Progress towards ultrasound-mediated targeted drug delivery in the small intestine

The intestinal mucosa acts as a selective barrier to permeation of material. Small molecules can usually pass the barrier provided they fulfil specific physicochemical requirements, but many macromolecular biotherapeutics cannot cross it. This restricts the delivery of biologics to injections, which can be associated with administration-related injuries and often require administration by a healthcare professional. However, the oral route is the drug administration route best accepted by patients. Ultrasound (US) and microbubbles (MBs) may allow this route to be used in future for biotherapeutics. Hence, an ingestible capsule incorporating an US transducer has the potential to offer a method for oral delivery of drugs to the small intestine. This capsule could both protect the drug payload against the destructive action of low stomach pH and facilitate delivery of a drug once it reaches the intestine. The thesis describes the development and testing of a proof of concept tethered therapeutic capsule for delivering medication to the small intestine. The first experimental chapters present in vitro work, progressing to ex vivo tests on porcine tissue and in vivo tests in pigs. Preliminary studies suggested how to increase the relevance of in vitro tests for in vivo systems, in order to help reduce the number of animals used for research. To this end, classical in vitro systems for testing US-mediated drug delivery were refined to include stem cell-derived cell layers. US combined with either MBs or nanodroplets decreased the barrier function of these improved cell layers to different extents. The in vitro pathway also identified suitable transducer types and US parameters to facilitate the delivery of compounds across relevant cell layers. It was found that the effect of focused single-element transducers was surpassed by unfocused single-element and phased array transducers, with the latter allowing most control over barrier permeation. Array transducers were therefore integrated into test capsules. The US parameters tested in vitro were frequency, cycle number, pulse repetition frequency, duty cycle, mechanical index and surface area insonated. A decrease in barrier function was associated with lower frequencies, more cycles, more pulses, a higher duty cycle, a higher mechanical index and insonating a larger surface area. The results obtained determined the insonation parameters for the in vivo test with capsules able to deliver insulin, MBs and fluorescent quantum dots (qDots). One control pig was administered insulin and qDots alone and two test pigs were administered insulin and qDots, with US and MBs. Blood glucose tests showed that the two test pigs displayed a smaller increase in glucose levels than the control pig, suggesting that more insulin reached the systemic circulation. This early result suggests US combined with MBs can facilitate drug delivery through the small intestine