A fragment of the HMGN2 protein homes to the nuclei of tumor cells and tumor endothelial cells in vivo.

We used a screening procedure to identify protein domains from phage-displayed cDNA libraries that bind both to bone marrow endothelial progenitor cells and tumor vasculature. Screening phage for binding of progenitor cell-enriched bone marrow cells in vitro, and for homing to HL-60 human leukemia cell xenograft tumors in vivo, yielded a cDNA fragment that encodes an N-terminal fragment of human high mobility group protein 2 (HMGN2, formerly HMG-17). Upon i.v. injection, phage displaying this HMGN2 fragment homed to HL-60 and MDA-MB-435 tumors. Testing of subfragments localized the full binding activity to a 31-aa peptide (F3) in the HMGN2 sequence. Fluorescein-labeled F3 peptide bound to and was internalized by HL-60 cells and human MDA-MB-435 breast cancer cells, appearing initially in the cytoplasm and then in the nuclei of these cells. Fluorescent F3 accumulated in HL-60 and MDA-MB-435 tumors after an i.v. injection, appearing in the nuclei of tumor endothelial cells and tumor cells. Thus, F3 can carry a payload (phage, fluorescein) to a tumor and into the cell nuclei in the tumor. This peptide may be suitable for targeting cytotoxic drugs and gene therapy vectors into tumors.