Cy5.5-Asp-Gly-Glu-Ala-Gly-Lys-(Arg)-OH

Integrin receptors are a family of cell-surface heterodimeric glycoproteins that mediate diverse biological events (e.g., cell adhesion, migration, differentiation, proliferation, and apoptosis) involving cell–cell and cell–matrix interactions (1, 2). They consist of an α and a β subunit. They are important for cell adhesion and signal transduction. On the other hand, integrins affect tumor growth, tumor invasiveness, and metastasis (3, 4). The αβ integrin binds mainly to collagen type I, laminins, E-cadherin, and matrix metalloproteinase 1 (5). The αβ integrin is strongly expressed on tumor cells and has been implicated in tumor progression and metastasis (6, 7). In particular, prostate cancer cells and prostate cancer stem cells express high levels of αβ integrin (8, 9). A tetrapeptide sequence consisting of Asp-Gly-Glu-Ala (DGEA) has been identified as a recognition motif used by the type I collagen to bind to αβ integrin (10). DGEA was conjugated with Cy5.5 to study biodistribution of the tracer in prostate tumor-bearing mice (11). Cy5.5-DGEA exhibited high accumulation in the αβ-positive PC-3 human prostate tumor cells and kidneys in nude mice. Optical and positron emission tomography imaging with various DGEA peptides showed high kidney accumulation and high tumor washout rates (11-13). To induce high tumor retention, multiple Arg molecules have been added to DGEA to help cell penetration (14). A small linker (Gly-Lys-OH) was added to the C-terminal Ala of DGEA to reduce kidney accumulation (15). The Gly-Lys bond is cleaved by the kidney brush border Lys-specific carboxypeptidase before entering the proximal tubule cells for kidney clearance. Huang et al. (16) prepared Cy5.5-Asp-Gly-Glu-Ala-Gly-Lys-(Arg)-OH (Cy5.5-DGEAGK(R8)-OH) for optical imaging in mice bearing αβ-positive PC-3 prostate tumors with lower kidney accumulation and better tumor retention than Cy5.5-DGEAGK(R4)-OH and R4-DGEAGK(Cy5.5)-OH.