In other words, the addition of a targeting entity to a carrier does not necessarily suffice for efficient deliver; the number of peptides conjugated to the delivery platform, the site of conjugation and the size and type of the linker play an important role. Integrin targeting has also been extensively explored for cancer gene delivery in general. After the discovery of adhesion molecules

as mediators of tumor metastasis, the identification of their binding motifs opened the possibilities for targeted therapies. Several peptide fragments have been employed to target these mediators, either as antagonists or as ligands for drug delivery Inhibitors,research,lifescience,medical purposes. One of the utmost targeted integrin Inhibitors,research,lifescience,medical is the αvβ3. αvβ3 plays a central role in angiogenesis—the formation of new vessels— and, by serving as receptor for extracellular

matrix proteins, it mediates migration of endothelial cells into the basement membrane, and regulates their growth, survival, and differentiation. It is therefore no surprise that such integrin is found upregulated in different tumor cells, where it is involved in processes that govern metastasis. The integrin’s binding peptide motif has been identified in 1990 [121]—Arginine-Glutamine-Aspartate Inhibitors,research,lifescience,medical or RGD—but studies that followed have shown that the cyclic version of RGD (cRGD) has higher binding affinities towards the integrin [86, 87]. Either alone or in combination with other ligands, cRGD has been conjugated to several nanocarriers for both diagnostic and therapeutic purposes [88–90]. Another integrin reported to have a dominant function Inhibitors,research,lifescience,medical in the metastatic spread is α4β1 or VLA-4. Okumura, and more recently Schlesinger, have shown, in different settings, that inhibition of Inhibitors,research,lifescience,medical VLA-4 by natalizumab (an antibody against α4 integrin) significantly decreased melanoma lung metastases in murine models [42, 44, 122]. In

1991, Makarem and Humphries have identified the Leucine-Aspartate-Valine (LDV) sequence as the integrin’s motif [123], and a few years later, Vanderslice et al. have reported on a series of cyclized peptides based on LDV that were assayed for the inhibition of the integrin [124]. However, and despite the numerous however reports relating this agent to tumor metastasis, and to melanoma in particular, most of the literature relies on the LDV sequence as an antagonist, rather than for deliver purposes, where, to our knowledge, there is only one paper reporting on in vitro studies [91]. Indeed, VLA-4 is found in multiple leukocyte populations; VLA-4 is a vital receptor of leukocytes, and it is involved in the immune Caspase inhibitor response. Hence, a systemic application of VLA-4 inhibitors, or binding peptides, could induce undesired partially immunosuppressive effects. In this context, the application of transcriptional-targeting strategies could potentially prevent off-target effects and prove this ligand a promising tool.