Abstract
A significant barrier to successful drug delivery is the limited penetration of nanoscale therapeutics beyond the vasculature. Building on recent in vivo findings in the context of cancer drug delivery, the current study investigates whether modification of nanoparticle drug-carriers to increase their density can be used to enhance their penetration into viscoelastic materials under ultrasound exposure. A computational model is first presented to predict the transport of identically sized nanoparticles of different densities in an ultrasonic field in the presence of an oscillating microbubble, by a combination of primary and secondary acoustic radiation forces, acoustic streaming and microstreaming. Experiments are then described in which near monodisperse (polydispersity index <0.2) nanoparticles of approximate mean diameter 200 nm and densities ranging from 1.01 g cm−3 to 5.58 g cm−3 were fabricated and delivered to a tissue-mimicking material in the presence or absence of a microbubble ultrasound contrast agent, at ultrasound frequencies of 0.5 MHz and 1.6 MHz and a peak negative pressure of 1 MPa. Both the theoretical and experimental results confirm that denser particles exhibit significantly greater ultrasound-mediated transport than their lower density counterparts, indicating that density is a key consideration in the design of nanoscale therapeutics.
Highlights
Cancerous tissue is highly heterogeneous in terms of perfusion and the pressure and composition of the extracellular matrix, posing a number of significant barriers to drug delivery
Building on recent in vivo findings in the context of cancer drug delivery, the current study investigates whether modification of nanoparticle drug-carriers to increase their density can be used to enhance their penetration into viscoelastic materials under ultrasound exposure
Tailoring the size and shape of nanoparticles can increase their ability to pass through pores in the ‘leaky’ vasculature that is characteristic of cancerous blood vessels and to be retained in the surrounding tumour tissue—an effect known as enhanced permeability and retention (EPR) (Maeda 2010, Prabhakar et al 2013)
Summary
Cancerous tissue is highly heterogeneous in terms of perfusion and the pressure and composition of the extracellular matrix, posing a number of significant barriers to drug delivery. Current methods of systemic drug delivery often do not enable therapeutics to penetrate sufficiently deep into tumour tissue for effective treatment (Minchinton et al 2006). This is problematic for relatively large therapeutics such as nanoparticles. Strategies for enhancing the transport of nanoscale drug carriers have included modifying their size, shape and surface chemistry - primarily surface charge and biological targeting (Blanco et al 2015). Tailoring the size and shape of nanoparticles can increase their ability to pass through pores in the ‘leaky’ vasculature that is characteristic of cancerous blood vessels and to be retained in the surrounding tumour tissue—an effect known as enhanced permeability and retention (EPR) (Maeda 2010, Prabhakar et al 2013). Using surface charge or ligands to enable particles to bind to specific receptors on cancer or endothelial cells is classed as active targeting (Kamaly et al 2012)
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