1. Pharmacokinetics of Nanoparticle
(Nanokinetics)
• Chemical composition
• Structural diversity
• Surface modifications
• Particle size
• Relevant routes of exposure
• Transplacental distribution
• Transport across the blood-brain barrier
• Tissue selectivity
• Metabolism
• Excretion

4. 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.

5. Factors affecting
pharmacokinetics

6. Chemical composition
Nanoscale materials may possess unexpected
physical, chemical, optical, electrical and
mechanical properties, different from their
macrosized counterparts.

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

8. Surface modifications
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. 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.
Neutral nanoparticles exhibit a decreased rate of MPS uptake and prolonged
blood circulation compared to charged ones.

9. • 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

11. PLGA versus PEG-PLGA
Liu et al.

12. 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

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

14. Particle

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

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

17. 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.

18. Inhalation exposure

19. 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.

21. 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.

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

23. 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.

26. Oral route Nano-Systems
• Nature’s intended mode of  Direct uptake through the
uptake of foreign material intestine
• most convenient  Protection of encapsulated
• preferred route of drug
administration  Slow and controlled release
• No pain (compared to  Can aid delivery of drugs
injections) with various
• Sterility not required pharmacological and
physicochemical properties
• Fewer regulatory issues
26

27. 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)
27
Bhardwaj et, al. Pharmaceutical Aspects of Polymeric Nanoparticles for Oral Delivery, Journal of Biomedical Nanotechnology (2005), 1, 1-23

28. Homogenize
Water
Anionic 15000 rpm, 5 min
nanoparticles 1000rpm, 40 oC
-
1000 rpm
PLGA
SUR-1 Primary
or
+ SUR-2 3h emulsion
Ethyl acetate or
SUR-3
in water
SUR-3 (80:20)
Cationic
Water
nanoparticles
1000rpm, 40 oC Homogenize
15000 rpm, 5 min
28

29. Distribution following oral absorption

30. Distribution following oral exposure
•Solid lipid nanoparticles (SLN).
•Wheat germ agglutinin-N-glutaryl-
phosphatylethanolamine (WGA-
modified SLN).
•WGA binds selectively to
intestinal cells lines.

31. 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.

36. Dermal absorption

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

38. Distribution following intravenous exposure
Free Cholesteryl Bodipy
3,5
Fluorescence Intensity
3 urine
2,5 blood
2
1,5
1
0,5
Cholesteryl Bodipy-liposomes
0 3,5
0 2 4 6 8 10 12
3
2,5
Fluorescence Intensity
Time-course of biodistribution of 2 urine
Cholesteryl Bodipy injected i.v. in 1,5 blood
healthy rats (157 g/rat).
1
spleen
0,5
0
0 2 4 6 8 10 12
Roveda et al., 1996

41. 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.

42. 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.

43. Excretion

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

47. 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/cm3.