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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)
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.
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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
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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.