Targeting and characterisation of magnetic microbubbles for drug delivery using passive acoustic mapping

Thesis

Passive acoustic mapping (PAM) is a versatile technique for monitoring of therapeutic ultrasound, in particular the generation of cavitation and subsequent bubble dynamics. The objective of this thesis was to apply PAM to investigate the activity of different types of cavitation agent and any correlation to therapeutic effects. The work focuses particularly on a new type of agent in the form of microbubbles that can be magnetically targeted, which have shown great potential for localised drug delivery.

In this thesis PAM was used to study the behaviour of magnetic microbubbles (MMB) in tissue phantoms, in vitro cell experiments and in vivo mouse models. In tissue phantoms magnetic localisation of microbubble-induced cavitation activity was demonstrated and resolved using PAM. Under clinically relevant flow conditions an increase in the energy of cavitation on the order of 2-5 times was observed using PAM, which was similar to doubling the injected microbubble dose.

To facilitate cell experiments a novel chamber system was used with improved variants of MMB as well as condensed magnetic nanodroplets which were shown to enhance uptake of fluorescent small interfering RNA (siRNA), transfection of knockdown siRNA and paclitaxel-induced cell kill. Magnetic targeting was associated with increased cavitation power in PAM as well as increased treatment efficacy measured by biological methods including fluorescence microscopy and flow cytometry.

Finally, improved MMB were tested for the first time in vivo under real-time B-mode imaging and PAM, followed by fluorescence and MR imaging to assess distribution. MMB cavitation activity was of similar magnitude to the commercial contrast agent SonoVue®. Cavitation induced by the microbubbles and magnetic targeting were both associated with increases in fluorescence and MRI contrast in tumours. The therapeutic potential of MMB and monitoring power of PAM were thus demonstrated.

Authors: Crake, C

• DOI: 10.5287/ora-vjydvarxr
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Magnetic; Drug delivery; Cavitation; Passive acoustic mapping; Microbubble; Ultrasound
• Subjects: Biomedical engineering