Toward targeted oral vaccine delivery systems: Selection of lectin mimetics from combinatorial libraries

• Published in: Pharmaceutical research 2003-08, Vol.20 (8), p.1258-1266
• Main Authors: LAMBKIN, Imelda, PINILLA, Clemencia, DEE, Jackie, WILSON, Carolyn, HOUGHTEN, Richard, O'MAHONY, Daniel, HAMASHIN, Christa, SPINDLER, Lisa, RUSSELL, Shannon, SCHINK, Amy, MOYA-CASTRO, Rosa, ALLICOTTI, Gina, HIGGINS, Lisa, SMITH, Melanie
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Biological and medical sciences; Caco-2 Cells; Cell Membrane - metabolism; Combinatorial Chemistry Techniques; Competition; Drug Carriers; Gallic Acid - analogs & derivatives; Gallic Acid - chemical synthesis; Gallic Acid - chemistry; General pharmacology; Humans; Immunomodulators; Lectins; Libraries; Medical sciences; Membranes; Mice; Mice, Inbred BALB C; Microscopy, Fluorescence; Molecular Mimicry; Peptide Library; Peptides; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Plant Lectins - chemical synthesis; Plant Lectins - chemistry; Plant Lectins - metabolism; Polystyrenes - chemistry; Protein Binding; Streptavidin - administration & dosage; Structure-Activity Relationship; Vaccines; Vaccines - administration & dosage; Vaccines - chemistry; Vaccines - pharmacokinetics
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1023/A:1025061317400

Various lectins bind specifically to oligosaccharides on intestinal cells. Exploiting this specificity, Ulex europaeus agglutinin I (UEA1) has been used as a ligand for targeted oral vaccine delivery to M cells (antigen-presenting cells) in follicle-associated epithelium. In this study we characterized compounds identified from mixture-based positional scanning synthetic combinatorial libraries, which mimic UEA1 and, thus, may have properties applicable to targeted drug delivery. Two UEA1 mimetics were synthesized and their activity was verified on live cells. The ability of the lead compound, a tetragalloyl D-Lysine amide construct (4-copy gallic acid construct), to deliver dye-loaded polystyrene particles to M cells was assessed in an in situ mouse gut loop model. The 4-copy gallic acid construct inhibited UEA1 binding to Caco-2 cell membranes with an IC50 of 3 microM, a 650- to 5000-fold increase over the natural UEA1 substrate alpha-L-fucose. The biotin-labeled derivative of this construct demonstrated comparable binding activity as verified on live cells by fluorescence-activated cell sorting. Preclinical studies confirmed its ability to mediate M cell-specific delivery of streptavidin-coated particles in vivo. Polyphenolic compounds, D-Lysine scaffolds with multiple galloyl groups, can mimic functional activities of UEA1. Properties of such molecules, including low molecular weight, stability, ease of synthesis and low cost, highlight their potential for application in targeted vaccine delivery.