Comparison of Conventional Chemotherapy, Stealth Liposomes and Temperature-Sensitive Liposomes in a Mathematical Model

Abstract

Various liposomal drug carriers have been developed to overcome short plasma half-life and toxicity related side effects of chemotherapeutic agents. We developed a mathematical model to compare different liposome formulations of doxorubicin (DOX): conventional chemotherapy (Free-DOX), Stealth liposomes (Stealth-DOX), temperature sensitive liposomes (TSL) with intra-vascular triggered release (TSL-i), and TSL with extra-vascular triggered release (TSL-e). All formulations were administered as bolus at a dose of 9 mg/kg. For TSL, we assumed locally triggered release due to hyperthermia for 30 min. Drug concentrations were determined in systemic plasma, aggregate body tissue, cardiac tissue, tumor plasma, tumor interstitial space, and tumor cells. All compartments were assumed perfectly mixed, and represented by ordinary differential equations. Contribution of liposomal extravasation was negligible in the case of TSL-i, but was the major delivery mechanism for Stealth-DOX and for TSL-e. The dominant delivery mechanism for TSL-i was release within the tumor plasma compartment with subsequent tissue- and cell uptake of released DOX. Maximum intracellular tumor drug concentrations for Free-DOX, Stealth-DOX, TSL-i, and TSL-e were 3.4, 0.4, 100.6, and 15.9 µg/g, respectively. TSL-i and TSL-e allowed for high local tumor drug concentrations with reduced systemic exposure compared to Free-DOX. While Stealth-DOX resulted in high tumor tissue concentrations compared to Free-DOX, only a small fraction was bioavailable, resulting in little cellular uptake. Consistent with clinical data, Stealth-DOX resulted in similar tumor intracellular concentrations as Free-DOX, but with reduced systemic exposure. Optimal release time constants for maximum cellular uptake for Stealth-DOX, TSL-e, and TSL-i were 45 min, 11 min, and <3 s, respectively. Optimal release time constants were shorter for MDR cells, with ∼4 min for Stealth-DOX and for TSL-e. Tissue concentrations correlated well quantitatively with a prior in-vivo study. Mathematical models may thus allow optimization of drug delivery systems to achieve a better therapeutic index.

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

“…A first order kinetics with a rate constant of 37 is used to describe the release of DOX in systemic plasma due to instability of TSL at body temperature [10].…”

“…Based on the concept of multi-compartment model, a number of mathematical models [7][8][9][10][11][12] have been developed to describe biological transport processes involved in stealth liposomes and TSL. These models have provided various levels of insight into the delivery of liposomal carriers, bioavailability in the tumour tissue, and its correlation to cytotoxic effect.…”

“…In particular, mathematical models of TSL delivery require tempo-spatial profiles of temperature as input (stimulus) to account for temperature-dependent release kinetics. This can be achieved by assuming a homogeneous distribution of desired temperature in the entire tumour region [10], or by coupling with a bio-heat transfer model. In their recently published computational studies, Gasselhuber et al [9,13] predicted distributions of temperature and drug concentration in response to two different heating modalities, and their numerical results showed a qualitative agreement with preliminary in vivo data.…”

“…Compared to the mathematical models employed by Gasselhuber et al [9,10,13], an additional compartment for tumour plasma is introduced in the present study, which allows distinction of TSL in systemic plasma from those in tumour plasma. A systematic study is then performed by contrasting and comparing numerical results in response to continuous and pulse temperature stimuli.…”

Systems for the delivery of chemotherapeutic drugs, new approaches and perspective

“…Thus it is possible to increase productivity and maintain drugs consumer properties. Uni-(mono), bi-or multi-laminar vesicular structures such as liposomes with a variety of desired properties can be applied as drug carriers for the anticancer drugs delivery [3,[7][8][9][10]. From the biomedical point of view, liposomes are biocompatible, cause very little or no antigenic, pyrogenic, allergic and toxic reactions; they easily undergo biodegradation.…”