DRUG PROBE DRUG PROBE Biological Barriers External barriers En route barriers Cellular barriers SkinMucosa BloodExtracellular matrix Endosomal/lysosomal degradation Inefficient translocation to the targeted sub-cellular organelles Cellular Delivery Human barriers
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.
Source: Grays Anatomy Histologic image of human epidermis
Source: DOI: 10.5772/23951 Composition of gastric mucus
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 Mononuclear phagocyte system: (MPS)
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
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
Cellular Barriers Possible degradation routes Acidic pH and enzymes (late endosomes -lysosomes). Viscosity and intracellular enzymes of the cytosol. Recycling (exocytosis) of the vesicle contents. Excretion Degraded nanoparticle SUCCESS FALIURE
Gases Hydrophobic molecule Polar (large) Polar (small) Charged molecule Diffusion of Agents Through Cellular Bilayer Hydrophobic molecule Charged molecule Polar (large) Glucose Polar (small) H 2 O, ethanol (a) ibuprofen, (b) aspirin, (c) erythromycin Charged molecule: activity of specific transport and channel proteins
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 Can There be a Direct Access to the Cytoplasm? How can we avoid endosomal escape pathway?
1988 1994 1996 1997 2000 2001 2004 2006 2008 Discovery TAT Covalent approach PENETRATIN TRANSPORTAN Complex approach MPG POLY R TP10 In vivo PEP-1 Clinical Trial PPTG SAP SynB M918 PrPr EB1 CADY Phase IIb-3 Cell Penetrating Peptides (CPPs)
Extra Vascular NP: How Far Below We Could Drive the Size Down? Kim, Lanza, Pan, Adv Health Mat 2012 Pan, Turner, Wooley Macromolecules, 2004, 37 (19), pp 7109–7115