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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.

SUBMITTER: Gasselhuber A

PROVIDER: S-EPMC3474827 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Comparison of conventional chemotherapy, stealth liposomes and temperature-sensitive liposomes in a mathematical model.

Gasselhuber Astrid A Dreher Matthew R MR Rattay Frank F Wood Bradford J BJ Haemmerich Dieter D

PloS one 20121017 10

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 bol ...[more]

PMID: 23082168

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Project description:BackgroundTemperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug at hyperthermic temperatures, typically above ~40°C. TSL have been combined with various heating modalities, but there is no consensus on required hyperthermia duration or ideal timing of heating relative to TSL administration. The goal of this study was to determine changes in drug uptake when heating duration and timing are varied when combining TSL with radiofrequency ablation (RF) heating.MethodsWe used computer models to simulate both RF tissue heating and TSL drug delivery, to calculate spatial drug concentration maps. We simulated heating for 5, 12 and 30 min for a single RF electrode, as well as three sequential 12 min ablations for 3 electrodes placed in a triangular array. To support simulation results, we performed porcine in vivo studies in normal liver, where TSL filled with doxorubicin (TSL-Dox) at a dose of 30 mg was infused over 30 min. Following infusion, RF heating was performed in separate liver locations for either 5 min (n = 2) or 12 min (n = 2). After ablation, the animal was euthanized, and liver extracted and frozen. Liver samples were cut orthogonal to the electrode axis, and fluorescence imaging was used to visualize tissue doxorubicin distribution.ResultsBoth in vivo studies and computer models demonstrate a ring-shaped drug deposition within ~1 cm of the visibly coagulated tissue. Drug uptake directly correlated with heating duration. In computer simulations, drug concentration increased by a factor of 2.2x and 4.3x when heating duration was extended from 5 to either 12, or 30 minutes, respectively. In vivo, drug concentration was by a factor of 2.4x higher at 12 vs 5 min heating duration (7.1 μg/g to 3.0 μg/g). The computer models suggest that heating should be timed to maximize area under the curve of systemic plasma concentration of encapsulated drug.ConclusionsBoth computer models and in vivo study demonstrate that tissue drug uptake directly correlates with heating duration for TSL based delivery. Computational models were able to predict the spatial drug delivery profile, and may serve as a valuable tool in understanding and optimizing drug delivery systems.

Dataset Information

Comparison of conventional chemotherapy, stealth liposomes and temperature-sensitive liposomes in a mathematical model.

Publications

Comparison of conventional chemotherapy, stealth liposomes and temperature-sensitive liposomes in a mathematical model.

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