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Quantitative Analysis of the Enhanced Permeation and Retention (EPR) Effect.

Wong AD, Ye M, Ulmschneider MB, Searson PC - PLoS ONE (2015)

Bottom Line: Tumor vasculature is characterized by a variety of abnormalities including irregular architecture, poor lymphatic drainage, and the upregulation of factors that increase the paracellular permeability.Studies in animal models have demonstrated a cut-off size of 500 nm - 1 µm for molecules or nanoparticles to extravasate into a tumor, however, surprisingly little is known about the kinetics of the EPR effect.Here we present a pharmacokinetic model to quantitatively assess the influence of the EPR effect on the uptake of a drug into a solid tumor.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America; Institute for Nanobiotechnology (INBT), Johns Hopkins University, Baltimore, Maryland, United States of America.

ABSTRACT
Tumor vasculature is characterized by a variety of abnormalities including irregular architecture, poor lymphatic drainage, and the upregulation of factors that increase the paracellular permeability. The increased permeability is important in mediating the uptake of an intravenously administered drug in a solid tumor and is known as the enhanced permeation and retention (EPR) effect. Studies in animal models have demonstrated a cut-off size of 500 nm - 1 µm for molecules or nanoparticles to extravasate into a tumor, however, surprisingly little is known about the kinetics of the EPR effect. Here we present a pharmacokinetic model to quantitatively assess the influence of the EPR effect on the uptake of a drug into a solid tumor. We use pharmacokinetic data for Doxil and doxorubicin from human clinical trials to illustrate how the EPR effect influences tumor uptake. This model provides a quantitative framework to guide preclinical trials of new chemotherapies and ultimately to develop design rules that can increase targeting efficiency and decrease unwanted side effects in normal tissue.

No MeSH data available.


Related in: MedlinePlus

The influence of the EPR effect on the rate of tumor uptake of doxorubicin for an administered dose of 100 mg (50 mg m-2).(A) Pharmacokinetics for doxorubicin. Symbols are data from a clinical trial reported by Gabizon et al. [12]. The solid red line is obtained from our model using values for kp, kd, and kel derived from median values of A, B, α, and β reported by Gabizon et al. [12] (Table 1), where kel ~ k10 when kel >> kepr. The dotted lines represents the pharmacokinetics for the minimum and maximum values of A, B, α, and β. (B) Simulations of the pharmacokinetics for doxorubicin with kepr/kel = 0, 10–1, 10–2, and 10–3, and kb = 0. (C) Amount of doxorubicin in tumor for kepr/kel = 10–1, 10–2, 10–3, and 10–4, and kb = 0. (D) Amount of doxorubicin in tumor for kepr/kel = 10–3 and kb/kepr = 0, 10, 100, 1000.
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pone.0123461.g003: The influence of the EPR effect on the rate of tumor uptake of doxorubicin for an administered dose of 100 mg (50 mg m-2).(A) Pharmacokinetics for doxorubicin. Symbols are data from a clinical trial reported by Gabizon et al. [12]. The solid red line is obtained from our model using values for kp, kd, and kel derived from median values of A, B, α, and β reported by Gabizon et al. [12] (Table 1), where kel ~ k10 when kel >> kepr. The dotted lines represents the pharmacokinetics for the minimum and maximum values of A, B, α, and β. (B) Simulations of the pharmacokinetics for doxorubicin with kepr/kel = 0, 10–1, 10–2, and 10–3, and kb = 0. (C) Amount of doxorubicin in tumor for kepr/kel = 10–1, 10–2, 10–3, and 10–4, and kb = 0. (D) Amount of doxorubicin in tumor for kepr/kel = 10–3 and kb/kepr = 0, 10, 100, 1000.

Mentions: Pharmacokinetic data for doxorubicin were obtained from Gabizon et al. (Fig 3A) [12]. Similar values have been reported in other clinical trials [17–19]. Values for the pharmacokinetic parameters A, B, α, and β, as well as the rate constants k12, k21, and k10, are provided in Table 1.


Quantitative Analysis of the Enhanced Permeation and Retention (EPR) Effect.

