Design of a dual-ligand system using a specific ligand and cell penetrating peptide, resulting in a synergistic effect on selectivity and cellular uptake

• Published in: International journal of pharmaceutics Vol. 396; no. 1; pp. 143 - 148
• Main Authors: Takara, Kazuhiro, Hatakeyama, Hiroto, Ohga, Noritaka, Hida, Kyoko, Harashima, Hideyoshi
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 30-08-2010; Elsevier
• Subjects: Active targeting; Animals; Arginine - chemistry; Biological and medical sciences; Biological Transport; CD13 Antigens - metabolism; Cell Membrane Permeability; Cell penetrating peptide; Cells, Cultured; Chemistry, Pharmaceutical; Drug Carriers; Drug Compounding; Dual-ligand; Endothelial Cells - metabolism; General pharmacology; Ligands; Liposomes; Medical sciences; Melanoma - blood supply; Mice; Mice, Nude; Nanotechnology; NGR; Oligopeptides - chemistry; Oligopeptides - metabolism; Particle Size; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polyethylene Glycols - chemistry; Stearates - chemistry; Technology, Pharmaceutical - methods; Tumor endothelial cells; NGR; Active targeting; Cell penetrating peptide; Tumor endothelial cells; Dual-ligand; Endothelial cell; Pharmaceutical technology; Targeting; Ligand; In vitro; Uptake; Design; Target; Tumor cell
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2010.05.002

In this study, a dual-ligand liposomal system comprised of a specific ligand and a cell penetrating peptide (CPP) is described to enhance selectivity and cellular uptake. Dual-ligand PEGylated liposomes were prepared by modifying the end of the PEG with an NGR motif peptide, followed by a surface coating of the liposomes with stearylated oligoarginine (STR-RX). The NGR motif recognizes CD13, a marker protein located on tumor endothelial cells. A suitable number of RX units was determined to be R4, since it can be masked by the PEG aqueous layer. Although no enhanced cellular uptake was observed when a single modification of PEGylated liposomes with either NGR- or STR-R4 was used, the dual-modification with NGR and STR-R4 stimulated uptake of PEGylated liposomes by CD13 positive cells, and this uptake was superior to that obtained by PEG-unmodified liposomes modified with STR-R4. The dual-ligand system shows a synergistic effect on cellular uptake. Collectively, the dual-ligand system promises to be useful in the development efficient and specific drug delivery systems.