Enhanced permeability and retention effect

The Enhanced Permeability and Retention (EPR) effect is the property by which certain sizes of molecules, typically liposomes or macromolecular drugs, tend to accumulate in tumor tissue much more than they do in normal tissues^1,2,3. The general explanation that is given for this phenomenon is that, in order for tumor cells to grow quickly, they must stimulate the production of blood vessels (VEGF). Tumor cell aggregates of size as small as 150-200 um, start to become dependent on blood supply carried out by neovasculature for their nutritional and oxygen supply. These newly formed tumor vessels are usually abnormal in form and architecture. They are poorly-aligned defective endothelial cells with wide fenestrations, lacking a smooth muscle layer, or innervation with a wider lumen, and impaired functional receptors for angiotensin II. Furthermore, tumor tissues usually lack effective lymphatic drainage. All these factors will lead to abnormal molecular and fluid transport dynamics especially for macromolecular drugs. Namely, this phenomenon was coined “enhanced permeability and retention (EPR)-effect” of macromolecules and lipids in solid tumors. The EPR-effect is even more enhanced by many pathophysiological factors involved in enhancement of the extravasation of macromolecules in solid tumor tissues. For instance, bradykinin, nitric oxide / peroxynitrite, prostaglandins, vascular permeability factor (also known as vascular endothelial growth factor VEGF), tumor necrosis factor and others.

The EPR effect is also becoming important for thermal therapies. Halas and coworkers have shown a possible alternative cancer therapy. This method takes advantage of strong optical extinction of gold nanoparticles. The EPR in this respect helps to carry the nanoparticles and spread inside carcinogen tissue.(4)

1. Matsamura Y., Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: mechanisms of tumoritropic accumulation of protein and the antitumor agent SMANCS. Cancer Res., 46: 6387-6392, 1986.

2. Duncan R., Sat Y-N. Tumour targeting by enhanced permeability and retention (EPR) effect. Ann. Oncol., 9 (Suppl.2): 39 1998

3. Vasey P. A., Kaye S. B., Morrison R., Twelves C., Wilson P., Duncan R., Thomson A. H., Murray L. S., Hilditch T. E., Murray T., Burtles S., Fraier D., Frigerio E., Cassidy J. Phase I clinical and pharmacokinetic study of PK1 (HPMA copolymer doxorubicin): first member of a new class of chemotherapeutic agents-drug-polymer conjugates. Clin. Cancer Res., 5: 83-94, 1999

4. O’Neal, D. P., et al., Cancer Lett. (2004) 209, 171