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Module 1-C Biological Barriers PowerPoint PPT Presentation


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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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Module 1 c biological barriers

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

Inefficient translocation

to the targeted sub-cellular organelles


Module 1 c biological barriers

Common Routes of Administration


Module 1 c biological barriers

Human Barrier (Errors)


Module 1 c biological 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.


Module 1 c biological barriers

Histologic image of human epidermis

Source: Grays Anatomy


Module 1 c biological barriers

Composition of gastric mucus

Source: DOI: 10.5772/23951


Module 1 c biological barriers

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


Module 1 c biological barriers

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


Module 1 c biological barriers

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


Module 1 c biological barriers

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.


Module 1 c biological barriers

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


Module 1 c biological barriers

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


Module 1 c biological barriers

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


Module 1 c biological barriers

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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