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

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 liposo... Full description

Journal Title: PLoS One Oct 2012, Vol.7(10), p.e47453
Main Author: Gasselhuber, Astrid
Other Authors: Dreher, Matthew , Rattay, Frank , Wood, Bradford , Haemmerich, Dieter
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 19326203 ; DOI: 10.1371/journal.pone.0047453
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title: Comparison of Conventional Chemotherapy, Stealth Liposomes and Temperature-Sensitive Liposomes in a Mathematical Model
format: Article
creator:
  • Gasselhuber, Astrid
  • Dreher, Matthew
  • Rattay, Frank
  • Wood, Bradford
  • Haemmerich, Dieter
subjects:
  • Maryland
  • United States–Us
  • South Carolina
  • Liposomes
  • Toxicity
  • Hyperthermia
  • Mathematical Analysis
  • Compartments
  • Temperature
  • Formulations
  • Fever
  • Metabolism
  • Toxicity
  • Pediatrics
  • Chemotherapy
  • Optimization
  • Studies
  • Body Temperature
  • Bioavailability
  • Mathematical Models
  • Hyperthermia
  • Biocompatibility
  • Drug Delivery
  • Chemotherapy
  • Differential Equations
  • Intracellular
  • Ultrasonic Imaging
  • Chemotherapy
  • Hyperthermia
  • Drug Carriers
  • Side Effects
  • Side Effects
  • Plasma
  • Mathematical Models
  • Cancer Therapies
  • Heart Diseases
  • Extravasation
  • Toxicity
  • Doxorubicin
  • Exposure
  • Drug Dosages
  • Tumor Cells
  • Drug Delivery Systems
  • Chemotherapy
  • Permeability
  • Mathematical Models
  • Radioactive Half-Life
  • Drug Delivery Systems
  • Differential Equations
  • Doxorubicin
  • Liposomes
  • Mathematical Models
  • Constants
  • Carrier Lifetime
  • Medical University of South Carolina
  • Vienna University of Technology
  • National Institutes of Health
  • Liposomes
  • Elimination Half-Life Calculation
  • Toxicity
  • Blood Plasma
  • Drug Administration
  • Hyperthermia
  • Body Temperature
  • Drug Delivery
ispartof: PLoS One, Oct 2012, Vol.7(10), p.e47453
description: 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
language: eng
source:
identifier: E-ISSN: 19326203 ; DOI: 10.1371/journal.pone.0047453
fulltext: fulltext_linktorsrc
issn:
  • 19326203
  • 1932-6203
url: Link


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titleComparison of Conventional Chemotherapy, Stealth Liposomes and Temperature-Sensitive Liposomes in a Mathematical Model
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ispartofPLoS One, Oct 2012, Vol.7(10), p.e47453
identifierE-ISSN: 19326203 ; DOI: 10.1371/journal.pone.0047453
subjectMaryland ; United States–Us ; South Carolina ; Liposomes ; Toxicity ; Hyperthermia ; Mathematical Analysis ; Compartments ; Temperature ; Formulations ; Fever ; Metabolism ; Toxicity ; Pediatrics ; Chemotherapy ; Optimization ; Studies ; Body Temperature ; Bioavailability ; Mathematical Models ; Hyperthermia ; Biocompatibility ; Drug Delivery ; Chemotherapy ; Differential Equations ; Intracellular ; Ultrasonic Imaging ; Chemotherapy ; Hyperthermia ; Drug Carriers ; Side Effects ; Side Effects ; Plasma ; Mathematical Models ; Cancer Therapies ; Heart Diseases ; Extravasation ; Toxicity ; Doxorubicin ; Exposure ; Drug Dosages ; Tumor Cells ; Drug Delivery Systems ; Chemotherapy ; Permeability ; Mathematical Models ; Radioactive Half-Life ; Drug Delivery Systems ; Differential Equations ; Doxorubicin ; Liposomes ; Mathematical Models ; Constants ; Carrier Lifetime ; Medical University of South Carolina ; Vienna University of Technology ; National Institutes of Health ; Liposomes ; Elimination Half-Life Calculation ; Toxicity ; Blood Plasma ; Drug Administration ; Hyperthermia ; Body Temperature ; Drug Delivery
descriptionVarious 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.
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descriptionVarious 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.
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titleComparison of Conventional Chemotherapy, Stealth Liposomes and Temperature-Sensitive Liposomes in a Mathematical Model
authorGasselhuber, Astrid ; Dreher, Matthew ; Rattay, Frank ; Wood, Bradford ; Haemmerich, Dieter
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4Toxicity
5Hyperthermia
6Mathematical Analysis
7Compartments
8Temperature
9Formulations
10Fever
11Metabolism
12Pediatrics
13Chemotherapy
14Optimization
15Studies
16Body Temperature
17Bioavailability
18Mathematical Models
19Biocompatibility
20Drug Delivery
21Differential Equations
22Intracellular
23Ultrasonic Imaging
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27Cancer Therapies
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31Exposure
32Drug Dosages
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36Radioactive Half-Life
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40Vienna University of Technology
41National Institutes of Health
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abstractVarious 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.
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