Routes for the formation of thin oil shelled microbubbles towards hydrophobic drug delivery

Advances in drug development and screening protocols have lead to a dramatic increase in the number of candidate drugs for clinical application. Many of these drugs show strong in vitro effects, however in vivo they suffer from off-site toxicity, reduced bioavailability, and poor water solubility. Drug delivery systems have been developed to encapsulate these drugs, only releasing them at target sites. This has led to a greater bioavailability at the target site, reducing the total drug dosage required for delivery, whilst increasing the concentration and potency of these drugs where they are required. However, one of the growing challenges for drug delivery systems is drug hydrophobicity.
Microbubbles (MBs) have been used in medicine for over 30 years as ultrasound contrast enhancing agents. More recently, they have been shown to enhance drug delivery through co-delivery and ultrasound exposure. For improved delivery, a number of MB-drug composites have been developed, with many showing a high degree of success for hydrophilic drugs. The effective delivery of primarily hydrophobic drugs remains a challenge. A number of research groups have looked into forming MBs with the inclusion of an oil layer for drug encapsulation into the MB shell, giving an Oil Layer Inside MB (OLI-MB). Problems arose in each study ranging from; polydispersity, low stability, clinically unviable size distributions, ultrasound requirements for drug release outside of clinical application, and a general lack of control over the formation and the oil layer thickness per OLI-MB.
This project aimed to develop a reliable and simple route for the formation of OLI-MBs with thin oil layers, at clinically relevant sizes and concentrations. Three formation routes were tested; oil nanodroplet self-assembly and spreading at MB surfaces, three-phase flow through a single microfluidic flow focused nozzle, and activation of liquid perfluorocarbon-oil droplets into OLI-MBs. With the use of microfluidics, the first formation route was found to produce OLI-MBs of 2.4 μm at 10^6 OLI-MBs/ml, with oil layers 10s of nanometres thick, which showed ultrasound response. As such, this formation route is of further clinical interest.