• 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)

ADMEAdministration, Distribution, Metabolism, Excretion

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.

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

GANGLIOSIDE

PLGA versus PEG-PLGA

Liu et al.

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

Liver, Spleen, Lung

• 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.

26

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

27

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

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

00,51

1,52

2,53

3,5

0 2 4 6 8 10 12

FluorescenceIntensity

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 µg/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.

POLYMERIC NANOPARTICLES

•Hydrolysis of ester bond; degradation products

alkylalcohol and poly(cyanoacrylic acid) are

eliminated by kidney filtration

GOLD NP studies from the literature show that very little gold is excreted from the body following intravenous (i.v.) administration of gold nanoparticles with a hydrodynamic (HD) diameter exceeding 8 nm. This is in part a consequence of the gold nanoparticles not being composed of subunits that can be easily broken down.

LIPOSOMESare completely degraded

Phospholipids and cholesterol follow lipid catabolic pathways

Fatty acids are oxidisedCholesterol is degraded into bile

acids

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

Mechanisms of Removal from Circulation• Fast removal from circulation-binding to cells, membranes, or plasma proteins-uptake by phagocytes (macrophages)-trapping in capillary bed (lungs)• Renal clearance-size restriction for kidney glomerulus is ~30-35 kDa for polymers(~20-30 nm)• Extravasation-depends on the permeability of blood vesselsthe primary route of excretion for nanoparticles greater than 8 nm is through the hepatobiliary system in which the particles may be excreted into bile by hepatocytes and eliminated in feces. Additionally, nanoparticles may be phagocytosed by Kupffer cells of the reticuloendothelial system (RES), and if not broken down by intercellular processes, will remain in this body location long-term.2, 3 and 9

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.