Toward Targeted Oral Vaccine Delivery Systems: Selection of Lectin Mimetics from Combinatorial Libraries
Abstract
Purpose 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.
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A tetragalloyl d-lysine amide construct leads to successful delivery of coated PS particles to mouse M cells and may specifically bind via α-l-fucose.
“A tetragalloyl d-lysine amide construct, as the main compound of two UEA1 mimetics, leads to successful delivery of coated PS particles to mouse M cells and might specifically bind via α-l-fucose [117].”
From Use of lectin-functionalized particles for oral immunotherapy (2012) · cites this paper as [117]
Lack of data on specific receptors on human M cells may make development of M-cell-specific targeting strategies more difficult than expected.
“As data on the expression of specific receptors on human M cells is lacking, the development of M-cell-specific targeting strategies, such as the coating of particles with lectins or lectin mimetics [117,119], might be more difficult than expected.”
From Use of lectin-functionalized particles for oral immunotherapy (2012) · cites this paper as [117]
Lectins are often toxic and susceptible to proteolytic degradation in GI tract, rendering some inappropriate for in vivo application.
“lectins are often toxic and susceptible to proteolytic degradation in the GI tract, which renders some of them inappropriate for in vivo application [105,117].”
From Use of lectin-functionalized particles for oral immunotherapy (2012) · cites this paper as [117]
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References 26 · Cited by 39
- Authors
- Lambkin, I., Pinilla, C., Hamashin, C., Spindler, L., Russell, S., Schink, A., Moya-Castro, R., Allicotti, G., Higgins, L., Smith, M., Dee, J., Wilson, C., Houghten, R., & O'Mahony, D.
- Affiliations
- Trinity College Dublin (IE)
- General Atomics (United States) (US)
- Torrey Pines Institute For Molecular Studies (US)
- Corresponding author
- Lambkin, Imelda
- Venue
- Pharmaceutical Research
- Published
- 2003-08
- Volume
- 20
- Issue
- 8
- Pages
- 1258-1266
- ISSN
- 0724-8741 (ISSN-L)
- 1573-904X
- OpenAlex
- W1574479676
- Cited by
- 39
- References
- 26
- Citations by year
- 2024: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2018: 1 · 2017: 1 · 2016: 2 · 2015: 4 · 2014: 1 · 2013: 2 · 2012: 2
- FWCI
- 2.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Pharmaceutical Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Elan
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Carbohydrate Chemistry and Synthesis
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glycosylation and Glycoproteins Research
- Keywords
- oral vaccine delivery, Ulex europaeus agglutinin I, M cells, follicle-associated epithelium, polyphenols, targeted drug delivery, Caco-2 cells, oligosaccharide binding
- MeSH terms
- Administration, Oral, Animals, Cell Membrane, Drug Carriers, Gallic Acid, Humans, Mice, Inbred BALB C, Microscopy, Fluorescence, Polystyrenes, Protein Binding, Structure-Activity Relationship, Vaccines, Molecular Mimicry, Caco-2 Cells, Peptide Library, Streptavidin, Combinatorial Chemistry Techniques, Plant Lectins, Mice
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