Improving accessibility of EPR-insensitive tumor phenotypes using EPR-adaptive strategies: Designing a new perspective in nanomedicine delivery

The enhanced permeability and retention (EPR) effect has underlain the predominant nanomedicine design philosophy for the past three decades. However, growing evidence suggests that it is over-represented in preclinical models, and agents designed solely using its principle of passive accumulation can only be applied to a narrow subset of clinical tumors. For this reason, strategies that can improve upon the EPR effect to facilitate nanomedicine delivery to otherwise non-responsive tumors are required for broad clinical translation. EPR-adaptive nanomedicine delivery comprises a class of chemical and physical techniques that modify tumor accessibility in an effort to increase agent delivery and therapeutic effect. In the present review, we overview the primary benefits and limitations of radiation, ultrasound, hyperthermia, and photodynamic therapy as physical strategies for EPR-adaptive delivery to EPR-insensitive tumor phenotypes, and we reflect upon changes in the preclinical research pathway that should be implemented in order to optimally validate and develop these delivery strategies.