Sonosensitive nanoparticle formulations for cavitation-mediated ultrasonic enhancement of local drug delivery

ABSTRACTInertial cavitation, namely the rapid expansion and subsequent violent collapse of micron-sized cavities under the effect of ultrasound-induced pressure variations, has widely been considered as an undesirable phenomenon for in-vivo biomedical applications. This is mainly because of its highly stochastic nature and difficulties in its reliable initiation in vivo using moderate ultrasound pressure levels. Methods of lowering the pressure required to initiate cavitation, which is known as the cavitation threshold, has been previously addressed with the use of ultrasound contrast agents in form of encapsulated stabilized micron sized bubbles. However, such agents do not readily extravasate into tumours and other target tissues due to their relatively large size. This paper investigates the engineering of core-shell nanoparticles and examines their ability to initiate inertial cavitation in the context of ultrasound-enhanced local drug delivery. The nanoparticulate formulations are size-engineered to target tumour vasculature whilst presenting high surface roughness, facilitating surface air entrapment upon drying. The core-shell nanoparticles have been demonstrated to substantially lower the cavitation threshold in aqueous solution, allowing the initiation of inertial cavitation with moderate ultrasound amplitudes and the low energy levels typically deployed by diagnostic systems. The peak focal pressure where the probability of cavitation is greater than 0.5 was found to decrease by factors of five to ten fold, dependant on particle size, total surface area and surface morphology.