In-Labeled-TNYLFSPNGPIARAW (TNYL-RAW)-polyethylene glycol–coated core-cross-linked polymeric micelle-Cy7

The ephrin (Eph) receptors constitute the largest member of the receptor tyrosine kinase family (1, 2). The Eph receptors and their ligands (ephrins) mediate numerous biological processes in normal development, particularly in the nervous and cardiovascular systems (3-5). Based on their structures and sequence relationships, ephrins are divided into the ephrin-A class, which are anchored to the cell membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B class, which are transmembrane proteins. The Eph family of receptors is divided into two groups, EphA and EphB, on the basis of the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. The Eph receptors transmit forward signals their kinase domain and reverse signals their transmembrane ephrin ligands (6). EphB–ephrin-B interactions are capable of mediating bi-directional signaling events upon cell–cell contact, either into the receptor-expressing cell as "forward signaling" or into the ligand-expressing cell as "reverse signaling" (7). Ephrin-2 is expressed on arterial and activated endothelial cells, whereas EphB4 is normally expressed on venous endothelial cells and various blood cells (8). EphB4 selectively binds to ephrin-2 to promote cell signaling and angiogenesis. EphB4 has been implicated in cancer progression and in pathological forms of angiogenesis. Overexpression of EphB4 has been observed in cancer cells and is associated with tumorigenesis forward signaling and angiogenesis reverse signaling through ephrin-2 interaction (9). EphB4 forward signaling stimulates cellular proliferation. Koolpe et al. (10) identified a 15-mer peptide, Tyr-Asn-Tyr-Leu-Phe-Ser-Pro-Asn-Gly-Pro-Ile-Ala-Arg-Ala-Trp (TNYL-RAW), to be a selective antagonist of EphB4 using phage display screening. Xiong et al. (11) reported the development of Cu-tetraazacyclododecane-,','','''-tetraacetic acid-TNYL-RAW (Cu-DOTA-TNYL-RAW) for positron emission tomography (PET) imaging of EphB4 in nude mice bearing tumor xenografts. Zhang et al. (12) conjugated TNYL-RAW to polyethylene glycol–coated core-cross-linked polymeric micelles (CCPMs) labeled with Cy7 and In (In-TNYL-RAW-CCPM) for multimodality detection of EphB4 in tumors.