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Module 1-C Biological Barriers

Module 1-C Biological Barriers. Biological Barriers. DRUG. DRUG. Human barriers . Skin. Mucosa. PROBE. PROBE. External barriers . Cellular Delivery . En route barriers . Cellular barriers . Blood. Extracellular matrix. Endosomal / lysosomal degradation.

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Module 1-C Biological Barriers

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  1. Module 1-C Biological Barriers

  2. Biological Barriers DRUG DRUG Human barriers Skin Mucosa PROBE PROBE External barriers Cellular Delivery En route barriers Cellular barriers Blood Extracellular matrix Endosomal/lysosomal degradation Inefficient translocation to the targeted sub-cellular organelles

  3. Common Routes of Administration

  4. Human Barrier (Errors)

  5. First Pass Mechanism Metabolism occurs during the absorption process. The fraction of the initial dose appearing in the portal vein is the fraction absorbed, and the fraction reaching the blood circulation after the first-pass through the liver defines the bioavailability of the drug.

  6. Histologic image of human epidermis Source: Grays Anatomy

  7. Composition of gastric mucus Source: DOI: 10.5772/23951

  8. Possible destabilization and degradation pathways of probes during in vivo circulation Immunoglobulins, complement proteins, albumin, apolipoprotein and fibrinogen. adsorbs on the surface of nanoparticles and tag them for attack by the MPS. Scavengers to engulf foreign particles

  9. Renal Clearance • Renal molecular weight cut-off: 48kDa • Renal size cut-off: ~10 nm • Anything beyond >10-20 nm may not be excreted • Size: ~10 nm

  10. Blood Brain Barrier (BBB) • Blood and brain junction, endothelial cells are tightly stitched together • Composed of smaller subunits, e.g. biochemical dimers, transmembrane proteins, occludin, claudins, junctional adhesion molecule (JAM), ZO-1 protein • Crossing BBB: disruption by osmotic means; biochemically by the use of vasoactive substances such as bradykinin; localized exposure to high-intensity focused ultrasound (HIFU) • Pore size upper limit ~12 nm (malignant glioma) • Polyethylenglycol, peptides….. A cortical microvessel stained for blood-brain barrier protein ZO-1

  11. Cellular Barriers SUCCESS Degraded nanoparticle Excretion FALIURE • Possible degradation routes • Acidic pH and enzymes (late endosomes-lysosomes). • Viscosity and intracellular enzymes of the cytosol. • Recycling (exocytosis) of the vesicle contents.

  12. Diffusion of Agents Through Cellular Bilayer Hydrophobic molecule Charged molecule Polar (large) Glucose Polar (small) H2O, ethanol Polar (large) Gases Hydrophobic molecule Charged molecule Polar (small) (a) ibuprofen, (b) aspirin, (c) erythromycin Charged molecule: activity of specific transport and channel proteins

  13. Can There be a Direct Access to the Cytoplasm? How can we avoid endosomal escape pathway? • Direct translocation across the plasma membrane is another suggested endocytic pathway • Does not depend on the metabolic activity of the cells. • Energy-independent • Receptor-independent • Transduction • Cell penetration peptides

  14. Cell Penetrating Peptides (CPPs) Covalent approach Complex approach In vivo Phase IIb-3 Clinical Trial Discovery PPTG SAP SynB M918 PrPr EB1 POLY R TP10 TAT PENETRATIN MPG PEP-1 CADY 1988 1994 1996 1997 2000 2001 2004 2006 2008 TRANSPORTAN

  15. Hydrophobic Hydrophillic Extra Vascular NP: How Far Below We Could Drive the Size Down? Co - Self-assembly Self-assembly Diblock copolymer 16-20 nm Micelle Kim, Lanza, Pan, Adv Health Mat 2012 Cross-linking PTD-SCK-FTSC PTD 40-60 nm TEM image Shell cross-linked nanoparticles (SCKs) Pan, Turner, WooleyMacromolecules, 2004, 37 (19), pp 7109–7115 Becker, Pan, Wooley Bioconjugate Chemistry 2003

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