Nanotechnology-mediated targeting of tumor angiogenesis

Since Judah Folkman emphasized the 'angiogenic switch' hypothesis for tumor progression in 1991, there has been a tremendous surge in targeting angiogenesis for cancer therapeutics [1]. In the past 30 years, many advances have been made in the field, with the elucidation of various angiogenic molecules that could be targeted to halt angiogenesis, and hence, tumor progression. Angiogenesis, the formation of new capillaries from preexisting vessels, is crucial for ensuring normal embryonic vascular development of all vertebrates, as well as regulating physiological processes such as menses and wound healing in adults [2-4]. Deregulation of angiogenesis hence underlies pathologies characterized by vessel overgrowth (e.g. cancer) as well as vessel insufficiency (e.g. cardiovascular disease, CVD) [4].It is now well-established that without angiogenesis, tumors cannot grow more than 2 mm in diameter [5-7]. Studies in breast cancer patients have showed that angiogenesis positively correlates with the degree of metastasis, tumor recurrence and shorter survival rates, thus demonstrating the value of angiogenesis as a prognostic cancer marker [1,8]. Tumor angiogenesis essentially entails the same sequences of events as physiological angiogenesis, however, the latter proceeds in an uncontrolled and excessive manner giving rise to leaky and tortuous vessels that are in a constant state of inflammation [6,9]. This is mainly due by an upregulation of angiogenic cytokines and growth factors, most notably the vascular endothelial cell growth factor (VEGF) and Angiopoietin (Ang) families, as well as integrins [10-12]. Integrin αvβ3 is the best-characterized heterodimer that is upregulated in most cancer settings, both on the vasculature and on the tumor cells themselves [13,14]. It is hence not surprising that these molecules are often targeted in both experimental and clinical cancer settings.As such, the first U.S. Food and Drug Administration (FDA) approved anti-angiogenic therap