A Mathematical Model for Thermosensitive Liposomal Delivery of Doxorubicin to Solid Tumour

Abstract

The effectiveness of anticancer treatments is often hampered by the serious side effects owing to toxicity of anticancer drugs and their undesirable uptake by healthy cells in vivo. Thermosensitive liposome-mediated drug delivery has been developed as part of research efforts aimed at improving therapeutic efficacy while reducing the associated side effect. Since multiple steps are involved in the transport of drug-loaded liposomes, drug release, and its uptake, mathematical models become an indispensible tool to analyse the transport processes and predict the outcome of anticancer treatment. In this study, a computational model is developed which incorporates the key physical and biochemical processes involved in drug delivery and cellular uptake. The model has been applied to idealized tumour geometry, and comparisons are made between continuous infusion of doxorubicin and thermosensitive liposome-mediated delivery. Results show that thermosensitive liposome-mediated delivery performs better in reducing drug concentration in normal tissues, which may help lower the risk of associated side effects. Compared with direct infusion over a 2-hour period, thermosensitive liposome delivery leads to a much higher peak intracellular concentration of doxorubicin, which may increase cell killing in tumour thereby enhancing the therapeutic effect of the drug.

Predicting drug delivery efficiency into tumor tissues through molecular simulation of transport in complex vascular networks

“…The diffusivity of doxil liposomes was based on broad -field fluorescence measurements of nanoparticles of similar size and mass within agar gel phantoms (in vitro) [33]. Many nanoparticles diffuse on the order of 10 -11 cm 2 /s in mucus covered epithelial tissues [34], but the selection of D tiss = 1.0x10 -9 cm 2 /s is closer line with previous simulations of doxil [35], and yields a similar drug penetration in the tumor, due to the square root dependence on diffusivity on permeation length.…”

“…Molecular diffusion constants through the interstitial space of living tissues are more difficult to obtain and are likely to vary between different tissue types. For the present study, we estimated tissue diffusivity for doxil liposomes to be 1x10 -9 cm 2 /s, in line with previous studies [35], [36], [66]. Varying the diffusivity by five orders of magnitude (10 -10 -10 -5 cm 2 /s) allowed us to implicitly investigate the impact of drug weight, size, polarity, and interaction with endothelia and tissue environments (see Figure 4).…”

“…Applications and comparison with previous structural models Previous efforts at modeling the spatial distribution of drugs have applied continuum finite -element [69][25] and finite-difference methods [18], fluid-mechanics formalisms [70], [71], time evolution of differential equations [35], [63], [72], and other methods [73]. These models generally treat both blood vessels and tissues as homogeneous continua and some have been shown to capture detailed advection and diffusion continuum physics including Michaelis-Menten kinetics within 3D networks of cylindrical blood vessels [74].…”

Biologically Inspired Bio-Cyber Interface Architecture and Model for Internet of Bio-NanoThings Applications

“…By using the experimental data in [61] for liposome exposure to ultraviolet light, the value of l  = 0.000104 min -1 is adopted in our work. 20 In this work, we use t  = 0.0078 min -1 [62] obtained by using the best fitting curve on nonlinear least square methods for experimental data obtained at 42°C [63].…”

Systems biology approaches to adverse drug effects: the example of cardio-oncology

“…65,66 Use of another computational tool has demonstrated that superior antitumour effects can be achieved using delivery of thermosensitive liposomes relative to continuous infusion over 2 h, and that the localization afforded by thermosensitive drug delivery leads to lower drug concentrations in normal tissues. 67 Other models have been useful in aiding our understanding of doxorubicin pharmacokinetics and drug delivery, as well as its effects on cellular biology and function. [68][69][70] Trastuzumab-induced cardiotoxicity…”