Enhanced Vascular Permeability in Solid Tumors and Tumor Targeted Delivery of Macromolecular Anticancer Drugs Based on EPR effect

摘要

@@Solid tumors are unique in their vascular anatomy which results in enhanced extravasations of macromolecules. In this context, the EPR (enhanced permeability and retention) effect in most solid tumors can be best utilized for selective tumor delivery of macromolecular polymeric drugs (1,2). It means not only passive drug targeting but also prolonged intratumoral drug retention is critically important for EPR effect. In addition to the microanatomical difference of tumor vasculature compared to the normal blood vessels, many vascular mediators are excessively generated in and vicinity of tumors such as nitric oxide, bradykinin, VEGF, prostacyclines, etc. They indeed facilitate the EPR effect. We have further developed methods to augment the EPR effect more. One method is to increase the drug delivery to tumor under elevated systolic blood pressure by infusing angiotensinⅡ(3). Anothor method to increase the tumor delivery is by use of nitroglycerin ointment (4). This is similar to the treatment of cardiac infarct or angina pectoris wherein hypoxic cardiac tissue is more selectively affected; This is also the case for many solid tumors. Namely, nitroglycerin is converted to nitrite in hypoxic state, and nitrite (NO2 －) is then reduced to nitric oxide (NO) in both tissues. NO not only affects vascular dilatation, it also facilitates vascular permeability, thus, augments the EPR effect. This nitroglycerin induced increase of tumor selective drug delivery, also augment the therapeutic effect of anthracycline and other polymeric anticancer agents (eg. PEG-ZnPP).