Imelda Lambkin

Toward Targeted Oral Vaccine Delivery Systems: Selection of Lectin Mimetics from Combinatorial Libraries

AbstractPurpose. 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. Methods. 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. Results. The 4-copy gallic acid construct inhibited UEA1 binding to Caco-2 cell membranes with an IC50 of 3 μM, a 650- to 5000-fold increase over the natural UEA1 substrate α-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. Conclusions. 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.

Targeting approaches to oral drug delivery

Delivery of pharmaceuticals, particularly biotechnology products such as proteins, peptides, genes, oligonucleotides and vaccines, via the oral route remains problematic to this day. Instability in the gastrointestinal environment and poor permeability across the intestinal epithelial cell barrier contribute to poor oral bioavailability for many of these compounds. Current targeting strategies to overcome these issues are focused on three-part systems in which the drug (i) is loaded into a protective particulate carrier (ii) which is coated with target-specific ligands (iii) which mediate site-specific delivery of the drug-carrier complex. Protection from gastrointestinal degradative processes combined with site-specific delivery to absorptive regions of the intestinal tract is purported to yield high local concentrations of the drug of choice in close proximity with the epithelial cell layer and hence, transport across that barrier through a variety of mechanisms. This review examines the impact of cutting-edge technologies such as genomics and combinatorial chemistry on targeted oral drug delivery strategies. The explosion in rate of identification of new targets using genomics, together with high-throughput screening for target-specific ligands using combinatorial chemistry and phage display, has the potential to revolutionise this field. Particular reference is made to advances associated with targeted delivery of vaccines to M-cells or antigen-presenting cells in gut-associated lymphoid tissues.