Optimisation of ultrasound exposure parameters for extravasation and drug delivery using submicron cavitation nuclei

Sub-micron cavitation nuclei with the ability to passively extravasate through the leaky tumor vasculature have been shown to enhance both extravasation and penetration of pharmaceuticals in tumors. The aim of the present work is to optimize the acoustic parameters and maximize drug delivery mediated by cavitational microstreaming. Either lipid-shell microbubbles, or gas-stabilizing polymeric submicron cups of mean diameter 480 nm are co-administered with a model drug through a flow channel formed in agarose gel. The effect of ultrasound frequency, pressure amplitude, pulse duration, duty cycle, and pulse repetition frequency on the delivery of the drug is first evaluated, using both a single-layer and a dual-layer flow phantom that better represents the leaky tumor vasculature and dense extracellular matrix. The optimal parameters at 0.5 MHz and 1.6 MHz are then selected and used to deliver an oncolytic virus, genetically modified to express the RFP reporter gene, thus allowing the quantification of the ...