A multiphysics computational model of focused ultrasound-enhanced drug delivery using temperature-sensitive liposomes

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Abstract
The efficacy of conventional chemotherapy in solid tumors remains limited due to tumor microenvironment barriers that impede efficient drug transport and compromise therapeutic outcomes. Thermosensitive liposomes (TSLs) combined with focused ultrasound-induced hyperthermia offer a promising strategy for localized, temperature-triggered drug release. Despite experimental progress, a quantitative understanding of the coupled physical and biological mechanisms underlying this therapy is yet to be fully elucidated. Here, a three-dimensional multiphysics computational model was developed to investigate the interplay between focused ultrasound-induced hyperthermia and temperature-sensitive liposome-mediated drug delivery in solid tumors, integrating acoustic propagation, tissue heating and temperature-dependent drug release. Model predictions were validated against published experimental data, demonstrating good agreement with tumor growth and intratumoral drug concentration data. Sensitivity analysis showed that focused ultrasound parameters and liposome properties strongly influence treatment efficacy. Prolonged focused ultrasound exposure (20–30 min) produced greater tumor reduction than frequency variations (2–5 MHz). Treatment timing was also critical: For highly proliferating tumors, early therapy yielded markedly improved outcomes. Faster drug release kinetics enhanced intracellular drug accumulation and tumor regression. Intermediate-sized TSLs ( ~  50 nm in radius) achieved optimal efficacy under moderate vascular permeability conditions, while larger liposomes (~ 65 nm in radius) were more effective in tumors with highly permeable vessels due to increased extravasation. This work provides a computational framework with predictive potential for optimizing the combined focused ultrasound-thermosensitive liposomes therapy and assisting to the design of thermally triggered nanocarriers.
Funding Information
  • European Research Council (ERC) under the European Union’s Horizon 2020 and Horizon Europe research and innovation programme (101076425)
  • European Research Council (ERC) under the European Union’s Horizon 2020 and Horizon Europe research and innovation programme (101141357)
  • University of Cyprus

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