ORIGINAL RESEARCH article

Front. Drug Deliv.

Sec. Cardiovascular Drug Delivery

Volume 5 - 2025 | doi: 10.3389/fddev.2025.1549098

This article is part of the Research TopicModelling of Intravascular Drug Delivery Using NanocarriersView all 4 articles

Synergistic Mechanotherapy and Sonopermeation Guided by Mathematical Modeling for Solid Tumor Treatment

Provisionally accepted
  • University of Cyprus, Nicosia, Cyprus

The final, formatted version of the article will be published soon.

The progression of tumors and their response to treatment are significantly influenced by the presence of elevated mechanical solid stress. This solid stress compresses intratumoral blood vessels, leading to reduced blood flow (hypoperfusion) and insufficient oxygen levels (hypoxia), both of which hinder the delivery of essential oxygen and therapeutic agents. As a result, these conditions promote tumor growth, resistance to treatment, and ultimately undermine the effectiveness of therapies. To address these challenges, strategies like mechanotherapeutics and ultrasound sonopermeation have been developed to enhance blood flow and improve drug delivery to tumors. Mechanotherapy aims to reduce the mechanical stress and stiffness within tumors, helping to decompress vessels and restore normal perfusion. Ultrasound sonopermeation temporarily increases the permeability of blood vessel walls in a non-invasive manner, boosting blood flow and improving the delivery of therapeutic drugs. Here, we developed a mathematical model to explore the combined effects of mechanotherapeutics and sonopermeation on optimizing nano-immunotherapy efficacy. The model integrates complex interactions between key components involved in tumor progression, including tumor cells, immune cells, and vascular elements such as endothelial cells, angiopoietins, and vascular endothelial growth factor. To assess the model's validity, its predictions for key parameters, including tumor volume, functional vascular density, and hypoxia levels, were compared with experimental data, demonstrating a strong correlation, and confirming the accuracy of the framework. Furthermore, we carried out a parametric analysis to establish critical guidelines aimed at optimizing both the sequence and timing of experimental procedures. Specifically, we investigated the therapeutic outcomes of two treatment orders: initiating with sonopermeation followed by nano-immunotherapy, and vice versa. Also, we determined the optimal time interval between the application of sonopermeation and the commencement of the combined nano-immunotherapy regimen to maximize therapeutic efficacy.

Keywords: computational modeling, nano-immunotherapy, breast cancer, Tumor Microenvironment, Drug delivery

Received: 20 Dec 2024; Accepted: 03 Jun 2025.

Copyright: © 2025 Koutsi, Stylianopoulos and Mpekris. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Triantafyllos Stylianopoulos, University of Cyprus, Nicosia, Cyprus
Fotios Mpekris, University of Cyprus, Nicosia, Cyprus

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.