Module 1-b Biological Barriers.
-
Upload
amie-stafford -
Category
Documents
-
view
246 -
download
2
description
Transcript of Module 1-b Biological Barriers.
Module 1-b Biological Barriers Biological Barriers Human
barriers Cellular Delivery Skin Mucosa DRUG
PROBE DRUG PROBE External barriers Cellular Delivery En route
barriers Blood Extracellular matrix Cellular barriers
Endosomal/lysosomal degradation Inefficient translocation to the
targeted sub-cellular organelles Human Barrier (Errors) Common
Routes of Administration 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.
Histologic image of human epidermis
Source: Grays Anatomy Composition of gastric mucus
Source: DOI: /23951 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. biochemicaldimers,
transmembrane proteins, occludin,claudins, junctional adhesion
molecule(JAM), ZO-1 protein Crossing BBB: disruption by
osmoticmeans; biochemically by the use of vasoactive substances
such asbradykinin; localized exposure tohigh-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 Degraded nanoparticle
Cellular Barriers Excretion Degraded nanoparticle SUCCESS FALIURE
Possible degradation routes Acidic pH and enzymes (late endosomes
-lysosomes). Viscosity and intracellular enzymes of the cytosol.
Recycling (exocytosis) of the vesicle contents. Charged molecule:
activity of specific transport and channel proteins
Diffusion of Agents Through Cellular Bilayer Hydrophobic molecule
Charged molecule Polar (large) Glucose Polar (small) H2O, ethanol
(a) ibuprofen, (b) aspirin, (c) erythromycin Charged molecule:
activity of specific transport and channel proteins Polar (large)
Gases Hydrophobic molecule Charged molecule Polar (small) 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 Cell Penetrating Peptides (CPPs)
Discovery TAT Covalent approach PENETRATIN TRANSPORTAN Complex MPG
POLY R TP10 In vivo PEP-1 Clinical Trial PPTG SAP SynB M918 PrPr
EB1 CADY Phase IIb-3 Extra Vascular NP: How Far Below We Could
Drive the Size Down?
Hydrophobic Hydrophillic Self-assembly Diblock copolymer Micelle
Cross-linking PTD PTD-SCK-FTSC 40-60 nm Shell cross-linked
nanoparticles (SCKs) Pan, Turner, Wooley
Macromolecules,2004,37(19), pp 71097115 Becker, Pan, Wooley
Bioconjugate Chemistry 2003 Its all about CONTROL A perfect
Therapeutic Approach
Precise Targeting (Tissue/Cell/Molecular) Precise Action (Maximize
therapeutic action and minimize toxicity and side effects) Precise
Timing (On when it is needed, Off when it is not needed) Implicit
in these design goals is the requirement for precise control
mechanisms that can either respond to local environments
automatically or respond to signals sent remotely. Characteristics
of an ideal tumor-targeted Agent
(1) Increase drug localization in the tumor through: (a) Passive
targeting (b) Active targeting (2) Decrease drug localization in
sensitive, non-target tissues (3) Ensure minimal drug leakage
during transit to target (4) Protect the drug from degradation and
from premature clearance (5) Retain the drug at the target site for
the desired period of time (6) Facilitate cellular uptake and
intracellular trafficking (7) Biocompatible and biodegradable
Lammers T, et al.British Journal of Cancer 2008;99: Absorption,
Distribution, Metabolism, and Excretion (ADME)
Describes the disposition of a pharmaceutical compound within an
organism. The four criteria all influence the drug levels and
kinetics of drug exposure to the tissues. Influence the performance
and pharmacological activity of the compound as a drug. LADME: L
stands for "liberation" and deals with details of the route of
administration such as what a tablet will do at a given gastric pH
level, the creation of extended-release injectables for IM or SC
use etc. ADME Other RES sites Distribution Absorption Liver
Systemic
Local barriers Distribution Absorption Liver Systemic Circulation
Target tissue Metabolism Kidney Excretion Clinically Utilized Drug
Targeting Strategies Targeting Approaches There is a search
dual-mode probes that can detect a tumor imaging) and destroy it
(therapy) Redox-potential Ultrasound Temperature DRUG PROBE
pH-sensitive DRUG PROBE DRUG PROBE Physical Targeting Active
Targeting Passive Targeting Based on nanoparticle functionalization
for specific targeting of disease cells Based on retention effect
of particle of certain hydrodynamic size in cancerous tissues(e.g.
Doxil) Proteins (antibodies and their fragments such as TAT),
nucleic acids (aptamers), receptor ligands (peptides, vitamins, and
carbohydrates EPR: Taking advantage of retention
A. Tumorous tissues suffer ofEnhanced Permeability and Retention
effect (RES) B. Nanoparticles injected in the blood stream do not
permeate through healthy tissues C. Blood vessels in the
surrounding of tumorous tissues are defective and porous D.
Nanoparticles injected in the blood permeate through blood vessels
toward tumorous tissues, wherein they accumulate Annu. Rev. Biomed.
Eng Vol. 9, pp. 25788 Clinical Example of EPR
Doxilis apolyethylene glycol coated liposomal formulation of
doxorubicin. Marketed by Ben Venue Laboratories ofJ&J. Outside
the US, Doxil is known as Caelyx(Janssen). Approved by the FDA for
treatment of ovarian cancer and multiple myeloma and anAIDS-related
cancer.