Modulating tumor interstitial fluid pressure using ultrasound and microbubble therapy: a preclinical study for enhanced drug delivery in cancer treatment

Abstract

Objective: The tumor microenvironment (TME) often hinders effective cancer treatment, where elevated interstitial fluid pressure (IFP) acts as a key barrier to drug penetration. This study investigates the distribution of IFP in VX2 tumors and the effect of ultrasound-mediated microbubble (USMB) therapy on reducing IFP to improve drug delivery. Methods: Following approval from the Animal Ethics Committee of the South China University of Technology and adhering to NIH animal care guidelines, forty-one healthy female New Zealand White rabbits with VX2 tumors underwent USMB therapy at varying ultrasound pressures (1 MPa, 2 MPa, 3 MPa, and 5 MPa). IFP measurements across different tumor regions were performed pre- and post-treatment using the wick-in-needle (WIN) method to assess IFP variability and distribution. Contrast-enhanced ultrasound (CEUS) was used to evaluate changes in tumor perfusion associated with USMB treatment. Results: Significant regional differences in tumor IFP were observed, with the central region (23.79 ± 8.07 mmHg) markedly higher than the peripheral 1/2 (15.58 ± 5.22 mmHg) and peripheral 1/4 regions (8.29 ± 3.47 mmHg). After treatment, 3 MPa and 5 MPa ultrasound pressures significantly reduced IFP in the central region to 18.05 ± 8.1 mmHg and 14.69 ± 4.72 mmHg, respectively. Histological analysis showed that higher pressures caused greater tumor cell and vascular damage, with extensive necrosis and vascular disruption in the central tumor area at 3 MPa and 5 MPa, demonstrating the impact of USMB therapy on the tumor microenvironment. Conclusion: USMB therapy reduces IFP in solid tumors. At 2 MPa, IFP reduction occurs with minimal perfusion change, potentially favoring drug delivery. In contrast, higher pressures (3–5 MPa) also lower IFP but markedly decrease perfusion through vascular disruption, which may hinder drug transport. These findings highlight the need to adjust ultrasound parameters based on regional IFP distribution and to balance IFP reduction with perfusion preservation to optimize treatment outcomes.