1. Pharmacokinetics of Nanoparticle
(Nanokinetics)
•
•
•
•
•
•
•
•
•
Chemical composition
Structural diversity
Surface modifications
Particle size
Relevant routes of exposure
Transport across barrier (Placenta, skin, GI, BBB)
Tissue selectivity
Metabolism
Excretion

3. Hurdles
• Interaction of NP with plasma proteins,
coagulation factors, platelets, red and white
blood cells.
• Cellular uptake by diffusion, channels or
adhesive interactions and transmembrane active
processes.
• Binding to plasma components relevant for
distribution and excretion of NP.

4. Factors affecting
pharmacokinetics

5. Chemical composition
Nanoscale materials may possess unexpected
physical, chemical, optical, electrical and
mechanical properties, different from their
macrosized counterparts.
E.g. silver nanoparticles are antibacterial/antifungal agents in biotechnology
and bioengineering, textile engineering, water treatment, and silver-based
consumer products.
There is also an effort to incorporate silver nanoparticles into a wide range of
medical devices, including but not limited to
bone cement,
surgical instruments,
surgical masks,
wound dressings.
Samsung has created and marketed a material called Silver Nano, that
includes silver nanoparticles on the surfaces of household appliances

6. Structural diversity
Organic nanoparticles
liposomes
dendrimers
carbon nanotubes
Inorganic nanoparticles
quantum dots
magnetic NPs
gold NPs

7. Surface modifications
PEGylated NP in “Brush ”
configuration attract less
Opsonins from plasma
Monuclear phagocyte system (MPS) is the major contributor for the clearance of
nanoparticles. Reducing the rate of MPS uptake by minimizing the opsonization
is the best strategy for prolonging the circulation of nanoparticles..

8. • opsonization
• NP is marked for ingestion and
destruction by phagocytes.
Opsonization involves the binding of
an opsonin. After opsonin binds to the
membrane, phagocytes are attracted.

10. poloxamine
PEG

11. PLGA versus PEG-PLGA
Liu et al.

12. Surface modification
Approaches for improving the phamacokinetics of
NP include maintaining the size around 100 nm,
keeping the Zeta potential within 10 mV, and
grafting PEG onto the surface
PEGylated NP in “Brush ” configuration attract less
Opsonins from plasma

13. Particle size
Arruebo M. et al. Nanotoday 2, 2007
NPs endowed with specific characteristics: size, way of conjugating the drug
(attached, adsorbed, encapsulated), surface chemistry, hydrophilicity/hydrophobicity,
surface functionalization, biodegradability, and physical response properties
(temperature, pH, electric charge, light, sound, magnetism).

14. Renal
elimination
100
<5.5
Elimination by RES
(Reticuloendothelial system)
Spleen opsonization
cut-off
200-250
Optimal NP size
nm

15. Particle

16. Routes of exposure
•
•
•
•
•
Inhalation
Absorption via the olfactory nervous system
Oral administration
Dermal absorption
Systemic administration

18. Inhalation exposure
• Distribution of inhalated NP was observed in
animal models, but not confirmed in human.

19. Inhalation exposure
• Particle deposition depends on particle size,
breathing force and the structure of the lungs.
• Brownian diffusion is also involved resulting in
the deep penetration of NP in the lungs and
diffusion in the alveolar region.
• NP >100 nm may be localized in the upper
airways before the transportation in the deep
lung.

20. Inhalation exposure

21. Absorption via the olfactory nervous system
• This is an alternative port of entry of NP via
olfactory nerve into the brain which circunventes
the BBB.
• Neuronal absorption depends on chemical
composition, size and charge of NP.

23. Absorption via the olfactory nervous
system
Surface enginnering of nanoparticles with lectins opened a
novel pathway to improve the brain uptake of agents
loaded by biodegradable PEG-PLA nanoparticles following
intranasal administration. Ulex europeus agglutinin I (UEA
I), specifically binding to L-fucose, which is largely located
in the olfactory epithelium was selected as ligand and
conjugated onto PEG-PLA nanoparticles surface.

