Polymeric Nanoparticles for

Oral Delivery
 Introducing

⚫ The oral route is still the most preferred route

because of its basic functionality and the advantages.
⚫ Nanoparticles (NPs) also have been extensively
studied for peroral drug delivery, for systemic effect
following uptake from the enteron, or to act locally in
the gastrointestinal tract (GIT).
⚫ NPs are expected to address some specific issues for
drug delivery like low mucosal permeability,
absorpsion windows, low solubility of the drug and
gut metabolism and first pass effect.
⚫ The potential advantages of NPs as oral drug
carriers are
1. Enhancement of bioavailability,
2. Delivery of vaccine antigents to the
gut-associated lymphoid tissues (GALT),
3. Controlled release,
4. Reduction of the gastrointestinal irritation
caused by drugs.
⚫ The utility of NPs for oral drug delivery arises out
of the particulate uptake mechanism that exist in
the GIT, especially the transport through M cells of
Peyer’s patches (PP).
⚫ From the surface of M cells, NPs are taken up and
transported to lymphocytes in the form of vesicles.
⚫ The lymphatic absorption of a drug via the GALT
prevents presystemic metabolism in the liver
because it bypasses the portal blood circulation.
⚫ After oral administration, colloidal drug carriers
have the ability to increase bioavailability by
protecting the drug from denaturation in the
gastrointestinal lumen or by prolonging the exposure
of the mucous membrane to elevated drug
concentration.
 Gastrointestinal Tract (GIT)

⚫ GIT provides a variety of physiological and

morphological barriers, such as proteolitic enzymes,
in the gut lumen and at the brush border membrane:
the mucous layer, the bacterial gut flora, and the
epithelial cell lining itself.
⚫ The mucus, built up from mucin molecules, covering
the absorptive enterocytes in the intestines, acts as a
barrier for oral absorption of foreign matter,
including NPs.
⚫ The mucus is a translucent viscoelastic hydrogel and
is mainly composed of glycoproteins that have both
acidic and basic chemical groups.
⚫ The chemical composition of mucus provides an
opportunity for both acidic and basic compounds to
interact with it, thereby increasing the residence
time of both drugs and NPs in close proximity to the
absorptive surfaces.
⚫ The immunological load ingested makes the mucosa
an ideal site for the identification and resistance of
antigenic challenges.
⚫ The local immune system is composed of GALT,
composed of lymphoid tissues, called PPs in the
small intestine, which are characterized by a
monolayer of specialized epithelium containing M
cells and absorptive enterocytes, i.e., follicle
associated epithelium (FAE).
⚫ FAE is adapted for endocytosis/transcytosis of
antigens and microorganism to the organized
lymphoid tissue within the mucosa and M cell
basement membrane.
⚫ M cells deliver the particles taken up to the
lymphatics then released into the bloodstream.
⚫ NPs have to cross the gastrointestinal barrier either
by passive diffusion via transcellular or paracellular
pathways or by active process mediated by
membrane-bound carriers or membrane-derived
vesicles.
⚫ Another possible mechanism for the transport of NP
across intestinal cells is paracellular uptake via
aqueous channels.
⚫ In human, the equivalent pore diameter has been
estimated to be between 4 and 8 Å.
⚫ The mucosal epithelium in the small intestine consist
of polarized cells, connected by tight intercellular
junctions, which account for < 1% of the surface area
of the intestine.
⚫ The uptake of particulate matter from between the
absorptive cells is inversely proportional to the
structural integrity of the tight junction barrier.
⚫ The epithelial transport of larger molecules or
particles can be increased by reversibly increasing
the permeability of the tissue by opening the tight
junctions under the influence of some mucoadhesive
polymers and penetration enhancers.
⚫ M cells (or microfold cells) are cells found in the
follicle-associated epithelium of the Peyer's patch as
well as in BALT (Bronchus-associated lymphoid
tissue).
⚫ They transport organisms and particles from the gut
lumen to immune cells across the epithelial barrier,
and thus are important in stimulating mucosal
immunity.
⚫ Unlike their neighbouring cells, they have the unique
ability to take up antigenUnlike their neighbouring
cells, they have the unique ability to take
up antigen from the lumenUnlike their neighbouring
cells, they have the unique ability to take
up antigen from the lumen of the small intestine via
endocytosis or phagocytosis or phagocytosis, and
then deliver it via transcytosis or phagocytosis, and
then deliver it via transcytosis to dendritic
cells or phagocytosis, and then deliver it
via transcytosis to dendritic cells (an antigen
presenting cell or phagocytosis, and then deliver it
via transcytosis to dendritic cells (an antigen
⚫ M cells differ from normal enterocytesM cells differ
from normal enterocytes in that they
lack microvilli on their apical surface, but instead
possess broader microfolds that give the cell its
name.
⚫ These cells are far less abundant than enterocytes.
⚫ M cells do not secrete mucus or digestive enzymes,
and have a thinner glycocalyx, which allows them to
have easy access to the intestinal lumen for
endocytosis of antigens.
⚫ M cells main function is the selective endocytosis of
antigens, and transporting them to intraepithelial
macrophages and lymphocytes, which then migrate
to lymph nodes (contains lymphoid tissue) where an
immune response can be initiated.
⚫ Macromolecules may be trapped between the
particle aggregates and their release is controlled by
a combination of diffusion (larger particles packed
together have larger spaces in the lattice, and this
allows for faster diffusion) and erosion (arising from
aggregates).
⚫ Nanoparticles that erode from the aggregate are
drained into the lymphatic system and may be
retained by the regional nodes.
⚫ Polymeric nanospheres can also target endothelial
cells on the blood-brain barrier.
⚫ For instance, following intravenous injection,
nanospheres attract apolipoprotein E from the blood,
thus mimicking low density lipoprotein (LDL) and
become recognizable by LDL receptors expressed by
the blood-brain barrier endothelial cells.
⚫ Polymeric nanoparticles also have numerous
applications following oral delivery.
⚫ Evidence suggests that the adsorption of particulates
in the intestine following oral administration take
place at the Peyer’s patches.
⚫ The epithelial cell layer overlying the Peyer’s patches
contains specialized M cells.
⚫ These cells can sample particles from the lumen and
transport them to the underlying macrophages and
dendritic cells.
⚫ Indeed, numerous studies have confirmed protective
immunity induced by mucosal immunization with
PLGA (poly(lactic- co -glycolic acid) ) and chitosan
based particulate systems.
⚫ Part of the success is due to the encapsulation of antigens
in polymeric particulate systems, which provides better
protection for the antigen during intestinal transit.
⚫ The immune outcomes have included mucosal (secretory
IgA) and serum antibody (IgG and IgM) responses, as
well as systemic cytotoxic T lymphocyte responses.
⚫ Similarly, improved drug bioavailability has also
been reported following ocular administration with
poly-(butylcyanoacrylate) and Eudragit
nanoparticles.
⚫ Depending on the polymer characteristics,
polymeric nanocarriers can also be engineered in
such a way that they can be activated by changes in
the environmental pH, chemical stimuli, or
temperature.
⚫ Such modifications offer control over particle
integrity, drug delivery rates, and the location of
drug release.
⚫ For instance, nanoparticles made from
poly(lactide-coglycolide), PLGA, can escape the
endo-lysosomal compartment within minutes of
internalization in intact cells and reach the cytosol.
Picture 2