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

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. [Display omitted] •Size, charge, softness, and surface properties of nanoparticles influence the EPR effect.•The EPR effect can be enhanced through physical and pharmacological strategies.•Understanding the key differences between animal and human tumors is critical for the translation of EPR enhancers.•EPR enhancers are in extensive clinical studies implying their clinical promise.