Pulsed focused ultrasound lowers interstitial fluid pressure and increases nanoparticle delivery and penetration in head and neck squamous cell carcinoma xenograft tumors

Abstract

Nanocarriers offer a promising approach to significantly improve therapeutic delivery to solid tumors as well as limit the side effects associated with anti-cancer agents. However, their relatively large size can negatively affect their ability to efficiently penetrate into more interior tumor regions, ultimately reducing therapeutic efficacy. Poor penetration of large agents such as nanocarriers is attributed to factors in the tumor microenvironment such as elevated interstitial fluid pressure (IFP) and fibrillar collagen in the extracellular matrix. Our previous studies reported that pretreatment of solid tumor xenografts with nondestructive pulsed focused ultrasound (pFUS) can improve the delivery and subsequent therapy of a variety of therapeutic formulations in different tumor models, where the results were associated with expanded extracellular spaces (ECS), an increase in hydraulic conductivity, and decrease in tissue stiffness. Here, we demonstrate the inverse relationship between IFP and the penetration of systemically administered nanoparticle (NP) probes, where IFP increased from the tumor periphery to their center. Furthermore, we show that pretreatment with pFUS can safely reduce IFP and improve NP delivery; especially into the center of the tumors. These results coincide with effects generated in the fibrillar collagen network microstructure in the ECS as determined by quantitative polarized light microscopy. Whole tumor and histomorphometric analysis, however, did not show significant differences in collagen area fraction or collagen feature solidity, as well as tumor cross-sectional area and aspect ratio, as a result of the treatments. We present a biophysical model connecting the experimental results, where pFUS-mediated cytoarchitectural changes are associated with improved redistribution of the interstitial fluid and lower IFP. The resulting improvement in NP delivery supports our previous therapeutic studies and may have implications for clinical applications to improve therapeutic outcomes in cancer therapy.

Pulsed Focal ultrasound as a non-invasive method to deliver exosomes in the brain/stroke

“…Previous studies showed that enhanced delivery of nanoparticles in the brain parenchyma and in the tumor areas when pFUS was applied without any microbubbles. This enhanced delivery was due to the lowering of interstitial pressure [43, 54].…”

The Role of Ultrasound in Modulating Interstitial Fluid Pressure in Solid Tumors for Improved Drug Delivery

“…Initially, therapeutic ultrasound was hypothesized to enhance drug delivery to cancer cells through “sonoporation”, or the use of sound to permeate cell membranes. − Although this continues to be an active area of research, studies using more realistic tumor models have shown that ultrasound may interact more directly with the tumor microenvironment (ECM and vasculature) than individual cancer cells. − Focused ultrasound (FUS) with or without microbubbles may cause either mechanical or thermal effects on the tumor microenvironment that can alter IFP to aid drug delivery to solid tumors (Figure , Table ).…”

“…During FUS-induced mechanical cavitation, millisecond focal boiling (induced during histotripsy) disrupts the dense collagen stroma allowing for physical separation of the collagen fibers, leading to increased hydraulic conductivity and reduced IFP. , FUS-induced mechanical disruption may also cause vascular permeability that can immediately enhance drug delivery efficacy . At acoustic pressures lower than what is traditionally used for histotripsy, FUS can cause microstructure changes in the collagen matrix that occur on the cellular level (microscale pore openings) without any obvious reduction in overall collagen content . One proposed mechanism for the creation of these shear-induced pore openings is acoustic radiation force, or the transfer of momentum from a propagating ultrasound wave resulting in the displacement of soft tissue. , These pore openings can also cause a net change in fluid flow toward the tumor rim, leading to a reduction in overall IFP .…”

“…At acoustic pressures lower than what is traditionally used for histotripsy, FUS can cause microstructure changes in the collagen matrix that occur on the cellular level (microscale pore openings) without any obvious reduction in overall collagen content . One proposed mechanism for the creation of these shear-induced pore openings is acoustic radiation force, or the transfer of momentum from a propagating ultrasound wave resulting in the displacement of soft tissue. , These pore openings can also cause a net change in fluid flow toward the tumor rim, leading to a reduction in overall IFP . Others have additionally posited that moderate pressure pulsed FUS may affect tumor cytokine and growth factor expression, which may also have a molecular modulatory effect on the tumor microenvironment that may be advantageous to cancer therapy, although the impact on IFP has not been studied.…”

Noninvasive Ultrasonic Glymphatic Induction Enhances Intrathecal Drug Delivery

“…As the glymphatic system is driven by convective pressures induced by arterial pulsation , and since ultrasound is a high-frequency wave of pressure oscillations in the medium, we hypothesized that ultrasound application could induce similar pressure oscillations in the perivascular and interstitial space as seen with glymphatic transport, and that this could be used to increase the brain parenchymal penetration of intrathecally administered agents. Several groups have shown that ultrasound may increase the diffusion of agents within tissue after either pairing ultrasound with exogenous microbubble contrast agents (Aryal et al, 2015;B et al, 2019;Etame et al, 2012;Wei et al, 2013) or by using high in situ pressures (Curley et al, 2020;Mead et al, 2019;Mohammadabadi et al, 2020). It has yet been determined whether a low-intensity ultrasound protocol on its own may increase the cisternal CSF-parenchymal transport that is the hallmark of the glymphatic pathway (Iliff et al, 2013).…”