Evaluation of sub-micron, ultrasound-responsive particles as a drug delivery strategy

Abstract

Substantial portions of tumors are largely inaccessible to drugs due to their irregular vasculature and high intratumoral pressure. The enhanced permeability and retention effect causes drug carriers within the size range of 100–800 nm to passively accumulate within tumors; however, they remain localized close to the vasculature. Failure to penetrate into and throughout the tumor ultimately limits treatment efficacy. Ultrasound-induced cavitation events have been cited as a method of stimulating greater drug penetration. At present, this targeting strategy is limited by the difference in size between the nano-scale drug carriers used and the cavitation nuclei available, i.e., the micron-scale contrast agent SonoVue. In vivo this results in spatial separation of the two agents, limiting the capacity for one to impact upon the other. Our group has successfully formulated two different monodisperse suspensions of nanoparticles that are of a size that will permit better co-localization of cavitation nuclei and therapeutics. A mixture of these nanoparticles and a model drug carrier were passed through a tissue mimicking phantom to provide an in vitro simulation of flow through a tumor. The impact of ultrasound on the penetration of drug carrier from the flow channel was compared between both of our ultrasound-responsive particles and SonoVue.