Sonosensitive nanoparticle formulations for cavitation-mediated ultrasonic enhancement of local drug delivery
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Sonosensitive nanoparticle formulations for cavitation-mediated ultrasonic enhancement of local drug delivery Sarah J. Wagstaffe, Manish Arora, Constantin-C Coussios and Heiko A. Schiffter Institute of Biomedical Engineering, Oxford University, Old Road Campus Research Building, Off Roosevelt Drive, Oxford, OX3 7DQ ABSTRACT Inertial 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. INTRODUCTION Ultrasound has a long history of use in diagnostic applications. A large increase in efforts to facilitate the interaction of ultrasound with cells and tissues has led to Therapeutic Ultrasound (0.75 – 5.0 MHz) becoming an established clinical tool and the multiplicity of its interactions with cells and tissues make it additionally a versatile technology. Therapeutic applications of ultrasound such as enhanced transdermal drug delivery [1-3], enhancement of drug uptake into cells and tissues [4], thrombolysis [5], focused ultrasound surgery [6] and localization of drug activation [7] has been the focus of intense research over the past few decades [8, 9]. Focused ultrasound results in periodic pressure oscillations at a certain frequency and amplitude, which are determined by the ultrasound source, in a biological sample. These simple pressure oscillations are themselves capable of affecting cells and tissues but it is the secondary effects of pressure oscillations that play a more important role in therapy due to sound wave absorption. If the depression phase of the ultrasound wave is strong enough, it cause
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