Modelling and fabrication of inhalable microbubbles for drug targeting in the lungs

Thesis

Microbubble ultrasound contrast agents have been used safely and effectively in diagnostic applications for several decades. Although their use in the lungs has not been widely explored due to safety concerns and poor ultrasound penetration through gas-filled tissue, the fragile and low-density properties of microbubbles make them attractive for drug delivery. This thesis aims to investigate the potential of microbubbles as inhalable agents for treating lung conditions.

Chapters 2 to 4 of the thesis explored the potential of microbubbles for targeting small conducting airways using an in silico method. Chapter 2 reviewed the existing literature on lung particle deposition models, and an in silico lung particle deposition model was developed in Chapter 3. However, an alternative approach to drug targeting in small conducting airways was proposed in Chapter 4. It was found that existing medical devices could achieve this without needing microbubbles by controlling the tidal volume and flow rate.

The latter part of the thesis focuses on exploring the feasibility of using inhalable microbubbles to treat neonatal respiratory distress syndrome (nRDS). Chapter 5 reviewed the relevant literature on nRDS, and identified three critical aspects for effective treatment: 1) delivering surfactant into the lungs of preterm infants, 2) maintaining low surface tension on the lung surface lining, and 3) the immunomodulatory action of lung surfactant proteins. Chapter 6 demonstrated that incorporating microbubbles in aerosols improved postextrathoracic penetration in a 3D printed preterm model. Chapter 7 showed that microbubbles enhance the surface activity of phospholipids, resulting in low surface tension on the airaqueous interface, even with a low concentration of phospholipids. In Chapter 8, in vitro experiments on LPS-induced RAW264.7 macrophages suggested that microbubbles may have immunomodulatory effects. Overall, the work in this second half of the thesis demonstrates that inhalable microbubbles hold the potential for treating nRDS through nebulization.

Authors: Min, H

• DOI: 10.5287/ora-wrk8aqnyp
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English