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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

Drug accumulation rate in the tumor per 100 μm vessel length assuming a 1 cm3 tumor with 150 m of vessels (150 mm mm-3).(A) Doxil and (B) Doxorubicin. Values for kp, kd, and kel are given in Table 1, where kel ~ k10 when kel >> kepr. In both cases kepr/kel = 10–3.
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pone.0123461.g004: Drug accumulation rate in the tumor per 100 μm vessel length assuming a 1 cm3 tumor with 150 m of vessels (150 mm mm-3).(A) Doxil and (B) Doxorubicin. Values for kp, kd, and kel are given in Table 1, where kel ~ k10 when kel >> kepr. In both cases kepr/kel = 10–3.

Mentions: Taking kepr/kel = 10–3 (0.1% ID with kb = 0), the local accumulation of Doxil along a 100 μm segment corresponds to 104 to 106 liposomes, depending on the value of kb. For doxorubicin, the total accumulation along a 100 μm vessel segment is 107–1010 molecules. The derivative of tumor accumulation versus time is the rate of extravasation. Based on the pharmacokinetics of Doxil and taking kepr/kel = 10–3, the accumulation rate for a 100 μm vessel segment is about 28 liposomes per second for the first hour after administration, independent of the magnitude of the back rate constant kb (Fig 4A). The accumulation rate remains relatively high, greater than 10 liposomes per second, for a day or more depending on the value of constant kb. The high accumulation rate is due to the long circulation time of the liposomes which also minimizes the effect of intravasation back into circulation except at very large values of kb.


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

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

Drug accumulation rate in the tumor per 100 μm vessel length assuming a 1 cm3 tumor with 150 m of vessels (150 mm mm-3).(A) Doxil and (B) Doxorubicin. Values for kp, kd, and kel are given in Table 1, where kel ~ k10 when kel >> kepr. In both cases kepr/kel = 10–3.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123461.g004: Drug accumulation rate in the tumor per 100 μm vessel length assuming a 1 cm3 tumor with 150 m of vessels (150 mm mm-3).(A) Doxil and (B) Doxorubicin. Values for kp, kd, and kel are given in Table 1, where kel ~ k10 when kel >> kepr. In both cases kepr/kel = 10–3.
Mentions: Taking kepr/kel = 10–3 (0.1% ID with kb = 0), the local accumulation of Doxil along a 100 μm segment corresponds to 104 to 106 liposomes, depending on the value of kb. For doxorubicin, the total accumulation along a 100 μm vessel segment is 107–1010 molecules. The derivative of tumor accumulation versus time is the rate of extravasation. Based on the pharmacokinetics of Doxil and taking kepr/kel = 10–3, the accumulation rate for a 100 μm vessel segment is about 28 liposomes per second for the first hour after administration, independent of the magnitude of the back rate constant kb (Fig 4A). The accumulation rate remains relatively high, greater than 10 liposomes per second, for a day or more depending on the value of constant kb. The high accumulation rate is due to the long circulation time of the liposomes which also minimizes the effect of intravasation back into circulation except at very large values of kb.

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