Oral Delivery of Proteins and Peptides: Concepts and Applications - Challenges in Delivery of Therapeutic Genomics and Proteomics - page 493

10.6.1.2 Payer's Patch Targeting
The gut-associated lymphoid tissue (i.e., Peyer's patches) has been considered the
primary site of particle uptake due to the presence of follicle-associated epithelium.
Transcytosis of particles is facilitated by the M (microfold or membranous) cells pres-
ent in this epithelium. Although there is some controversy in the literature on the extent
of particle uptake by Peyer's patches, there is evidence that particle translocation can
occur in them. However, the complete mechanism of uptake and endocytic transport
by M cells is unclear, although it is generally accepted that the entry of micro- and
nanoparticles into M cells occurs via this type of transport. Various physicochemical
parameters, such as particle size, zeta potential, hydrophobicity, and coating with adhe-
sion factors of particulate systems, determines the extent of their absorption by M cells
[125] . It has been proposed that M cells function to sample and transport luminal par-
ticles, macromolecules, and antigens into lymphoid follicles for immunologic surveil-
lance and initiation of appropriate immunologic responses. Because of this, M cells
are considered the target sites of oral protein absorption. In order to gain efficiency in
the delivery of peptides and proteins to the Peyer's patch by particulate carriers, their
uptake by the Peyer's patch must be enhanced [65] . For this purpose, there is a require-
ment to identify M cell-specific surface antigens and receptors that may permit the
production of specific antibodies and ligands for M cell selective targeting. Another
option is to develop particles having optimal surface properties for effective delivery to
M cells [125] .
10.6.2 Chemical Alteration in the Structure
Chemical modification of peptides, to fabricate their prodrugs and analogs, is a use-
ful tool for increasing the lipophilicity of peptides and thus increasing the passage of
peptides through biological membranes. But this type of modification is only useful
for small peptides with less than 10 amino acid residues [126] . These types of modi-
fications increase not only the lipophilicity but also the resistance power of peptides
against proteolytic enzymes present at various sites of the GI tract. A prior condition
for these types of modifications is that peptides retain their pharmacological actions,
and such modifications are performed only after confirming the pharmacological
activity of the modified peptide [127] .
10.6.2.1 N-Terminal Acylation
The N-terminal of peptides is conjugated with lipophilic molecules by acylation or
alkylation, to increase the lipophilic nature of the peptides [53,60,127] . Primarily,
fatty acids are conjugated to peptides to increase their lipophilicity and their trans-
port across the membrane. Lysozyme [128] , insulin [129,130] , thyroxin-releasing
hormone [131-134] , calcitonin [135] , tetragastrin [136-139] , and some enkephalin
analogs [140] have been studied for acyl modification and have showed encouraging
results in terms of improved absorption of these peptides and retention of pharmaco-
logical activities. Bovine-insulin when acylated with fatty acids having an increasing