The EPR effect results from the extravasation of macromolecules or nanoparticles through tumor blood vessels. We here provide a historical review of the EPR effect, including its features, vascular mediators found in both cancer and inflamed tissue. In addition, architectural and physiological differences of tumor blood vessels vs that of normal tissue are commented. Furthermore, methods of augmentation of the EPR effect are described, that result in better tumor delivery and improved therapeutic effect, where nitroglycerin, angiotensin I-converting enzyme (ACE) inhibitor, or angiotensin II-induced hypertension are employed. Consequently, better therapeutic effect and reduced systemic toxicity are generally observed. Obviously, the EPR effect based delivery of nanoprobes are also useful for tumor-selective imaging agents with using fluorescent or radio nuclei in nanoprobes. We also commented a key difference between passive tumor targeting and the EPR effect in tumors, particularly as related to drug retention in tumors: passive targeting of low-molecular-weight X-ray contrast agents involves a retention period of less than a few minutes, whereas the EPR effect of nanoparticles involves a prolonged retention time-days to weeks.
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