Phthalocyanine–Peptide Conjugates for Epidermal Growth Factor Receptor Targeting

• Published in: Journal of medicinal chemistry Vol. 55; no. 8; pp. 3725 - 3738
• Main Authors: Ongarora, Benson G, Fontenot, Krystal R, Hu, Xiaoke, Sehgal, Inder, Satyanarayana-Jois, Seetharama D, Vicente, M. Graça H
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 26.04.2012
• Subjects: Animals; Cercopithecus aethiops; Colorectal Neoplasms - diagnosis; Fluorescent Dyes - metabolism; HT29 Cells; Humans; Indoles - metabolism; Ligands; Mice; Mice, Nude; Models, Molecular; Oligopeptides; Peptides - chemistry; Peptides - metabolism; Receptor, Epidermal Growth Factor - metabolism; Vero Cells
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm201544y

Four phthalocyanine (Pc)–peptide conjugates designed to target the epidermal growth factor receptor (EGFR) were synthesized and evaluated in vitro using four cell lines: human carcinoma A431 and HEp2, human colorectal HT-29, and kidney Vero (negative control) cells. Two peptide ligands for EGFR were investigated: EGFR-L1 and -L2, bearing 6 and 13 amino acid residues, respectively. The peptides and Pc-conjugates were shown to bind to EGFR using both theoretical (Autodock) and experimental (SPR) investigations. The Pc–EGFR-L1 conjugates 5a and 5b efficiently targeted EGFR and were internalized, in part due to their cationic charge, whereas the uncharged Pc–EGFR-L2 conjugates 4b and 6a poorly targeted EGFR maybe due to their low aqueous solubility. All conjugates were nontoxic (IC50 > 100 μM) to HT-29 cells, both in the dark and upon light activation (1 J/cm2). Intravenous (iv) administration of conjugate 5b into nude mice bearing A431 and HT-29 human tumor xenografts resulted in a near-IR fluorescence signal at ca. 700 nm, 24 h after administration. Our studies show that Pc–EGFR-L1 conjugates are promising near-IR fluorescent contrast agents for CRC and potentially other EGFR overexpressing cancers.