Exploiting the dynamics of the EPR effect and strategies to improve the therapeutic effects of nanomedicines by using EPR effect enhancers

The enhanced permeability and retention (EPR) effect is a unique phenomenon of solid tumors that is related to their particular anatomical and pathophysiological characteristics, e.g. defective vascular architecture; large gaps between endothelial cells in blood vessels; abundant vascular mediators such as bradykinin, nitric oxide, carbon monoxide, and vascular endothelial growth factor; and impaired lymphatic recovery. These features lead to tumor tissues showing considerable extravasation of plasma components and nanomedicines. These data comprise the basic theory underlying the development of macromolecular agents or nanomedicines. The EPR effect is not necessarily valid for all solid tumors, because tumor blood flow and vascular permeability vary greatly. Tumor blood flow is frequently obstructed as tumor size increases, as often seen clinically; early stage, small tumors show a more uniform EPR effect, whereas advanced large tumor show heterogeneity in EPR effect. Accordingly, it would be very important to apply enhancers of EPR effect in clinical setting to make EPR effect more uniform. In this review, we discuss the EPR effect: its history, factors involved, and dynamics and heterogeneity. Strategies to overcome the EPR effect’s heterogeneity may guarantee better therapeutic outcomes of drug delivery to advanced cancers.