Toward targeted oral vaccine delivery systems: selection of lectin mimetics from combinatorial libraries.
OBJECTIVE
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 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.


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.
Lambkin
Imelda
I
Elan Drug Delivery, Biotechnology Building, Trinity College, Dublin 2, Ireland. ilambkin@eircom.net
Pinilla
Clemencia
C
Hamashin
Christa
C
Spindler
Lisa
L
Russell
Shannon
S
Schink
Amy
A
Moya-Castro
Rosa
R
Allicotti
Gina
G
Higgins
Lisa
L
Smith
Melanie
M
Dee
Jackie
J
Wilson
Carolyn
C
Houghten
Richard
R
O'Mahony
Daniel
D
D000284:Administration, Oral; D000818:Animals; D018938:Caco-2 Cells; D002462:Cell Membrane / Q000378:metabolism; D020650:Combinatorial Chemistry Techniques; D004337:Drug Carriers; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D018716:Molecular Mimicry; D019151:Peptide Library; D037121:Plant Lectins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011137:Polystyrenes / Q000737:chemistry; D011485:Protein Binding; D019809:Streptavidin / Q000008:administration & dosage; D013329:Structure-Activity Relationship; D014612:Vaccines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics
D004337:Drug Carriers; D019151:Peptide Library; D037121:Plant Lectins; D011137:Polystyrenes; C036850:Ulex europaeus lectins; D014612:Vaccines; D005707:Gallic Acid; D019809:Streptavidin