Investigation of Macromolecular Transport Variation in Tissues for Focused Ultrasound Sonication in the Presence of Microbubbles

Macromolecular drug carrier is one of the major research subjects in anti-cancer drug development today due to its long half-life and specific targeting ability. However, its penetration ability into the tumor tissue is constrained by the tumor’s microenvironments. To improve the anti-cancer drug distribution in the tumor tissue, we can modify the drug’s functions and characteristics or change the tumor’s vascular properties and microenvironments. It has been shown that focused ultrasound with microbubbles could disrupt the vascular wall and the use of specific parameters could enhance the drug delivery. In this study, we investigated the permeability variation of blood vessels into tissue for focused ultrasound sonication in the presence of microbubbles (ultrasound contrast agent). We used dextran rhodamine as micromolecular drug carrier and used two-photon microscope to observe the permeation of dextran from the blood vessels into the tissue of normal mouse. The focused ultrasound used is 1.0 MHz driving frequency, 0.6 MPa peak negative pressure, 1 Hz repetition frequency, and 10 ms burst, and the ultrasound contrast agent dose was 200 μL/kg injected into the mouse tail vein. The experimental results showed that focused ultrasound with microbubbles can effectively disrupt the blood vessel walls of normal mouse tissue and cause the extravasation of macromolecules. We used a mathematical model with diffusion (Nakamura et al.,1974) to calculate and analyze the transport parameters of macromolecules during ultrasound sonication. We found that the diffusion coefficient of macromolecules during sonication was greater than that published in literatures. The methods used in this study can further be employed to investigate the transport characteristics of tumor blood vessels and the dose distribution in tumor tissue for focused ultrasound with microbubbles, and the results may provide useful information for future cancer treatment strategy.