Strategies to improve the EPR effect: A mechanistic perspective and clinical translation

Mayumi Ikeda-Imafuku; Lily Li-Wen Wang; Danika Rodrigues; Suyog Shaha; Zongmin Zhao; Samir Mitragotri

doi:10.1016/j.jconrel.2022.03.043

Strategies to improve the EPR effect: A mechanistic perspective and clinical translation

J Control Release. 2022 May:345:512-536. doi: 10.1016/j.jconrel.2022.03.043. Epub 2022 Mar 23.

Authors

Mayumi Ikeda-Imafuku¹, Lily Li-Wen Wang², Danika Rodrigues¹, Suyog Shaha¹, Zongmin Zhao³, Samir Mitragotri⁴

Affiliations

¹ John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 20138, USA.
² John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 20138, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
³ Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA; Translational Oncology Program, University of Illinois Cancer Center, Chicago, IL 60612, USA. Electronic address: zhaozm@uic.edu.
⁴ John A. Paulson School of Engineering & Applied Sciences, Harvard University, Cambridge, MA 02138, USA; Wyss Institute for Biologically Inspired Engineering, Cambridge, MA 20138, USA. Electronic address: mitragotri@seas.harvard.edu.

PMID: 35337939
DOI: 10.1016/j.jconrel.2022.03.043

Abstract

Many efforts have been made to achieve targeted delivery of anticancer drugs to enhance their efficacy and to reduce their adverse effects. These efforts include the development of nanomedicines as they can selectively penetrate through tumor blood vessels through the enhanced permeability and retention (EPR) effect. The EPR effect was first proposed by Maeda and co-workers in 1986, and since then various types of nanoparticles have been developed to take advantage of the phenomenon with regards to drug delivery. However, the EPR effect has been found to be highly variable and thus unreliable due to the complex tumor microenvironment. Various physical and pharmacological strategies have been explored to overcome this challenge. Here, we review key advances and emerging concepts of such EPR-enhancing strategies. Furthermore, we analyze 723 clinical trials of nanoparticles with EPR enhancers and discuss their clinical translation.

Keywords: Clinical trials; EPR effect; Nanomedicine; Tumor microenvironment.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents* / pharmacology
Antineoplastic Agents* / therapeutic use
Drug Delivery Systems
Humans
Nanomedicine
Nanoparticles*
Neoplasms* / drug therapy
Permeability
Tumor Microenvironment

Substances

Antineoplastic Agents