Quantitative Analysis of the Enhanced Permeation and Retention (EPR) Effect.
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.
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.
Andrew D
AD
Wong
Department of Physics and Astronomy, Johns Hopkins University, Baltimore, Maryland, United States of America.
Mao
M
Ye
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.
Martin B
MB
Ulmschneider
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; Department of Physics and Astronomy, Johns Hopkins University, Baltimore, Maryland, United States of America.
Peter C
PC
Searson
D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D016503:Drug Delivery Systems; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000378:metabolism; D010539:Permeability; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D059016:Tumor Microenvironment / Q000187:drug effects
C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin