Therapeutic Microbubbles and Ultrasound Pulse Sequences for Noninvasive and Localised Drug Delivery.

Motivation and Background. The most common reason drugs fail in clinical trials is side effects. Drugs administered systemically effect not only the disease, but the entire body. Considerable work has been committed to localise the effects of drugs to diseased sites by manipulating their distribution pattern. Yet the leading approaches of drug modification (e.g., reduction of drug size) and drug attachment to a delivery carrier cannot localise the drug without incurring off-target side effects. The only method that can locally deliver drugs is focussed ultrasound and microbubbles, which is the technique we would like to develop in this project.

Purpose. The purpose of this PhD project is to enhance the safety and performance of ultrasound drug delivery by the simultaneous development of ultrasound sequences and microbubbles. New ultrasound sequences will be based on low pressure, short-pulse sequences (Choi et al., PNAS 2011) that we have developed (Pouliopoulos et al., JASA 2017). We have shown that our sequence suppresses the collateral interactions that are undesirable in drug delivery. Therapeutic microbubbles will be developed with the collaborating company, which are designed specifically to be controlled by the ultrasound beam. Both the sequence and microbubbles will be developed here in a single study to develop the following:
• Therapeutic microbubbles. The student will identify optimal microbubble designs for ultrasound drug delivery and report the mechanisms behind the interactions that are beneficial or harmful.
• Ultrasound sequences. The student will design optimal sequences for drug delivery and explain why certain features promote or suppress interactions that are beneficial or harmful to tissue.

Programme of Work. The programme of work will span 3 years in laboratories at Imperial College London and the company (in the EU). A PhD student with a background in physics or engineering is desired. A multi-disciplinary team of supervisors will guide the PhD student’s work and will be comprised of Dr. James Choi (Department of Bioengineering, Imperial), Dr. Valeria Garbin (Department of Chemical Engineering, Imperial), and a principal investigator at the company. The student will be primarily based at Imperial, but will also have the opportunity to work at the company.

To achieve the purpose of this project, we will begin by understanding the kind of interactions produced within a therapeutic ultrasound beam by direct optical observation, passive acoustic imaging, and modelling. We will then modify the ultrasound pulse shape and microbubble composition and track how the diversity and types of interactions change. This process will be repeated in an iterative manner until the desired interaction is controlled while the other interactions are suppressed. Near the end of the project, we will evaluate in vivo the safety and performance of drug delivery using our new pulse sequences and microbubbles.

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