The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its Application
Abstract
:1. Introduction
2. The EPR Effect: The Universal Pathophysiological Phenomena in Rodents, Other Mammalian Animals and Human Solid Tumors
- (1)
- Massive irregular neovascularization in tumors with structural and functional abnormalities in tumor blood vessels. To meet urgent demands for nutrient and oxygen supplies, the tumor vasculature is very dense and tortuous, with deficient basement membranes and fenestrated structures of endothelial tubes in some immature vessels. The pericytes and smooth muscle cells surrounding tumor blood vessels are either deficient or malfunctional in smooth muscle alpha actin when responding to blood pressure regulation stimuli [14,15,16]. Recent studies have found that the gaps between endothelial cells in tumor vessels are at low frequency, and the transendothelial pathways are the dominant mechanism of nanoparticle extravasation in tumors [17]. This is consistent with the previous observation that macromolecules are highly permeable in the mature veins or venules, constructed by a continuous endothelium with closed interendothelial cell junctions [18]. These structures render them highly permeable to nutrients, especially macromolecules, to be extravasated from tumor blood vessels into the interstitial space of tumor tissue.
- (2)
- Elevated expression of inflammatory factors such as prostaglandins, bradykinin, nitric oxide, peroxynitrite, interleukin 1 beta, interleukin 2, interleukin 6, proteases, interferon gamma, VEGF and HIF−1 alpha. All these factors coordinate in solid tumor tissues and sustain the EPR effect [7,19,20,21].
- (3)
3. The Significance and Challenges in Concept and Application of the EPR Effect in Human Cancer Therapy
4. Potential Solutions for Improving EPR Effect-Based Nanomedicine in Human Cancer Therapy
4.1. Better Design of Drug and Combination with EPR Effect Enhancing Modulators
4.2. Improving EPR Effect-Based Nanomedicine by Enhancing Blood Flow in Solid Tumor during Drug Administration
4.3. Improving EPR Effect-Based Nanomedicine Therapeutic Effect by Arterial Infusion via Tumor Feeding Artery
4.4. Improving EPR Effect-Based Nanomedicine Preclinical Development by Using Large Animal Tumor Models
5. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Wu, J. The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its Application. J. Pers. Med. 2021, 11, 771. https://doi.org/10.3390/jpm11080771
Wu J. The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its Application. Journal of Personalized Medicine. 2021; 11(8):771. https://doi.org/10.3390/jpm11080771
Chicago/Turabian StyleWu, Jun. 2021. "The Enhanced Permeability and Retention (EPR) Effect: The Significance of the Concept and Methods to Enhance Its Application" Journal of Personalized Medicine 11, no. 8: 771. https://doi.org/10.3390/jpm11080771