Biomedical Engineering Reference
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and viral vectors expressing TAA that naturally infect oral mucosa like Salmonella.
These microorganisms have been described capable to overcome the default status
of the intestinal immune system and promote the production of IL-12 by DCs in
Peyer's patches and MLNs (Mowat
2003
).
In general, a successful vaccination requires two components: an antigen and an
adjuvant. When designing oral anticancer vaccines, the adjuvant, an amplifier of the
response induced by the antigen itself, should be extremely potent in order to
surpass both the oral tolerance and the tumor suppressive environment.
Synthetic particles have been widely investigated, on the one hand, as adjuvants
for mucosal vaccination (Chadwick et al.
2010
; Des Rieux et al.
2006
) with appli-
cations other than cancer therapy and, on the other hand, as adjuvants for parenteral
cancer vaccination (Xiang et al.
2008
; Krishnamachari et al.
2010
). Orally adminis-
tered, the carriers offer a number of advantages that well justify their application as
adjuvant for oral vaccination. They protect the antigen (Ag) cargo from degradation.
Moreover, as previously described these carriers preferentially target the M-cells in
the follicle-associated epithelium, where are transferred to local DCs. These DCs
present the Ag directly to T-cells in the Peyer's patch or migrate to mesenteric
lymph nodes and could augment or not the mucosal and systemic immune response
(Primard et al.
2010
; Slutter et al.
2009
).
In spite of preferential targeting of particles by M-cells the studies show that, in
general, a very low fraction of administered particles bind to the gastrointestinal
tract. Particles in the range of 500-nm or/and hydrophobic were better uptaken than
the larger or more hydrophilic ones (Brayden
2001
). In order to improve the adhe-
sion of the particles to M-cells, a common strategy has been the coating of the
particulate Ag with lectins that selectively bind M-cell specific surface carbohy-
drates (Jepson et al.
2004
). Other interesting approach has been the covering of the
particles with compounds involved in the process of micro-organisms colonization
like flagellin, trying to mimic the bacteria Salmonella (Irache et al.
2010
). However,
glycocalix of mucus barrier act as a size selective barrier that limits the accessibility
to the targeted particles towards cell surface receptor.
Beside strategies to improve the deposit of particles in the immune inductive
(Peyer's patch) sites of the gastrointestinal tract, nanoparticles based vaccines
should be interpreted by the immune system as an invasive pathogen in order to
generate immune response. Although it has been described that particles activate
NALP3 inflammosome, only the TLR triggering can produce local inflammation
that induce complete maturation of DCs in the Peyer's patch. As a result, these
activated DCs after taking up antigen (signal 1), produce IL-12 (signal 3) and present
antigenic fragment to T-cells with appropriate co-stimulation (signal 2). These DCs
prime Th-cells results into their activation and differentiation. Keeping this idea in
mind, CpG motifs and mutant of two bacterial toxins, heat labile enterotoxin (LT)
and cholera toxin (CT), have been combined with particles and evaluated as oral
vaccines against some microorganisms (Chen et al.
2010
).
Once effector specific T-cells are generated they must migrate, recognize and
destroy tumoral cells. Particles targeting DCs from Peyer's patches tend to induce
gut-homing properties in T-cells. Moreover, tumors have developed immunosup-
pressive mechanisms as down-regulation of MHC molecules or production of
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