Drug Discovery Today  Volume 11, Numbers 17/18  September 2006 REVIEWS Exploiting the enhanced permeability and retention effect for tumor targeting Arun K. Iyer 1 , Greish Khaled 2 , Jun Fang 1 and Hiroshi Maeda 1 1 Laboratory of Microbiology and Oncology, Faculty of Pharmaceutical Sciences, Sojo University, Ikeda 862-0082, Japan 2 BioDynamics Research Laboratory, Cooperative Research Centre of Kumamoto University, Tabaru, Mashiki-machi, Kumamoto, 860-0811, Japan Of the tumor targeting strategies, the enhanced permeability and retention (EPR) effect of macromolecules is a key mechanism for solid tumor targeting, and considered a gold standard for novel drug design. In this review, we discuss various endogenous factors that can positively impact the EPR effect in tumor tissues. Further, we discuss ways to augment the EPR effect by use of exogenous agents, as well as practical methods available in the clinical setting. Some innovative examples developed by researchers to combat cancer by the EPR mechanism are also discussed. Cancer has been, and still remains, one of the most dreaded diseases and a major threat to human life. Most of the conven- tional cancer chemotherapy – the standard treatment – is not always successful, even after 50 years of research, although lymphocytic leukemia and Hodgkin’s lymphoma are treated rather successfully in this way [1]. Conventional chemotherapy delivers the toxic anticancer agent indiscriminately, to tumors or normal organs and tissues. Therefore, we need to devise cancer-selective drug delivery to avoid undesirable systemic side-effects. One way of tackling these problems is to deliver anticancer drugs selectively to the tumor site. Among the most effective strategies, in terms of drug delivery, is exploiting the anatomical and pathophysiological abnormalities of tumor tis- sue, particularly the tumor vasculature, utilizing the enhanced permeability and retention (EPR) effect [2]. By harnessing this unique characteristic (EPR effect) of solid tumors, the selective delivery of macromolecular anticancer drugs to the tumor site, with pin-pointed accuracy, has become a reality. This approach can be compared to the ‘magic bullet’ concept put forward by Paul Ehrlich at the turn of the 20th century. This review dis- cusses the concept of the EPR effect and the factors influencing the EPR effect, as well as demonstrating examples of macromo- lecular tumor targeting and suggesting possible ways to further enhance this effect in vivo. Enhanced permeability and retention effect: theory, principles and consequence The theory behind enhanced permeability and retention, pathophysiology and anatomy of tumor vasculature When tumor cells multiply, cluster together and reach a size of 2– 3 mm angiogenesis is induced, to cater for the ever-increasing nutrition and oxygen demands of the growing tumor [3]. This neovasculature differs greatly from that of normal tissues in microscopic anatomical architecture [4]. For instance, the blood vessels in the tumor are irregular in shape, dilated, leaky or defective, and the endothelial cells are poorly aligned or disorga- nized with large fenestrations. Also, the perivascular cells and the basement membrane, or the smooth-muscle layer, are frequently absent or abnormal in the vascular wall. Tumor vessels have a wide lumen, whereas tumor tissues have poor lymphatic drainage [2,4– 7]. This anatomical defectiveness, along with functional abnorm- alities, results in extensive leakage of blood plasma components, such as macromolecules, nanoparticles and lipidic particles, into the tumor tissue. Moreover, the slow venous return in tumor tissue [8,9] and the poor lymphatic clearance mean that macromolecules are retained in the tumor, whereas extravasation into tumor interstitium continues. This phenomenon, termed the EPR effect, was described by us almost 20 years ago, and is the basis for the selective targeting of macromolecular drugs to the site of solid tumors [2]. It is possible to achieve very high local concentrations of polymeric drugs at the tumor site, for instance 10–50-fold higher than in normal tissue within 1–2 days. More recently, Reviews  POST SCREEN Corresponding author: Maeda, H. (hirmaeda@ph.sojo-u.ac.jp) 812 www.drugdiscoverytoday.com 1359-6446/06/$ - see front matter ß 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.drudis.2006.07.005