Ultrasound-Enhanced Transport of Nanoparticles Through Extracellular Matrix-Acoustic Streaming and Diffusion

Chemotherapy efficiency is limited by poor drug accumulation and heterogeneous distribution within tumors. Combining ultrasound (US) with circulating microbubbles (MBs) has shown promise in enhancing the delivery of both free drugs and nanoparticle (NP)-encapsulated drugs, thereby improving therapeutic outcomes. These promising findings suggest that the administered drugs reach a larger fraction of cancer cells. However, the mechanisms governing the US-induced transport of drugs and NPs through the extracellular matrix (ECM) remain poorly understood. This review summarizes findings from experimental and computational approaches and discusses key limitations in current understanding of US-mediated drug delivery through ECM. Transport occurs through convection and diffusion, driven by pressure and concentration gradients, respectively. US may induce acoustic fluid flow and enhance diffusion. When applying low-frequency-low-intensity US, commonly used for drug delivery and excluding effects of oscillating MBs in the vasculature, reports indicate that US primarily enhances diffusion through the ECM with minimal influence on acoustic flow. Considering attractive interactions between the NPs and the ECM, US has been found to shorten the NP-network contact time when the US pulses encompass several oscillation cycles, thereby enhancing diffusion. On the other hand, low-frequency-low-intensity US has no effect on interstitial hydraulic conductivity, and thus acoustic flow is not increased.