Nanoparticles for the Oral Administration of Cancer Therapies - Intracellular Delivery: Fundamentals and Applications - page 496

the mucus and increase the permeability of the drug across the intestinal barrier
(Roger et al. 2010a ). In some cases, nanodevices themselves can cross the epithelial
membrane and translocate the drug cargo from the lumen to the blood or lymph
(Fig. 1b ). However, in general, nanoparticles are not absorbed, but at least can pro-
long the time of contact with the mucosa or epithelia and, therefore, increase the
drug concentration gradient from the lumen to the epithelia (Fig. 1b -14). The fate of
nanoparticles in the mucosa and in subcellular domains is dependent on their size
and their surface properties. Very small particles (up to 200 nm) seem to be endo-
cytosable by enterocytes (Fig. 1b -11). Particles between 200 nm and 3 mm are
preferentially uptaked by phagocytic M-cells in the Peyer patches, although they
have not been detected further than mesenteric lymph nodes (Fig. 1b -9). Particles
higher than 3 mm have been found in follicle-associated epithelia but they did not
show passage to associated lymphoid tissues (Des Rieux et al. 2006 ). The uptake
of nanoparticles by M-cells produces higher accumulation of the drug in the local
lymph nodes from it can be directly transported to the systemic circulation without
first passing through the liver. This route of delivery can enhance the activity of
immunomodulatory drugs or vaccines or drugs aimed to target the lymphoid tissue
(Hussain et al. 2001 ). However, for drugs that need to reach the blood circulation,
their transport across absorptive epithelial cells produce a higher improvement in
their oral bioavailability.
The uptake of the particles by enterocytes could be by clathrine or caveolae-
mediated or independent endocytosis (Fig. 1b -10 and 11). Particles captured by
clathrine-mediated endocytosis are localized in the endolysosomes where they are
degraded by enzymes although some of them can escape from endolysosome vesicles
and to be released by exocytosis outside enterocytes via the basolateral cell side. Also
caveolae-mediated endocytosis could lead to direct exocytosis of the carrier on the
basolateral side of enterocytes. If nanoparticles are exocyted by the enterocytes, the
impermeability of the vascular endothelium combined with the large inter-endothelial
gaps present in the lymphatic endothelium would facilitate the entry of these carriers
in the lymphatic system rather than the blood capillaries (Cai et al. 2010 ).
Thus, either through enterocytes or M-cells, nanoparticles that cross the epithe-
lium and remained intact would reach the bloodstream through the lymphatic system
(Fig. 1b -13). To the best of our knowledge, it has not been detected intact nano-
particles in the bloodstream after oral delivery although an increase in the drug
bioavailability has been frequently observed.

3.3.1 Lipophilic Devices

The presence of lipids in the diet, as well as the use of lipophilic formulations, can
influence and modulate drug absorption, especially water-insoluble compounds
(Porter et al. 2007 ). Lipid-based formulations can increment the dissolution rate of
the drug by a modification of the interfacial tension between the drug and the dis-
solution medium. The particles of hydrophobic drugs offer high surface resistance
which prevents its solubilization. In contrast, formulations containing lipids as drug