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A mathematical model of the enhanced permeability and retention effect for liposome transport in solid tumors. | LitMetric

A mathematical model of the enhanced permeability and retention effect for liposome transport in solid tumors.

PLoS One

Department of Medical Biophysics, University of Toronto, Ontario, Canada ; STTARR Innovation Centre, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.

Published: August 2014

AI Article Synopsis

  • The enhanced permeability and retention (EPR) effect has led to the development of liposome-based nanomedicines for cancer therapy, improving drug accumulation in tumors, though therapeutic outcomes have not significantly improved yet.
  • Research shows that inconsistent liposome accumulation in tumors is due to abnormal transport microenvironments, leading to variations both between different subjects and within the same tumor.
  • A mathematical model has been developed to better understand liposome transport by relating it to tumor microenvironment properties, revealing that differences in interstitial fluid pressure can explain varying drug accumulation in different patients and tumors.

Article Abstract

The discovery of the enhanced permeability and retention (EPR) effect has resulted in the development of nanomedicines, including liposome-based formulations of drugs, as cancer therapies. The use of liposomes has resulted in substantial increases in accumulation of drugs in solid tumors; yet, significant improvements in therapeutic efficacy have yet to be achieved. Imaging of the tumor accumulation of liposomes has revealed that this poor or variable performance is in part due to heterogeneous inter-subject and intra-tumoral liposome accumulation, which occurs as a result of an abnormal transport microenvironment. A mathematical model that relates liposome accumulation to the underlying transport properties in solid tumors could provide insight into inter and intra-tumoral variations in the EPR effect. In this paper, we present a theoretical framework to describe liposome transport in solid tumors. The mathematical model is based on biophysical transport equations that describe pressure driven fluid flow across blood vessels and through the tumor interstitium. The model was validated by direct comparison with computed tomography measurements of tumor accumulation of liposomes in three preclinical tumor models. The mathematical model was fit to liposome accumulation curves producing predictions of transport parameters that reflect the tumor microenvironment. Notably, all fits had a high coefficient of determination and predictions of interstitial fluid pressure agreed with previously published independent measurements made in the same tumor type. Furthermore, it was demonstrated that the model attributed inter-subject heterogeneity in liposome accumulation to variations in peak interstitial fluid pressure. These findings highlight the relationship between transvascular and interstitial flow dynamics and variations in the EPR effect. In conclusion, we have presented a theoretical framework that predicts inter-subject and intra-tumoral variations in the EPR effect based on fundamental properties of the tumor microenvironment and forms the basis for transport modeling of liposome drug delivery.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846845PMC
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081157PLOS

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