Abstract
Anti-vascular therapy directly causes abnormal tumor vessel disruption to starve tumor cells by using vascular disrupting agents (VDAs) and ultrasound stimulated microbubble destruction (USMD). Combining anti-vascular therapy and chemotherapy, vascular disruption can break the barrier of tumor microenvironments to improve drug penetration and further inhibit tumor growth. Acoustic phase-changed nanodroplets contain with liquid core to improve the in vivo lifetime and drug-loaded stability than gaseous microbubbles. When drug-loaded nanodroplets receive ultrasound stimulation, liquid core will be vaporized to gaseous phase to form bubbles and release drugs. This phenomenon of acoustic droplet vaporization (ADV) simultaneously produces ultrasound contrast imaging and drug delivery to provide theranostic applications in medical research. Furthermore, the process of ADV also produces mechanical force to induce bioeffect on vascular endothelial cells, which might be a novel and potential strategy for anti-vascular therapy. This thesis tried to induce anti-vascular therapy by ADV and evaluate the intratumoral blood perfusion, drug penetration, and cellular bioeffects after treatment. Firstly, the feasibility of using ADV to disrupt vessel wall and improve the nanoparticle penetration in solid tumors was evaluated in chapter 2. Comparison with micro- and nano-sized droplet vaporization, nanodroplets showed longer effective treatment time to continuously disrupt vessels and improve nanoparticle penetration. Moreover, the mechanical force induced by intertissue ADV and ADV-generated bubble (ADV-B) cavitation can extend the penetration distance of nanoparticles to improve the uniformity of intratumoral distribution. The second part presented in chapter 3 attempted to use drug-loaded nanodroplet vaporization to produce anti-vascular therapy and chemotherapy simultaneously. Ultrasound contrast imaging indicated the real-time location of ADV occurring during treatment and the subsequent reduction of tumor perfusion for theranostic applications. The intratumoral spatial cooperation of combination therapy revealed vascular disruption in the central region and drug penetration in both central and peripheral region to complement the treatment resistance of each other. In chapter 4, the behaviors of intertissue ADV-Bs were investigated to assess the feasibility of moving intertissue ADV-Bs into the poorly perfused regions of solid tumors. Intravital imaging demonstrated intertissue ADV-Bs can be pushed to distant tissue away from the adjacent vessels and activated for cavitation by ultrasound stimulation. The in vitro experiments revealed cell membrane damage induced by ADV-B formation and movement, which proposed a potential ability of intertissue ADV-Bs to directly damage tumor cells by physical therapy. Therefore, this thesis demonstrated the feasibility for achieving anti-vascular therapy and improving drug penetration by ADV, and evaluated the theranostic applications for nanodroplets in tumor vessels and tissue. These results provided valuable information for medical development of ADV in future.