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
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.
Surface modificationsMonuclear phagocyte system (MPS) is the major contributor for the clearance ofnanoparticles. Reducing the rate of MPS uptake by minimizing the opsonizationis the best strategy for prolonging the circulation of nanoparticles. Approachesfor improving the phamacokinetics of NP include maintaining the size around100 nm, keeping the Zeta potential within 10 mV, and grafting PEG onto thesurface.Neutral nanoparticles exhibit a decreased rate of MPS uptake and prolongedblood circulation compared to charged ones.
• 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
Particle size Arruebo M. et al. Nanotoday 2, 2007NPs endowed with specific characteristics: size, way of conjugating the drug(attached, adsorbed, encapsulated), surfacechemistry, hydrophilicity/hydrophobicity, surfacefunctionalization, biodegradability, and physical response properties
Elimination by RES (Reticuloendothelial system)Renal Spleen opsonizationelimination 100 cut-off <5.5 200-250 nm Optimal NP size
Routes of exposure• Inhalation• Absorption via the olfactory nervous system• Oral administration• Dermal absorption• Systemic administration
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.
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.
Absorption via the olfactory nervous systemSurface enginnering of nanoparticles with lectins opened anovel pathway to improve the brain uptake of agentsloaded by biodegradable PEG-PLA nanoparticles followingintranasal administration. Ulex europeus agglutinin I (UEAI), specifically binding to L-fucose, which is largely locatedin the olfactory epithelium was selected as ligand andconjugated onto PEG-PLA nanoparticles surface.
Absorption via the olfactory nervous system BLOOD OLFACTORY BULB OLFACTORY TRACT CEREBRUM CEREBELLUM
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.
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
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) 27Bhardwaj et, al. Pharmaceutical Aspects of Polymeric Nanoparticles for Oral Delivery, Journal of Biomedical Nanotechnology (2005), 1, 1-23
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 waterSUR-3 (80:20) Cationic Water nanoparticles 1000rpm, 40 oC Homogenize 15000 rpm, 5 min 28
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.
MetabolismInert NP are not metabolized (gold andsilver, fullerenes, carbon nanotubes).Functionalized or “biocompatible” NP can bemetabolized effectively by enzymes in thebody, especially present in liver and kidney.The intracellularly released drug is metabolizedaccording to the usual pathways.
ExcretionData are not available regarding the accumulationof NP in vivo.The elimination route of absorbed NP remainedlargely unknown and it is possible that not allparticles will be eliminated from the body.Accumulation can take place at several sites inthe body. At low concentrations or singleexposure the accumulation may not besignificant, however high or long-term exposuremay play a relevant role in the therapeuticaleffects of the active ingredient.
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.