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

Pharmacokinetics of Nanoparticle (Nanokinetics)

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.

Factors affecting pharmacokinetics

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 tobone 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

Structural diversity Organic nanoparticles

liposomes dendrimers carbon nanotubes

Inorganic nanoparticles

quantum dots magnetic NPs gold NPs

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..

Surface modifications

PEGylated NP in “Brush ” configuration attract less Opsonins from plasma

• 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.

PEG

poloxamine

PLGA versus PEG-PLGA

Liu et al.

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

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).

<5.5 200-250 nm

Renal elimination

Elimination by RES (Reticuloendothelial system) opsonizationSpleen

cut-off100

Optimal NP size

Particle size

• Inhalation• Absorption via the olfactory nervous system• Oral administration• Dermal absorption• Systemic administration

Routes of exposure

Inhalation exposure

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

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.

Inhalation exposure

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.

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.

Absorption via the olfactory nervous system

Absorption via the olfactory nervous systemOLFACTORY BULB OLFACTORY TRACT

CEREBELLUMCEREBRUM

BLOOD

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

• Nature’s intended mode of

uptake of foreign

material

• most convenient

• preferred route of

administration

• No pain (compared to

injections)

• Sterility not required

• Fewer regulatory issues

Nano-Systems

Direct uptake through

the intestine

Protection of

encapsulated drug

Slow and controlled

release

Can aid delivery of

drugs with various

pharmacological and

physicochemical

properties

28

Liver

Blood vessel

Systemic circulation

NP

PPs

Intestinal lumen

(II) (l)

(lll)

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)

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

Lymphatic uptake of nanoparticles

29

Homogenize15000 rpm, 5 min

-

1000 rpm

3 h

Homogenize15000 rpm, 5 minAnionic

nanoparticles

Water

1000rpm, 40oC

Cationic nanoparticles

Primary emulsion

Water

1000rpm, 40oC

PLGA+

Ethyl acetate

SUR-1or

SUR-2or

SUR-3in water

Homogenize15000 rpm, 5 min

-

1000 rpm

3 h

Homogenize15000 rpm, 5 minAnionic

nanoparticles

Water

1000rpm, 40oC

Cationic nanoparticles

Primary emulsion

Water

1000rpm, 40oC

PLGA+

Ethyl acetate

SUR-3 (80:20)

Distribution following oral absorption

Distribution following oral exposure

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

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.

Dermal absorption

Distribution following intravenous exposure

• NP kinetics depends on size charge and functional coating.

• Delivery to RES tissues: liver, spleen, lungs and bone marrow.

Distribution following intravenous exposure

00,5

11,5

22,5

33,5

0 2 4 6 8 10 12

Fluo

resc

ence

Inte

nsit

y

Free Cholesteryl Bodipy

urineblood

0

0,5

1

1,5

2

2,5

3

3,5

0 2 4 6 8 10 12

urine

blood

spleen

Cholesteryl Bodipy-liposomes

Flu

ore

sce

nce

In

ten

sity

Time-course of biodistribution of Cholesteryl Bodipy injected i.v. in healthy rats (157 g/rat).

Roveda et al., 1996

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.

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.

Excretion

Excretion

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

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.