APPLICATIONS OF THERAPEUTIC ULTRASOUND AND CAVITATION ENHANCING AGENTS TO OVERCOME BIOLOGICAL BARRIERS

The practice of medicine, both in the creation of therapeutic agents and the administration of care, is a delicate balancing act of negatively affecting disease and preserving healthy biological systems. Many medicines effective against disease have consequences for the rest of the body which must be considered and mitigated for effective treatment. Localized therapy can reduce unwanted systemic effects and concentrate the intervention at the site where it is most needed. To deliver therapy locally, a variety of biological barriers must be overcome. The strategy of this thesis is to demonstrate how the challenges of a variety of biological barriers can be addressed using ultrasound and cavitation agents to improve the efficacy of therapeutic interventions.In this thesis, we describe how ultrasound and cavitation agents can be employed to improve treatment of local diseases by overcoming the biological barriers to drug delivery in bacterial biofilms, hypoxic tumors, and the brain. We begin by using phase-change nanodroplets to improve antibiotic efficacy against drug-resistant bacterial biofilms. Through the use of ultrasound and nanodroplets, we created bubbles on demand to disrupt the physical matrix of biofilms and increase drug penetration to clear infection. Next we shift to the tumor hypoxia barrier, where low oxygen levels in tumors reduce the effectiveness of radiation therapy. We explore the use of oxygen-filled microbubbles, which can be burst at the tumor using ultrasound, to augment the tumor’s susceptibility to radiation. After characterizing the circulation kinetics of the oxygen microbubbles, we then tested their potential to change radiation outcomes, and elucidated how differences in animal and tumor model can alter the response to ultrasound, microbubbles and radiation.Finally, our focus settles on the challenge of drug delivery to the brain. We begin by first characterizing ultrasound parameters that can temporarily increase permeability in a targeted region of the brain, and demonstrate the ability to reproducibly deliver compounds across the blood-brain barrier. We then use this capability to deliver a model drug to reloadable drug reservoir in the brain, increasing the longevity of the compound at the target site, allowing for sustained drug presence.