging-Guided Noninvasive High Intensity Focused Ultrasound and Photothermal Therapy

Abstract

A variety of therapeutic methods (i.e. invasive surgery, radiation therapy, cystectomy, and photodynamic therapy) have been investigated to treat non-neoplastic diseases and to treat the damaged internal organs. However, some of these therapeutic approaches are still performed in an ionizing or invasive manner and can thus cause a lot of side-effects such as bleeding, wound infection, damage normal tissues and long recovery time, etc. In particular, no clamping can be accessible to damaged tissue components in microsizes such as the carotid artery, veins, and nerves. Therefore, there is an urgent demand for developing a novel minimally- or non-invasive treatment approaches to improve the survival rates of patients. Recently, high intensity focused ultrasound (HIFU) and photothermal therapy (PTT) have been suggested as a non-invasive or minimally invasive, harmless and highly efficient therapeutic techniques and have been widely used in tissue coagulation as well as dissolution for ischemic stroke. To improve the efficacy of HIFU and PTT treatments, the progress and marginal outcomes of thermal therapeutics still needs to be monitored and evaluated. Thus, HIFU and PTT treatments can be performed totally noninvasively. Currently, HIFU and PTT treatment have been extensively carried out with imaging guidance modalities such as magnetic resonance imaging (MRI), ultrasound imaging (US) or optical coherence tomography (OCT). However, US imaging still suffers from the lack of accuracy and specificity as well as low image contrast, particularly for noninvasive localization and treatment evaluation. MRI scanners are still expensive and bulky systems with lengthy scanning time. OCT suffers from the limited visualization of tumors less than a few millimeters in the body which are difficult to obtain information from the depth of the tissue. In this study, we employed photoacoustic imaging (PAI) technique, which has been developed as a novel promising hybrid imaging modality for early cancer detection, to guide HIFU and PTT treatment. In addition, theranostic agents have been addressed to enhance photothermal efficacy and to boost the sensitivity and specificity of PAI for targeting the diseased tissue. The objective of this study is to investigate the potential application of HIFU, PTT and HIFU integrated PTT thermal modalities with PAI to detect the location of the tumor and to monitor denatured lesion for the safe and effective thermal therapy. In this dissertation, as the first step, a new evaluation platform PAI integrated with HIFU treatment had been presented to provide information on the location of HIFU treated lesions, indicating the great potential to provide feedback on HIFU thermal reatment under ex vivo conditions. Then, the system was developed to PAI-guided dual-thermal treatments (laser and HIFU). In the HIFU therapy, laser light was utilized to irradiate the sample simultaneously with HIFU radiation. It was demonstrated that the integration of acoustic intensity with optical energy additively augmented the degree of irreversible tissue denaturation at a low thermal dosage and the margin of thermally-treated regions after the dual-thermal therapy were detected with high contrast PAI, resulting in PA signals can be used as the indicator for tissue coagulation. We then summarized the development of exogenous photoacoustic contrast agents and demonstrated their utility in ultrahigh sensitivity imaging of tumors as well as in photothermal therapy studies. Finally, we further investigated a novel smart nanocarriers for multifunctional chemotherapy, photothermal therapy (PTT) and photoacoustic image (PAI) contrast and demonstrated it provided nontoxic, enhanced the heating effect, improved sensitivity images and the efficacy of the drug delivery in living rabbit bearing eye tumor.