Wong AD, Ye M, Ulmschneider MB, Searson PC - PLoS ONE (2015)

The influence of the EPR effect on the rate of tumor uptake of doxorubicin for an administered dose of 100 mg (50 mg m-2).(A) Pharmacokinetics for doxorubicin. Symbols are data from a clinical trial reported by Gabizon et al. [12]. The solid red line is obtained from our model using values for kp, kd, and kel derived from median values of A, B, α, and β reported by Gabizon et al. [12] (Table 1), where kel ~ k10 when kel >> kepr. The dotted lines represents the pharmacokinetics for the minimum and maximum values of A, B, α, and β. (B) Simulations of the pharmacokinetics for doxorubicin with kepr/kel = 0, 10–1, 10–2, and 10–3, and kb = 0. (C) Amount of doxorubicin in tumor for kepr/kel = 10–1, 10–2, 10–3, and 10–4, and kb = 0. (D) Amount of doxorubicin in tumor for kepr/kel = 10–3 and kb/kepr = 0, 10, 100, 1000.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4418820&req=5

pone.0123461.g003: The influence of the EPR effect on the rate of tumor uptake of doxorubicin for an administered dose of 100 mg (50 mg m-2).(A) Pharmacokinetics for doxorubicin. Symbols are data from a clinical trial reported by Gabizon et al. [12]. The solid red line is obtained from our model using values for kp, kd, and kel derived from median values of A, B, α, and β reported by Gabizon et al. [12] (Table 1), where kel ~ k10 when kel >> kepr. The dotted lines represents the pharmacokinetics for the minimum and maximum values of A, B, α, and β. (B) Simulations of the pharmacokinetics for doxorubicin with kepr/kel = 0, 10–1, 10–2, and 10–3, and kb = 0. (C) Amount of doxorubicin in tumor for kepr/kel = 10–1, 10–2, 10–3, and 10–4, and kb = 0. (D) Amount of doxorubicin in tumor for kepr/kel = 10–3 and kb/kepr = 0, 10, 100, 1000.
Mentions: Pharmacokinetic data for doxorubicin were obtained from Gabizon et al. (Fig 3A) [12]. Similar values have been reported in other clinical trials [17–19]. Values for the pharmacokinetic parameters A, B, α, and β, as well as the rate constants k12, k21, and k10, are provided in Table 1.

Bottom Line: Tumor vasculature is characterized by a variety of abnormalities including irregular architecture, poor lymphatic drainage, and the upregulation of factors that increase the paracellular permeability.Studies in animal models have demonstrated a cut-off size of 500 nm - 1 µm for molecules or nanoparticles to extravasate into a tumor, however, surprisingly little is known about the kinetics of the EPR effect.Here we present a pharmacokinetic model to quantitatively assess the influence of the EPR effect on the uptake of a drug into a solid tumor.

View Article: PubMed Central - PubMed

Affiliation: Department of Materials Science and Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America; Institute for Nanobiotechnology (INBT), Johns Hopkins University, Baltimore, Maryland, United States of America.

ABSTRACT
Tumor vasculature is characterized by a variety of abnormalities including irregular architecture, poor lymphatic drainage, and the upregulation of factors that increase the paracellular permeability. The increased permeability is important in mediating the uptake of an intravenously administered drug in a solid tumor and is known as the enhanced permeation and retention (EPR) effect. Studies in animal models have demonstrated a cut-off size of 500 nm - 1 µm for molecules or nanoparticles to extravasate into a tumor, however, surprisingly little is known about the kinetics of the EPR effect. Here we present a pharmacokinetic model to quantitatively assess the influence of the EPR effect on the uptake of a drug into a solid tumor. We use pharmacokinetic data for Doxil and doxorubicin from human clinical trials to illustrate how the EPR effect influences tumor uptake. This model provides a quantitative framework to guide preclinical trials of new chemotherapies and ultimately to develop design rules that can increase targeting efficiency and decrease unwanted side effects in normal tissue.

No MeSH data available.


Related in: MedlinePlus