Effect of Acoustic Radiation Force on the Distribution of Nanoparticles in Solid Tumors.

Acoustic radiation force (ARF) might improve the distribution of nanoparticles (NPs) in tumors. To study this, tumors growing subcutaneously in mice were exposed to focused ultrasound (FUS) either 15 min or 4 h after the injection of NPs, to investigate the effect of ARF on the transport of NPs across the vessel wall and through the extracellular matrix. Quantitative analysis of confocal microscopy images from frozen tumor sections was performed to estimate the displacement of NPs from blood vessels. Using the same experimental exposure parameters, ARF was simulated and compared with the experimental data. Enhanced interstitial transport of NPs in tumor tissues was observed when FUS (10 MHz, acoustic power 234 W/cm2, 3.3% duty cycle) was given either 15 min or 4 h after NP administration. According to acoustic simulations, the FUS generated an ARF per unit volume of 2.0×106 N/m3. The displacement of NPs was larger when FUS was applied 4 h after NP injection compared with after 15 min. This study shows that ARF might contribute to a modest improved distribution of NPs into the tumor interstitium.

Effect of Acoustic Radiation Force on Displacement of Nanoparticles in Collagen Gels.

Penetration of nanoscale therapeutic agents into the extracellular matrix (ECM) of a tumor is a limiting factor for the sufficient delivery of drugs in tumors. Ultrasound (US) in combination with microbubbles causing cavitation is reported to improve delivery of nanoparticles (NPs) and drugs to tumors. Acoustic radiation force (ARF) could also enhance the penetration of NPs in tumor ECM. In this work, a collagen gel was used as a model for tumor ECM to study the effects of ARF on the penetration of NPs as well as the deformation of collagen gels applying different US parameters (varying pressure and duty cycle). The collagen gel was characterized, and the diffusion of water and NPs was measured. The penetration of NPs into the gel was measured by confocal laser scanning microscopy and numerical simulations were performed to determine the ARF and to estimate the penetration distance and extent of deformation. ARF had no effect on the penetration of NPs into the collagen gels for the US parameters and gel used, whereas a substantial deformation was observed. The width of the deformation on the collagen gel surface corresponded to the US beam. Comparing ARF caused by attenuation within the gel and Langevin pressure caused by reflection at the gel-water surface, ARF was the prevalent mechanism for the gel deformation. The experimental and theoretical results were consistent both with respect to the NP penetration and the gel deformation.

Effect of Ultrasound on the Vasculature and Extravasation of Nanoscale Particles Imaged in Real Time.

Ultrasound and microbubbles have been found to improve the delivery of drugs and nanoparticles to tumor tissue. To obtain new knowledge on the influence of vascular parameters on extravasation and to elucidate the effect of acoustic pressure on extravasation and penetration of nanoscale particles into the extracellular matrix, real-time intravital multiphoton microscopy was performed during sonication of tumors growing in dorsal window chambers. The impact of vessel diameter, vessel structure and blood flow was characterized. Fluorescein isothiocyanate-dextran (2 MDa) was injected to visualize blood vessels. Mechanical indexes (MI) of 0.2-0.8 and in-house-made, nanoparticle-stabilized microbubbles or Sonovue were applied. The rate and extent of penetration into the extracellular matrix increased with increasing MI. However, to achieve extravasation, smaller vessels required MIs (0.8) higher than those of blood vessels with larger diameters. Ultrasound changed the blood flow rate and direction. Interestingly, the majority of extravasations occurred at vessel branching points.