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 gutassociated 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
Peyers 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 .

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 antigen from the lumen of the

small intestine via endocytosis or phagocytosis, and
then deliver it via transcytosis to dendritic
cells (an antigen presenting cell)
and lymphocytes (namely T cells) located in a unique
pocket-like structure on their basolateral side

M 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 Peyers patches.
The epithelial cell layer overlying the Peyers 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