A systematic study of temperature sensitive liposomal delivery of doxorubicin using a mathematical model

Background: Temperature-sensitive liposomes (TSL) in combination with hyperthermia (HT) exposure have emerged as a potentially attractive option to achieve therapeutic drug concentration at targeted tumour site while reducing adverse side effects associated with systemic administration of anticancer drugs. The aim of this study is to elucidate the interplay among different kinetic steps by means of computational modelling. Methods: A multi-compartment model for TSL-mediated delivery of doxorubicin (DOX) is developed, which incorporates descriptions of the pharmacokinetics of TSL and DOX, and their accumulation in tumour tissue following intravascular triggered release. By examining dynamic interactions among TSL properties, tumour physiological properties and treatment regimen, peak intracellular DOX concentration is predicted for continuous and pulse HT exposures. Results: Drug release rate from TSL has a saturable effect on peak intracellular drug concentration, and no further gain could be achieved for release rates greater than 0.1018 s(-1). A similar effect has also been found for heating duration, such that for a given bolus injection, peak intracellular drug concentration reaches its maximum and then levels off after HT duration of 2 h. These results suggest that both TSL release rate and HT duration can be optimised in accordance with other parameters, e.g. clearance rate of TSL and administration mode, in order to achieve a desirable level of intracellular drug concentration. However, prolonged heating is not effective for resistant tumour cells with overexpression of ABC (ATP-binding cassette) transporter proteins. Conclusions: The results obtained in this study can be used to guide the design and optimisation of TSL parameters and treatment regimens. (c) 2015 Elsevier Ltd. All rights reserved.