Enhancement and mapping of ultrasonic drug release from thermosensitive liposomes by acoustic cavitation

Thesis

One of the major limiting factors of cancer therapy is the inability to deliver a sufficient dose of drugs to a target tumour without incurring significant side effects. Recent advances in nano-sized liposome formulations have enabled encapsulation of anti-cancer agents that simultaneously reduce off-target toxicity and allow increased accumulation in tumours due to the enhanced permeability and retention effect. Yet, a method for reliably releasing the drug from encapsulation has yet to be found. In this work, low-temperature sensitive liposomes, which release an encapsulated anti-cancer agent (doxorubicin) in the temperature range of 39-45±C, are combined with focused ultrasound-induced mild hyperthermia to deliver a predictable, site-specific, and high dose of anti-cancer agents that has the potential of overcoming the current limitations of targeted drug delivery for cancer.

To reach this aim, acoustic cavitation-enhanced heating was harnessed to produce rapid and efficient temperature rises that could be spatiotemporally monitored and eventually controlled. For this purpose, a reproducible, non-exothermic, cell-embedding tissue-mimicking model was first developed to have an attenuation coefficient, thermal response and cavitation threshold similar to liver. The phantom platform was then utilised to allow for high-throughput optimisation of ultrasound exposure parameters that efficiently and safely produced mild hyperthermia and drug release. Inertial cavitation-enhanced heating was successfully shown to enhance drug release from the liposomes and subsequent cancer cell death due to release of the encapsulated agents, using a 25% Duty Cycle, 1Hz PRF 6 s sonication sequence. The remotely detectable acoustic emissions associated with cavitation were then exploited to enable real-time monitoring and spatial mapping of drug release using a novel passive acoustic mapping method. Finally, these developments and techniques were combined to demonstrate the feasibility of cavitation enhanced drug release and delivery in a world-unique isolated normothermic liver perfusion model that provides blood-flow rates comparable to those encountered in humans.

Authors: Mylonopoulou, E

• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford