Optimizing therapeutic outcomes with Mechanotherapy and Ultrasound Sonopermeation in solid tumors

Mechanical solid stress plays a pivotal role in tumor progression and therapeutic response. Elevated solid stress compresses intratumoral blood vessels, leading to hypoperfusion, and hypoxia, which impair oxygen and drug delivery. These conditions hinder the efficacy of drugs and promote tumor progression and treatment resistance compromising therapeutic outcomes. To enhance treatment efficacy, mechanotherapeutics and ultrasound sonopermeation have been developed to improve tumor perfusion and drug delivery. Mechanotherapy aims to reduce tumor stiffness and mechanical stress within tumors to normal levels leading to decompression of vessels while simultaneously improving perfusion. On the other hand, ultrasound sonopermeation strategy focuses on increasing non-invasively and transiently tumor vessel wall permeability to boost perfusion and thus, improve drug delivery. Within this framework and aiming to replicate published experimental data in silico, we developed a pilot mathematical model designed to derive optimal conditions for the combined use of mechanotherapeutics and sonopermeation, with the goal of optimizing efficacy of nano-immunotherapy. The model incorporates complex interactions among diverse components that are crucial in the multifaceted process of tumor progression. These components encompass a variety of cell populations in tumor, such as tumor cells and immune cells, as well as components of the tumor vasculature including endothelial cells, angiopoietins, and the vascular endothelial growth factor. Seeking initial model verification, we carried out validation of model predictions with published experimental data, wherein a strong correlation was observed between the model predictions and the actual experimental measurements of critical parameters, which are essential to reinforce the overall accuracy of the mathematical framework employed. In addition, a parametric analysis was performed with primary objective to investigate the impact of various critical parameters that influence sonopermeation. Model predictions showed maximal drug delivery and tumor volume reduction at an acoustic pressure range of 0.24–0.27 MPa and mechanical index of 0.17, consistent with values used in clinical trials following sonopermeation treatment. The analysis provided optimal guidelines for the use of sonopermeation in conjunction with mechanotherapy, that contribute to identify optimal conditions for sonopermeation.Author summary: Solid tumors consist not only of malignant cells but also of stromal cells and an extracellular matrix, collectively shaping a complex tumor microenvironment. In tumors with significant fibrosis, excessive extracellular matrix accumulation—primarily collagen and hyaluronan—results in increased rigidity and mechanical solid stress accumulation. This stress can compress blood vessels, leading to reduced blood flow (hypoperfusion) and oxygen deprivation (hypoxia), which in turn impede drug delivery and fuel tumor progression. Mechanotherapeutic approaches focus on alleviating tumor stiffness and solid stress by targeting extracellular matrix components or Cancer-Associated Fibroblasts, ultimately relieving vessel compression and enhancing perfusion. Ultrasound sonopermeation, a technique combining ultrasound waves with microbubbles, has been explored to temporarily increase vascular permeability and alleviate intratumoral solid stress, thereby facilitating drug penetration. Recent experimental studies indicate that integrating mechanotherapy with sonopermeation may yield synergistic benefits, further enhancing treatment effectiveness. Here, we developed a mathematical model to optimize these combined therapeutic strategies by incorporating crucial tumor microenvironmental dynamics. The model provides preliminary results for the most effective treatment conditions, aligning closely with experimental and clinical findings. Additionally, we performed a parametric analysis to determine the optimal values of ultrasound frequency and mechanical index required for sonopermeation to maximize drug delivery and improve the overall efficacy of cancer therapy.