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Novel peptide ligand directs liposomes toward EGF-R high-expressing cancer cells in vitro and in vivo

Shuxian Song^*,1, Dan Liu^*,1, Jinliang Peng, Hongwei Deng, Yan Guo^*, Lisa X. Xu^*, Andrew D. Miller^,||,2 and Yuhong Xu^,2

^* School of Life Science and Biotechnology,

Shanghai Centre for Systems Biomedicine, and

School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China;

Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College, London, UK; and

^|| ImuThes Limited, London, UK

² Correspondence: Y.X., School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Rd, Shanghai 200240, P.R. China. E-mail: yhxu{at}sjtu.edu.cn; A.D.M., Imperial College Genetic Therapies Centre, Department of Chemistry, Imperial College London, London SW7 2AZ, UK. E-mail: a.miller{at}imperial.ac.uk

Epidermal growth factor receptor (EGF-R) is an important target in anticancer therapy. Here we report how a novel EGF-R peptide ligand (D4: Leu-Ala-Arg-Leu-Leu-Thr) is identified using a computer-aided design approach from a virtual peptide library of putative EGF-R binding peptides by screening against the EGF-R X-ray crystal structure in silico and in vitro. The selected peptide is conjugated with a polyethylene glycol (PEG) lipid, and the lipid moiety of the peptide-PEG-lipid conjugate is inserted into liposome membranes by a postmodification process. D4 peptide-conjugated liposomes are found to bind to and enter cells by endocytosis specifically and efficiently in vitro in a process apparently mediated by EGF-R high-expressing cancer cells (H1299). In vivo, the D4 peptide-conjugated liposomes are found to accumulate in EGF-R-expressing xenograft tumor tissues up to 80 h after intravenous delivery, in marked contrast to controls. These results demonstrate how structure-based peptide design can be an efficient approach to identify highly novel binding ligands against important receptors. These data could have important consequences for the development of peptide-directed drug delivery systems with engineered specificities and prolonged times of action.—Song, S., Liu, D., Peng, J., Deng, H., Guo, Y., Xu, L. X., Miller, A. D., Xu, Y. Novel peptide ligand directs liposomes toward EGF-R high-expressing cancer cells in vitro and in vivo.

Key Words: AutoDock • epidermal growth factor • computer aided design • proteomic code • PEG • lipid