Temperature sensitive liposomes combined with thermal ablation: Effects of duration and timing of heating in mathematical models and in vivo

Temperature 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...

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Veröffentlicht in:	PloS one Jg. 12; H. 6; S. e0179131
Hauptverfasser:	Rossmann, Christian, McCrackin, M. A., Armeson, Kent E., Haemmerich, Dieter
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States Public Library of Science 12.06.2017 Public Library of Science (PLoS)
Schlagworte:	Ablation Algorithms Animal models Animals Area Under Curve Biology and Life Sciences Coagulation Computer and Information Sciences Computer applications Computer models Computer Simulation Correlation analysis Deposition Doxorubicin Drug delivery Drug Delivery Systems Drug dosages Electrodes Encapsulation Female Fever Fluorescence Heat transfer Heating Hyperthermia Hyperthermia, Induced Imaging In vivo methods and tests Infusion Liposomes Liver Liver cancer Mathematical analysis Mathematical models Medicine and Health Sciences Models, Theoretical Nanoparticles NMR Nuclear magnetic resonance Optimization Pediatrics Plasma Radiofrequency ablation Research and Analysis Methods Simulation Spatial analysis Spatial distribution Studies Swine Temperature Temperature effects Tissue Distribution Tumors Ultrasonic imaging United States > US South Carolina
ISSN:	1932-6203, 1932-6203
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Zusammenfassung:	Temperature 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. We 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. Both 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. Both 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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Conceptualization: CR DH.Data curation: CR MAM KEA DH.Formal analysis: CR KEA DH.Funding acquisition: DH.Investigation: CR MAM DH.Methodology: CR DH.Project administration: DH.Resources: CR MAM KEA DH.Software: CR KEA DH.Supervision: DH.Validation: CR DH.Visualization: CR KEA DH.Writing – original draft: CR KEA DH.Writing – review & editing: CR MAM KEA DH. Competing Interests: The authors have declared that no competing interests exist. These authors also contributed equally to this work.
ISSN:	1932-6203 1932-6203
DOI:	10.1371/journal.pone.0179131