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

Descripción del proyecto

Modelización del transporte de nanopartículas inducido por ultrasonidos para mejorar la administración de fármacos

La administración de fármacos encapsulados en nanopartículas (NP) representa un enfoque prometedor en el tratamiento del cáncer. Sin embargo, la administración de NP en las células de los tumores se ve obstaculizada por la matriz extracelular (MEC), una red de fibras de colágeno en un gel de proteoglicanos. Asimismo, se ha demostrado que la irradiación con ultrasonidos focalizados (USF) y su combinación con microburbujas mejoran la administración de NP en los tumores. El éxito de la administración depende de factores como la patología, la estructura de la MEC, las características de las NP y los parámetros de exposición de los USF, lo cual es un problema complejo y difícil de abordar mediante metodologías experimentales. El proyecto ModEMUS, financiado por las Acciones Marie Skłodowska-Curie, utilizará la modelización molecular para encontrar correlaciones entre dichos parámetros y el transporte de las NP a través de la MEC, con el fin de mejorar el suministro de NP a los tejidos enfermos.

Objetivo

Cancer is the second most important cause of death in Europe, with an estimated 2.27 million new cases and 1.3 million deaths in 2020. The prerequisite for a successful medicinal therapy is that the drug reaches its target and that toxicity towards healthy tissue is limited, however the systemic injection of drugs leads to less than 1 % of the drugs accumulating in solid tumours. Relying on the permeability of the blood vessel in cancer tumours, the encapsulation of drugs in nanoparticles (NPs) constitutes a promising approach for cancer treatment. However, the homogeneous distribution of NPs in the tumour tissue remains a challenge. To reach all cells in the tumour the NPs must cross the extracellular matrix (ECM), a major component of solid tumours consisting mainly of a network of collagen fibres embedded in a hydrophilic gel of proteoglycans. Together, they limit the diffusion of drugs across the tumour. Focused UltraSound (FUS) exposure has been reported to improve the delivery of NPs to tumour cells. FUS induces acoustic radiation force and cavitation that can lead to microstreaming or shock waves but the underlying mechanism(s) for the improved transport are not well understood. Successful delivery depends on many factors including the pathology, structure and composition of the diseased tissue, the characteristics of the NPs, and the exposure parameters of the FUS, making it a complex problem difficult to solve using an experimental approach. In this project, we will use molecular modelling to identify correlations between the molecular details of NPs and ECM, and FUS exposure parameters with NP transport across the ECM, creating a predictive model for FUS delivery of NPs and drugs to diseased tissue. The model, validated by experimental data, will contribute to the design of personalized medicine for improved NP-based drug delivery.