Effect of Ultrasound Combined With Microbubble Therapy on Interstitial Fluid Pressure and VX2 Tumor Structure in Rabbit

Abstract

Interstitial fluid pressure (IFP) in tumor tissue is significantly higher than that in normal tissue, which reduces the effectiveness of therapeutic drugs. There are several methods to decrease the IFP, such as normalizing blood vessel, decreasing hyaluronic acid and collagen fiber content in the extracellular matrix (ECM), and recovering lymphatic function. Reducing tumor IFP might be developed as a novel approach in cancer therapy. In this study, we aimed to elucidate the relationship between ultrasound combined with microbubble therapy and IFP, and the associated mechanism. VX2 tumor in rabbit was treated with ultrasound combined with microbubbles at different intensities. The IFP was measured using the wick-in-needle (WIN) method. The collagen and reticular fibers were stained by Masson and Gordon–Sweets, respectively. The results showed that low-frequency non-focus ultrasound combined with microbubbles therapy influences the IFP in tumor tissues; low-frequency non-focus ultrasound with low pressure increased the IFP, whereas middle–high pressure decreased the IFP. The results showed that the structure and content of collagen and reticular fibers in tumor tissue were rarely influenced by the treatment. Our study provides a novel approach of reduced IFP antitumor therapy.

Image-Guided Treatment of Primary Liver Cancer in Mice Leads to Vascular Disruption and Increased Drug Penetration

“…One possible explanation for this is that the enhanced permeability and retention (EPR) effect seen in many highly angiogenic tumors can result in a high interstitial fluid pressure that can compromise drug delivery (Semela and Dufour, 2004). One proposed mechanism of how ultrasound and microbubbles increase drug penetration in tumors is that cavitation activity actually temporarily alleviates the tumor interstitial fluid pressure, allowing for enhanced drug diffusion (Zhang et al, 2019). Most likely is that the two aspects of USCTx, drug penetration and anti-vascular action, work synergistically to target the outer rim and core of the tumor, respectively (Goertz et al, 2012).…”

Improving the Therapeutic Effect of Ultrasound Combined With Microbubbles on Muscular Tumor Xenografts With Appropriate Acoustic Pressure

“…VX2 tumor tissue specimens were purchased from the cell bank of Sun Yat-sen University (Guangzhou, China). The tumor tissues were cut into small pieces (1 mm3) and placed in a culture dish with physiological saline solution, and then injected into the muscle layer of the rabbit right hind limb (2.6 ± 0.5 mm from the surface) (Zhang et al, 2019). The USMB treatment was performed when the tumor reached a length of 10.0 ± 0.7 mm and width of 5.0 ± 0.3 mm.…”

“…A needle hydrophone (TNU001A, NTR, Seattle, WA, USA) was positioned to measure the acoustic output at a depth of 0.5 cm from the surface. A non-focused ultrasound was used with the following acoustic parameters: frequency of transducer = 1.0 MHz, acoustic pressure = 1.0-5.0 MPa, pulse repetition frequency = 10 Hz, intermittent mode of transducer = 9 s (on) and 3 s (off), duty cycle = 0.2%, insonation time = 5 min (Zhang et al, 2019). Treatment was initiated at least 15 min after the previous CEUS imaging to ensure the clearance of all contrast agents.…”

Assessment of the hepatic tumor extracellular matrix using elastin-specific molecular magnetic resonance imaging in an experimental rabbit cancer model

“…However, it has been shown that once transformed into a tumor-associated neighborhood by various stimuli, the stromal-derived effects can actively contribute to the tumor aggressiveness and responsiveness to anti-tumor therapies 2 , 28 . In a recently published US- based study the application of US microbubbles of different intensity and the response of the interstitial fluid pressure in the ECM was investigated 14 . It can be anticipated that more therapeutic studies will focus on the ECM tumor component in the future.…”

“…The VX2 rabbit model for liver cancer is a well-studied model for testing and evaluation of preclinical interventional 11 , 12 and systemic therapies 13 on an HCC surrogate tumor. A recent ultrasound-based therapy study has linked the importance of the ECM for therapy options by using microbubbles to influence the interstitial fluid pressure in this model 14 . Furthermore, it could already be shown that brachytherapy using the genetically engineered peptide polymer elastin-like polypeptide labelled with I(131) in the VX2 liver tumors has a strong labelling efficiency and thus a high antitumor effect 15 .…”