Modelling nanoparticle transport in the extracellular matrix: improving drug delivery with ultrasounds

Project Information

ModEMUS

Grant agreement ID: 101062456

DOI

10.3030/101062456

Project closed

EC signature date 9 June 2022

Start date 1 August 2023

End date 31 August 2025

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 210 911,04

Coordinated by

NORGES TEKNISK-NATURVITENSKAPELIGE UNIVERSITET NTNU
Norway

Periodic Reporting for period 1 - ModEMUS (Modelling nanoparticle transport in the extracellular matrix: improving drug delivery with ultrasounds)

Reporting period: 2023-08-01 to 2025-08-31

Summary of the context and overall objectives of the project

Cancer remains the second leading cause of death in Europe, with 2.27 million new cases and 1.3 million deaths recorded in 2020. Despite advances in therapy, fewer than 1 % of systemically administered drugs reach solid tumours, limiting treatment effectiveness and increasing side effects. Nanoparticle (NP) drug delivery offers a promising strategy by exploiting tumour vasculature permeability, but achieving uniform NP distribution within tumour tissue remains a major challenge.

A key barrier is the extracellular matrix (ECM) — a dense network of collagen fibres and proteoglycans that hinders drug diffusion. Focused ultrasound (FUS), especially when combined with microbubbles, has shown potential to enhance NP penetration by generating mechanical effects such as acoustic radiation force and cavitation. However, the mechanisms driving these improvements are not fully understood, and the outcome depends on multiple interacting factors, including tumour pathology, ECM composition, NP properties, and FUS parameters.

This project addresses these challenges by developing a molecular modelling framework to predict NP transport through the ECM under FUS exposure. By correlating molecular-scale interactions with experimental data, the model will identify optimal NP designs and FUS protocols for enhanced delivery. The results are expected to accelerate the development of personalised, NP-based cancer therapies, supporting EU health priorities to reduce cancer mortality and improve patients’ quality of life.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We developed and applied a coarse-grained Langevin Dynamics simulation framework to investigate the molecular mechanisms driving ultrasound (US)-enhanced nanoparticle (NP) diffusion in polymeric hydrogels, serving as a model for the tumour extracellular matrix. The model captures the essential physics of NP motion within a polymer network under US exposure, allowing systematic exploration of how network retention strength and US amplitude influence transport.

Our simulations reproduce key experimental trends from the literature. For moderately or strongly retained NPs, US markedly enhances long-time diffusion via a “stick-and-release” mechanism, in which acoustic forces reduce NP–network contact times and promote escape events. This explains experimental reports of effective acoustic diffusion in agarose gels under continuous or high-duty-cycle US exposure. In contrast, weakly retained NPs show negligible enhancement, consistent with studies observing no improvement.

We further demonstrate that US exposure duration is critical: enhanced diffusion arises only when pulse lengths span multiple oscillation cycles, providing a mechanistic explanation for the absence of enhancement in low-duty-cycle conditions. Finally, we show that the specific physical model of US–hydrogel coupling strongly influences both the magnitude and character of NP transport enhancement, underscoring the importance of accurate modelling for treatment design.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

This project provides the first systematic, molecular-scale framework linking nanoparticle–matrix interactions and ultrasound (US) parameters to transport enhancement in polymeric networks. Our findings identify NP retention strength and US exposure characteristics as the primary determinants of acoustically enhanced diffusion, offering a mechanistic explanation that reconciles previously contradictory experimental observations. This framework can guide the rational design of ultrasound-mediated drug delivery protocols in biological hydrogels and tumour extracellular matrix (ECM).

While our coarse-grained Langevin Dynamics approach enables controlled, bottom-up investigation, it necessarily simplifies the ECM as a homogeneous, periodic polymer network. Future work should incorporate structural heterogeneity, variable crosslinking, and patchy interactions to better capture in vivo conditions. Similarly, hydrodynamic effects are currently represented through friction terms, omitting long-range coupling between NPs, the network, and surrounding fluid; explicit modelling of these interactions will be important for predictive accuracy.
Thermal effects of US, excluded here via constant-temperature control, may influence in vitro systems but are expected to be physiologically regulated in vivo.

Addressing these aspects through extended modelling and targeted experiments will be essential for translating these insights into clinical strategies, supporting further research, experimental validation, and eventual integration into personalised nanomedicine delivery systems.

Simulation snapshot of nanoparticles diffusing in a hydrogel under ultrasound