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Jan van Hest, Masterclass Een medicijn : Waarom werkt het? 8 april2014

Hoe vindt een medicijn zijn weg? . Jan van Hest, Masterclass Een medicijn : Waarom werkt het? 8 april2014. Routes of administration. A long and winding road. A long and winding road. Nanoparticles and Medicine. Advantages : Carrier and reservoir system

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Jan van Hest, Masterclass Een medicijn : Waarom werkt het? 8 april2014

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  1. Hoe vindt een medicijn zijn weg? Jan van Hest, MasterclassEenmedicijn: Waaromwerkt het? 8 april2014

  2. Routes of administration

  3. A long and winding road

  4. A long and winding road

  5. Nanoparticles and Medicine • Advantages: • Carrier and reservoir system • Protectionagainstdegradation/immune system • Controlleddelivery and release

  6. Popular carrier systems micelles vesicles polymer micro- and nanoparticles Macromolecular carrier systems Albumin

  7. Hydrophilic polymer Hydrophobic polymer polymersome liposome Polymer vesicles vs Liposomes Common features: Capsules Delivery vehicles Stealth functionalization Differences: Block copolymer amphiphiles Phospholipids Synthetic Natural Rigid and stable Dynamic

  8. Stealth properties The immune system does not recognize the particles Poly(ethylene glycol): PEG

  9. Nanoparticles and Medicine • Advantages: • Carrier and reservoir system • Protectionagainstdegradation/immune system • Controlleddelivery and release • Disadvantages: • Size • Cellularuptake • Release mechanismsnecessary

  10. Nanoparticles and biodistribution: natural filter systems Spleen Liver pores of 40-60 and up to 150 nm • Optimum size for circulation in the blood stream is <100 nm • Flexible particles are more efficient

  11. Effect of sizeonbiodistribution SPECT/CT scans 90 nm polymersomes 120 nm polymersomes BalB/C mice 4 hours post injection Brinkhuis et al. BioconjChem2012, 23, 958

  12. Enhanced Permeability and Retention (EPR) effect Nanoparticles accumulate in tumor tissue H. Maeda 1986

  13. Nanoparticles and cancer treatment Annu. Rev. Med. 2008. 59:251–65

  14. Cellularuptake

  15. Sizeeffectsoncellularuptake Small particles of about 25nm, preferably spheres, are most efficient for cellular uptake

  16. Active cellular uptake Polymersomes modified with cell penetrating peptides Positively charged peptides (Tat, derived from HIV) interact with cell membrane

  17. Escape from the endosome

  18. Escape from the endosome Bindsprotons: proton sponge effect destroysendosomes Binds DNA and then formsmicelles Givesstealthcharacter Kataoka et al. JACS 2008, 130, 6001

  19. Proton sponge effect

  20. Controlled Delivery Antibody conjugates

  21. Antibodies With biotechnology techniques, antibodies can be made that recognize specific biomolecules

  22. Antibody drug conjugates

  23. Crossing the Blood-Brain-Barrier

  24. G23 peptide for crossing the Blood-Brain-Barrier Brinkhuis et al. AngewChemInt Ed. 2012, 51, 8339

  25. Georgieva and Brinkhuis et al. In prep. Crossing the Blood-BrainBarrier Intracarotidinjection in Balb/C mice Brain slices Arteries (blue, CD31) BBB (green nuclei) Polymersomes (red)

  26. Georgieva and Brinkhuis et al. In prep. Crossing the Blood-BrainBarrier Intracarotidinjection in Balb/C mice

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