Scodeller et al. performed in vivo phage display on cells from tumor-bearing mice and identified a peptide (UNO) that homes to M2-like tumor-associated macrophages (MEMs) in tumors and sentinel lymph nodes, interacts with CD206, and gets internalized. Binding to MEMs required linearization of the cyclic peptide, which is facilitated by the TME. Coating nanoparticles with UNO allows for specific drug delivery to MEMs in solid tumors; UNO could also be used to guide contrast agents to the sentinel lymph node for live-imaging or diagnostic testing.
Tumor-associated macrophages (TAMs) expressing the multi-ligand endocytic receptor mannose receptor (CD206/MRC1) contribute to tumor immunosuppression, angiogenesis, metastasis, and relapse. Here, we describe a peptide that selectively targets MRC1-expressing TAMs (MEMs). We performed in vivo peptide phage display screens in mice bearing 4T1 metastatic breast tumors to identify peptides that target peritoneal macrophages. Deep sequencing of the peptide-encoding inserts in the selected phage pool revealed enrichment of the peptide CSPGAKVRC (codenamed "UNO"). Intravenously injected FAM-labeled UNO (FAM-UNO) homed to tumor and sentinel lymph node MEMs in different cancer models: 4T1 and MCF-7 breast carcinoma, B16F10 melanoma, WT-GBM glioma and MKN45-P gastric carcinoma. Fluorescence anisotropy assay showed that FAM-UNO interacts with recombinant CD206 when subjected to reducing conditions. Interestingly, the GSPGAK motif is present in all CD206-binding collagens. FAM-UNO was able to transport drug-loaded nanoparticles into MEMs, whereas particles without the peptide were not taken up by MEMs. In ex vivo organ imaging, FAM-UNO showed significantly higher accumulation in sentinel lymph nodes than a control peptide. This study suggests applications for UNO peptide in diagnostic imaging and therapeutic targeting of MEMs in solid tumors.
Author Info: (1) Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, Tartu, 50411, Estonia. pablo.david.scodeller@ut.ee. Cancer R
Author Info: (1) Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, Tartu, 50411, Estonia. pablo.david.scodeller@ut.ee. Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N, Torrey Pines Road, La Jolla, 92097, California, USA. pablo.david.scodeller@ut.ee. (2) Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, Tartu, 50411, Estonia. (3) Institute of Chemistry, University of Tartu, Ravila 14, Tartu, 50411, Estonia. (4) Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, Tartu, 50411, Estonia. (5) Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, Tartu, 50411, Estonia. (6) Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, Tartu, 50411, Estonia. (7) Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, Tartu, 50411, Estonia. (8) School of Life Sciences, Ecole Polytechnique Federale de Lausanne (EPFL), Swiss Federal Institute of Technology, Lausanne, CH-1015, Lausanne, Switzerland. (9) Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N, Torrey Pines Road, La Jolla, 92097, California, USA. (10) Institute of Chemistry, University of Tartu, Ravila 14, Tartu, 50411, Estonia. (11) School of Life Sciences, Ecole Polytechnique Federale de Lausanne (EPFL), Swiss Federal Institute of Technology, Lausanne, CH-1015, Lausanne, Switzerland. (12) Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N, Torrey Pines Road, La Jolla, 92097, California, USA. Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara Santa Barbara, 93106, California, USA. (13) Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, Ravila 14B, Tartu, 50411, Estonia. tambet.teesalu@ut.ee. Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 N, Torrey Pines Road, La Jolla, 92097, California, USA. tambet.teesalu@ut.ee. Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara Santa Barbara, 93106, California, USA. tambet.teesalu@ut.ee.
