Modelling the effect of acoustic streaming and ultrasound-enhanced diffusion on nanoparticle transport in a soft porous media

Abstract

Cancer remains a major health concern, despite significant progress in developing effective treatments. One of the most important treatments is chemotherapy, which suffers from insufficient accumulation of the drug in the cancerous cells, as well as being unspecific in its delivery. Encapsulating the therapeutics in nanoparticles, makes it possible to perform more targeted drug delivery into the cancerous tumor, and limit the damage on healthy tissue, because of the enhanced permeability and retention effect. However, the accumulation of the medicine is still low, due to the relatively complicated transport path of having to extravasate over the capillary wall of the blood vessel and navigate through the heavily obstructed tumor interstitium.

More recently, there has been promising research on combining the nanoparticle drug delivery with focused ultrasound. Results indicate an increase in drug uptake when combined with microbubbles, but there remains a significant gap in understanding the underlying mechanisms behind this increase. Gaining this understanding is crucial for optimizing the procedure. Focused ultrasound-mediated delivery of nanoparticles into cancer cells, can be divided into four transport steps: the vascular network and its perfusion, extravasation over the capillary wall, penetration through the extracellular matrix in the tumor and the internalization into cancer cells. In our work we have focused on studying the penetration through the extracellular matrix through theoretical analysis and simulations.

There are several mechanisms that may be important during the focused ultrasound-enhanced transport of the nanoparticles through the extracellular matrix. One of these effects is acoustic streaming, which is the net movement of fluid generated by propagation of sound waves. We derived equations for acoustic streaming in a soft porous medium, and compared them to highly controlled experiments on a macroporous gel, obtaining good agreement. Microbubbles exposed to ultrasound will expand and contract with the local pressure causing them to oscillate, and is often believed to be the main contributor to the nanoparticle transport. However, to optimally tune the acoustic parameters, a better understanding of the focused ultrasound on nanoparticle penetration without microbubbles is needed. We conducted experiments on nanoparticles in tissue-mimicking gels exposed to focused ultrasound at frequencies typically used to oscillate microbubbles, but where microbubbles were excluded. From these experiments we observed no discernible acoustic streaming. However, we did observe an increase in diffusion when exposed to focused ultrasound at higher duty cycles. This can be significant in areas where the microbubble effect is limited and diffusion dominates, since diffusion is a slow process, and an increase will therefore be beneficial. A non-equilibrium molecular dynamics model of nanoparticles in a hydrogel was created, using an enforced oscillation force to mimic the effect of the focused ultrasound. The mean square displacement obtained from the simulations, was compared to the experiments and similar trends were observed. This indicates that oscillation of particles in combination with obstruction can explain the increase in diffusion. Lastly, we performed simulations on acoustic streaming in tumors incorporating the temperature. Results from these simulations showed that it may be possible to obtain discernible acoustic streaming values in a tumor while staying below 50 ◦C.