It is generally accepted that macromolecules, particularly food proteins, do cross the mature small intestinal epithelium in small amounts and reach the systemic circulation. The potential as delivery route for orally administered macromolecular drugs including proteins is being widely explored51. There have been several studies on the mechanism and substrate structure-affinity relationship for this transport system. Rapid progress has been made recently in studies on the molecular basis of the intestinal peptide transport system. A protein apparently involved in peptide transport has been isolated from rabbit small intestine, and genes for human intestinal peptide transporters have been cloned, sequenced and functionally expressed52. The cellular uptake of small peptides such as di-, tri- and tetrapeptides and peptidomimetic drugs proceeds via specialized proton-coupled transporters53. The proton-dependent uptake at the apical cell membrane of the enterocytes results in subsequent exit of intact di- or tri-peptides across the basolateral membrane or, alternatively, intracellular hydrolysis and exit of component amino acids across the basolateral membrane54. The peptide carrier has a broad substrate specificity.
Lectins are resistant to digestion and binding to brush-border membranes, hence appreciable amounts of lectins and/or toxins of the general structure of A (toxin)-B (lectin), either free or included in liposomes, may be taken up by and transported through the epithelial cells of the small intestine. As a result tomato lectins have been explored as potential drug delivery agents55.
Various strategies have been used to target vaccine antigens to the gut-associated lymphoid tissues, such as microspheres prepared from various polymers. Certainly in mice the size of the microspheres has to be less than 5 pm for them to be transported within macrophages through the efferent lymphatics56. Transcytosis through Peyer's patches is most suited for highly potent compounds since there are a limited number of Peyer's patches, hence the overall surface area is relatively small. Patch tissue is rich in lymphocytes, thus substances which interact with lymphocytes are best targeted to Peyer's patches when using the oral route57.
It is known that a number of microorganisms are able to bind selectively to a receptor on the M-cell surface and thereby enter the host. Utilizing the microorganism's ligand could be beneficial for specific targeting to Peyer's patches, bypassing lysosomal degradation in absorptive cells. Moreover, transport of membrane-bound macromolecules by M cells is about 50 times more efficient than that of soluble, non-adherent macromolecules. The colonization of the small intestine by Escherichia coli strains is mediated by cell surface antigens called fimbriae which enable bacteria to adhere to the brush border of epithelial cells. Due to the very close contact between the epithelial cells and the bacteria an enhanced absorption of substances including peptides and proteins can occur. To use bacterial adhesion for the design of drug delivery and drug targeting systems the fimbrial anti-genicity has to be reduced. One approach was to truncate the NH2-terminal on K99-fimbrial proteins by recombinant DNA-technology58.
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