6farmaco kin


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6farmaco kin

  1. 1. Pharmacokinetics of Nanoparticle (Nanokinetics) • • • • • • • • • Chemical composition Structural diversity Surface modifications Particle size Relevant routes of exposure Transport across barrier (Placenta, skin, GI, BBB) Tissue selectivity Metabolism Excretion
  2. 2. 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.
  3. 3. Factors affecting pharmacokinetics
  4. 4. 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 to bone 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
  5. 5. Structural diversity Organic nanoparticles liposomes dendrimers carbon nanotubes Inorganic nanoparticles quantum dots magnetic NPs gold NPs
  6. 6. Surface modifications PEGylated NP in “Brush ” configuration attract less Opsonins from plasma 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..
  7. 7. • 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.
  8. 8. poloxamine PEG
  9. 9. PLGA versus PEG-PLGA Liu et al.
  10. 10. 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
  11. 11. 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).
  12. 12. Renal elimination 100 <5.5 Elimination by RES (Reticuloendothelial system) Spleen opsonization cut-off 200-250 Optimal NP size nm
  13. 13. Particle
  14. 14. Routes of exposure • • • • • Inhalation Absorption via the olfactory nervous system Oral administration Dermal absorption Systemic administration
  15. 15. Inhalation exposure • Distribution of inhalated NP was observed in animal models, but not confirmed in human.
  16. 16. 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.
  17. 17. Inhalation exposure
  18. 18. 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.
  19. 19. 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.
  20. 20. Absorption via the olfactory nervous system BLOOD OLFACTORY BULB CEREBRUM OLFACTORY TRACT CEREBELLUM
  21. 21. 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.
  22. 22. Oral route • Nano-Systems Nature’s intended mode of  uptake of foreign material • preferred intestine most convenient • route  No pain (compared Protection of encapsulated drug of administration • Direct uptake through the  to Slow and controlled release  Can aid delivery of drugs injections) • • with Sterility not required pharmacological Fewer regulatory issues various and physicochemical properties 27
  23. 23. 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) 28 Bhardwaj et, al. Pharmaceutical Aspects of Polymeric Nanoparticles for Oral Delivery, Journal of Biomedical Nanotechnology (2005), 1, 1-23
  24. 24. Homogenize 15000 rpm, 5 min Water Anionic nanoparticles 1000rpm, 40 oC - SUR -1 or SUR -2 or SUR -3 in water PLGA + Ethyl acetate SUR-3 (80:20) Cationic nanoparticles 1000 rpm 3h Primary emulsion Water 1000rpm, 40 oC Homogenize 15000 rpm, 5 min 29
  25. 25. Distribution following oral absorption
  26. 26. Distribution following oral exposure •Solid lipid nanoparticles (SLN). •Wheat germ agglutinin-N-glutarylphosphatylethanolamine (WGAmodified SLN). •WGA binds selectively to intestinal cells lines.
  27. 27. 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.
  28. 28. Dermal absorption
  29. 29. Distribution following intravenous exposure • NP kinetics depends on size charge and functional coating. • Delivery to RES tissues: liver, spleen, lungs and bone marrow.
  30. 30. F n c s e r o u l y i s e t n I Distribution following intravenous exposure Free Cholesteryl Bodipy 3,5 3 2,5 2 1,5 1 0,5 0 urine blood Cholesteryl Bodipy-liposomes 0 2 4 6 8 10 12 3,5 3 Time-course of biodistribution of Cholesteryl Bodipy injected i.v. in healthy rats (157 µg/rat). Fluorescence Intensity 2,5 urine 2 blood 1,5 1 spleen 0,5 0 0 2 4 6 8 10 12 Roveda et al., 1996
  31. 31. 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.
  32. 32. 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.
  33. 33. Excretion
  34. 34. Devalapally H., J.Pharm.Sci. 96:2547-2565, 2007
  35. 35. 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/cm 3.