A stapled chromogranin A-derived peptide homes in on tumors that express ?v?6 or ?v? 8 integrins

Rationale: The alpha v[36-and alpha v[38-integrins, two cell-adhesion receptors upregulated in many tumors and involved in the activation of the latency associated peptide (LAP)/TGF[3 complex, represent potential targets for tumor imaging and therapy. We investigated the tumor-homing properties of a chromogranin A-derived peptide containing an RGDL motif followed by a chemically stapled alpha-helix (called "5a"), which selectively recognizes the LAP/TGF[3 complex-binding site of alpha v[36 and alpha v[38.Methods: Peptide 5a was labeled with IRDye 800CW (a near-infrared fluorescent dye) or with 18F-NOTA (a label for positron emission tomography (PET)); the integrin-binding properties of free peptide and conjugates were then investigated using purified alpha v[36/alpha v[38 integrins and various alpha v[36/alpha v[38 single -or double-positive cancer cells; tumor-homing, biodistribution and imaging properties of the conjugates were investigated in subcutaneous and orthotopic alpha v[36-positive carcinomas of the pancreas, and in mice bearing subcutaneous alpha v[38-positive prostate tumors. Results: In vitro studies showed that 5a can bind both integrins with high affinity and inhibits cell-mediated TGF[3 activation. The 5a-IRDye and 5a-NOTA conjugates could bind purified alpha v[36/alpha v[38 integrins with no loss of affinity compared to free peptide, and selectively recognized various alpha v[36/alpha v[38 single-or double-positive cancer cells, including cells from pancreatic carcinoma, melanoma, oral mucosa, bladder and prostate cancer. In vivo static and dynamic optical near-infrared and PET/CT imaging and biodistribution studies, performed in mice with subcutaneous and orthotopic alpha v[36-positive carcinomas of the pancreas, showed high target-specific uptake of fluorescence-and radio-labeled peptide by tumors and low non-specific uptake in other organs and tissues, except for excretory organs. Significant target-specific uptake of fluorescence-labeled peptide was also observed in mice bearing alpha v[38-positive prostate tumors.Conclusions: The results indicate that 5a can home to alpha v[36-and/or alpha v[38-positive tumors, suggesting that this peptide can be exploited as a ligand for delivering imaging or anticancer agents to alpha v[36/alpha v[38 single-or double-positive tumors, or as a tumor-homing inhibitor of these TGF[3 activators.