Tumor vasculature, EPR effect, and anticancer nanomedicine: Connecting the dots

Abstract

The progression of a tumor cell mass beyond 2 mm is critically dependent on neoangiogenesis. Angiogenic factors secreted by tumor cells, infiltrating macrophages, and stromal cells aggressively promote proliferation and migration of endothelial cells. The nascent primitive vasculatures are usually morphologically and functionally abnormal due to several features such as the lack of a vascular smooth muscle cell layer, abrupt change of the blood vessel diameter, tortuosity, and leakiness. Those characteristics which alter the blood flow and the transport of molecules in tumors led to the discovery of the enhanced permeability and retention (EPR) of nanosize molecules in tumor tissues. Following its discovery, various anticancer nanoconstructs have been developed with the EPR effect as a central mechanism for tumor targeting. However, the development of these nanodrugs has been hampered by a slow progress towards the clinic. Only nine nanomedicines have been approved for anticancer treatment for the last 26 years. In this chapter, we discuss various aspects that may explain the limited transition for an efficient anticancer nanomedicine. The specificity of the tumor vasculature, the discrepancy in tumor biology, the role of animal tumor models, and the physicochemical characteristics of nanoconstructs are closely examined. This chapter provides new considerations for successful development of EPR-based anticancer nanomedicine.