Capsule-based Ultrasound-mediated Targeted Drug Delivery

Abstract

Over the last 20 years, capsule endoscopy (CE) has emerged as an important clinical tool for the diagnosis of gastrointestinal (GI) diseases such as Crohn’s disease. Despite the success of CE for diagnosis, there has been minimal progress in advancing therapeutic CE (TCE). Targeted drug delivery (TDD) is a therapeutic modality that could be combined with CE. It allows drugs to be delivered to the diseased tissue, enhancing effectiveness and reducing side effects. Several proof of concept TCEs for TDD exist (Parr et al., 1999; Wilding, Hirst and Connor, 2000; Woods, Constandinou and Member, 2013). However, they have either not progressed beyond bench testing, or cannot enhance drug uptake into or through GI tissues. Focused ultrasound (US) could be combined with TDD (in ultrasound-mediated TDD, UmTDD) to improve the uptake of drug into tissue. However, there is currently no TCE developed for UmTDD.

This thesis describes the development of a TCE device for UmTDD. A prototype TCE was developed containing an UmTDD system (Stewart et al., 2018). This involved developing a fabrication process for miniature focused US transducers. Bench testing of this capsule revealed that acoustic forces produced by the transducers could redirect a stream of microbubbles. This is a promising effect as MBs can enhance the effects of UmTDD and can be couple with drugs. Experimental insonation systems were developed that allowed experiments on cells and tissue (Stewart et al., 2016, 2017). Barrier function of a small intestinal epithelium cell model was found to decrease during insonation (Stewart et al., 2017). The transport of dextran across cells was investigated and there was an increased transport after insonation. To investigate the mechanism responsible for these effects, a microscope was developed that allowed concurrent imaging and insonation. This revealed that the length of intercellular junctions increased during insonation, an effect that was linked to increased permeability. A TCE device for UmTDD was developed and tested in vivo. Fluorescent quantum dots (Qdots) were delivered and their uptake was shown to be enhanced with insonation. Immunofluorescent staining was performed on the tissue sections and revealed the Qdots to be in the mucous layer, not in the tissue. Further experiments are proposed to use mucolytic agents or mucous penetrating particles to overcome the mucous barrier.

This thesis described the progress towards developing UmTDD as a new modality for TCE that could improve treatment of GI diseases such as CD. Results were promising and showed that an ingestible UmTDD system has the potential to improve uptake in the GI tract. Further work is required to translate this system to clinical practice.

Date of Award	2018
Original language	English
Sponsors	Engineering and Physical Sciences Research Council
Supervisor	Inke Nathke (Supervisor), Zhihong Huang (Supervisor) & Sandy Cochran (Supervisor)