24. Absorption via the olfactory nervous system
BLOOD
OLFACTORY BULB
CEREBRUM
OLFACTORY TRACT
CEREBELLUM

25. Oral absorption
• Gastrointestinal tract represents an important port of
entry of NP. The size and shape and the charge of NP
are critical for the passage into lymphatic and blood
circulation.
• 50 nm – 20 µm NP are generally absorbed through
Peyer’s patches of the small intestine
• NP must be stable to acidic pH and resistant to protease
action. Polymeric NP (e.g. PLGA ,polylactic-co-glycolic,
and SLN
• Small NP < 100 nm are more efficiently absorbed
• Positively charged NP are more effectively absorbed
than neutral or negatively charged ones.

27. Oral route
•
Nano-Systems
Nature’s intended mode of

uptake of foreign material
•
preferred
intestine
most convenient
•
route

No
pain
(compared
Protection of
encapsulated
drug
of
administration
•
Direct uptake through the

to
Slow and controlled release

Can aid delivery of drugs
injections)
•
•
with
Sterility not required
pharmacological
Fewer regulatory issues
various
and
physicochemical properties
27

28. Lymphatic uptake of nanoparticles
Liver
NP
(II)
(l)
PPs
(lll)
Intestinal lumen
Blood vessel
Systemic circulation
Mechanism of uptake of orally administered nanoparticles. NP: Nanoparticles
PPs: Peyers patches, (l) M-cells of the Peyer’s patches, (ll) Enterocytes, (lll)
Gut associated lymphoid tissue (GALT)
28
Bhardwaj et, al. Pharmaceutical Aspects of Polymeric Nanoparticles for Oral Delivery, Journal of Biomedical Nanotechnology (2005), 1, 1-23

29. Homogenize
15000 rpm, 5 min
Water
Anionic
nanoparticles
1000rpm, 40 oC
-
SUR -1
or
SUR -2
or
SUR -3
in water
PLGA
+
Ethyl acetate
SUR-3 (80:20)
Cationic
nanoparticles
1000 rpm
3h
Primary
emulsion
Water
1000rpm, 40 oC
Homogenize
15000 rpm, 5 min
29

30. Distribution following oral absorption

31. Distribution following oral exposure
•Solid lipid nanoparticles (SLN).
•Wheat germ agglutinin-N-glutarylphosphatylethanolamine (WGAmodified SLN).
•WGA binds selectively to
intestinal cells lines.

32. Dermal absorption
• Dermal absorption is an important route for
vaccines and drug delivery.
• Size, shape, charge and material are critical
determinants for skin penetration.
• Negatively charged and small NP (<100nm)
cross more actively the epidermis than neutral or
positively charged ones.

37. Dermal absorption

38. Distribution following intravenous exposure
• NP kinetics depends on size charge and
functional coating.
• Delivery to RES tissues: liver, spleen, lungs and
bone marrow.

39. F
n
c
s
e
r
o
u
l
y
i
s
e
t
n
I
Distribution following intravenous exposure
Free Cholesteryl Bodipy
3,5
3
2,5
2
1,5
1
0,5
0
urine
blood
Cholesteryl Bodipy-liposomes
0
2
4
6
8
10
12
3,5
3
Time-course of biodistribution of
Cholesteryl Bodipy injected i.v. in
healthy rats (157 µg/rat).
Fluorescence Intensity
2,5
urine
2
blood
1,5
1
spleen
0,5
0
0
2
4
6
8
10
12
Roveda et al., 1996

42. Metabolism
Inert NP are not metabolized (gold and silver,
fullerenes, carbon nanotubes).
Functionalized or “biocompatible” NP can be
metabolized effectively by enzymes in the body,
especially present in liver and kidney.
The intracellularly released drug is metabolized
according to the usual pathways.

43. Excretion
Data are not available regarding the accumulation
of NP in vivo.
The elimination route of absorbed NP remained
largely unknown and it is possible that not all
particles will be eliminated from the body.
Accumulation can take place at several sites in
the body. At low concentrations or single
exposure the accumulation may not be
significant, however high or long-term exposure
may play a relevant role in the therapeutical
effects of the active ingredient.

44. Excretion

47. Devalapally H., J.Pharm.Sci. 96:2547-2565, 2007

48. Defining dose for NP in vitro
• Particles are assumed to be spherical, or can be represented as spheres,
• d is the particle diameter in cm,
• surface area concentration is in cm2/ml media,
• mass concentration is in g/ml media,
• # indicates particle number, and particle density is in g/cm 3.