Drug Delivery to Tumors: the role of EPR

T. Anchordoquy
University of Colorado, Denver, US

Keywords: drug delivery, nanoparticles

Summary:

The passive accumulation of macromolecules and nanoparticles in tumors was originally demonstrated in animal models by Matsumura and Maeda in 1986, and the “enhanced permeation and retention” effect has become well-accepted by drug delivery researchers. In fact, the use of nanoparticles relies heavily upon the EPR effect to explain particle distribution to tumors, and studies have demonstrated that targeting ligands serve to promote retention of particles after the initial deposition. Despite the widespread acceptance of “leaky tumor vasculature”, recent work has suggested that the EPR effect is highly variable, and dependent on the tumor model. The results from these investigations raise questions regarding the extent to which the EPR effect occurs in humans, and whether the development of nanoparticles that rely upon EPR for delivery is justified. In addition, the vast majority of studies employing nanoparticles for tumor delivery do not observe increased accumulation over time as predicted by EPR. Furthermore, delivery studies in animal models typically report tumor accumulation of <1% of the injected dose, suggesting that EPR cannot prevent the majority of nanoparticles from distributing to sites other than the tumor, i.e., liver, lung and spleen. Acceptance of this fundamental premise should encourage researchers to design delivery vehicles that exhibit low toxicity in non-target tissues. This is particularly problematic for nucleic acid delivery due to the need for synthetic cationic agents that are known to be cytotoxic. These issues will be discussed, and the predominant reliance on EPR critically evaluated.