Ultrasound-enhanced delivery of therapeutic agents to tumours using submicron cavitation nuclei

• Main Author: Myers, Rachel
• Other Authors: Coussios, Constantin ; Carlisle, Robert
• Published: University of Oxford 2016
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.728777

Cancer therapy is severely hampered by the poor delivery of agents out of the blood vessels and into tumours. This is due to the irregular vasculature, high interstitial pressure and dense extracellular matrix associated with tumour tissue. As a consequence, high doses of agents must be administered intravenously for effective accumulation in the tumour. This leads to a low therapeutic index, necessitates multiple administrations of the same drug, and for many cancer drugs, also leads to toxic side-effects. Increasingly complex therapeutics, such as antibodies and viruses, only exacerbate this delivery problem as their greater size leads to lower coefficients of diffusion and, consequently, even greater portions of the tumour remain untreated. There have been studies aimed at improving therapeutic outcomes using microbubble-nucleated, ultrasound-induced cavitation, which provides a mechanical impetus to drive drugs out of the vasculature and into tumours. However, microbubbles are limited by their large size, their instability in the blood and their destruction upon cavitation. This thesis details the formulation of two alternative cavitation nuclei to overcome the limitations of microbubbles: mesoporous carbon particles and polymer cups. These are solid, submicron particles that contain crevices into which nanobubbles can be stabilised. Initial studies of their biocompatibilty have indicated that these formulations may be safe for intravenous administration. A tumour mimicking phantom was first used to quantify drug delivery caused by cavitation. Both polymer cups and mesoporous carbon particles were found to significantly enhance delivery of a model therapeutic agent by this method. In vivo the polymer cups were used to enhance the delivery of an oncolytic vaccinia virus: intravenous administration of 1x105 pfu vaccinia virus, polymer cups and ultrasound treatment was shown to cause a 780-fold increase in genome copies in the tumours of a SKOV-3 tumour model, and 5,700-fold, in the tumours of a HEPG2 tumour model 20 days after the treatment. In mice treated with 1x106 pfu of virus cavitation caused by cups and ultrasound was shown to cause regression in 7 of the 8 tumours in comparison to just 1 of the 8 tumours that were treated with virus alone.