Towards a multiphysics modelling framework for thermosensitive liposomal drug delivery to solid tumour combined with focused ultrasound hyperthermia

Abstract

Systemic toxicity and insufficient drug accumulation at the tumour site are main barriers in chemotherapy. Thermosensitive liposomes (TSL) combined with high intensity focused ultrasound (HIFU) has emerged as a potential solution to overcome these barriers through targeted drug delivery and localised release. Owing to the multiple physical and biochemical processes involved in this combination therapy, mathematical modelling becomes an indispensable tool for detailed analysis of the transport processes and prediction of tumour drug uptake. To this end, a multiphysics model has been developed to simulate the transport of chemotherapy drugs delivered through a combined HIFU-TSL system. All key delivery processes are considered in the model; these include interstitial fluid flow, HIFU acoustics, bioheat transfer, drug release and transport, as well as tumour drug uptake. The capability of the model is demonstrated through its application to a 2-D prostate tumour model reconstructed from magnetic resonance images. Our results not only demonstrate the feasibility of the model to simulate this combination therapy, but also confirm the advantage of HIFU-TSL drug delivery system with enhancement of drug accumulation in tumour regions and reduction of drug availability in normal tissue. This multiphysics modelling framework can serve as a useful tool to assist in the design of HIFU-TSL drug delivery systems and treatment regimen for improved anticancer efficacy.

Thermosensitive Liposome-Mediated Drug Delivery in Chemotherapy: Mathematical Modelling for Spatio–temporal Drug Distribution and Model-Based Optimisation

“…HT exposure is the required external stimulus to trigger anticancer drug release from TSLs. Although the spatio-temporal distribution of temperature in tumour tissue can be predicted by coupling bio-heat transfer models (e.g., Pennes' model) with drug transport models [6,9,10], the current study focuses on resolving drug distributions only by assuming uniform temperature in the tumour microenvironment (i.e., capillary and its surrounding interstitial space). This is justifiable when intense heating is applied via an external source and consequently a temperature increase occurs instantaneously.…”

“…As in previous studies [8,10], pharmacokinetics of TSLs and an anticancer drug and/or nanosized drug carrier can be described by a two-compartment model, with the assumption that only anticancer drug can move between the central (systemic plasma) and peripheral compartments (lumped tissue).…”

“…Solving Equations 7, (10) and 11requires boundary conditions for c e and u i . Starling's law and Kedem-Katchalsky equations are used to prescribe the transmural blood flow velocity and drug flux at the capillary walls, i.e., at r = R c .…”

“…Over the last decade, computational modelling has served as an effective tool to assess the therapeutic potential of chemotherapy using TSLs and to provide information on intratumoural distribution of anticancer agents [5][6][7][8][9][10][11]. Compared to conventional delivery of free anticancer agents and stealth liposomes, evaluating the efficacy of TSLs involves additional complexities due to heat transfer phenomena in tumour tissues induced by focused ultrasound, which gives rise to spatio-temporal variations of temperature and temperature-dependent blood perfusion and vascular permeability.…”

“…Gasselhuber et al [6,9] improved the mathematical model by incorporating Penne's heat transfer equation, temperature-dependent perfusion rates and release kinetics in order to predict the spatio-temporal distribution of temperature as well as heterogeneous profiles of drug concentration. More recently, Zhan et al [10] reported a multiphysics modelling framework for TSL-mediated drug delivery by coupling high intensity focused ultrasound acoustics with spatially revolved drug transport models. Their model also incorporated temperature-dependent tumour and drug properties.…”