Targeted drug delivery to the brain Flashcards
What is the role of the BBB?
Protect the brain from any harmful substance in the circulation ( microbes or toxins).
Shield the CNS and the body from the effect of chemokines.
Control the CNS environment and maintain homeostasis.
It consists of a basement membrane lined by endothelial cells with tight junction to control the movement of substance.
How do molecules move into the brain?
Hydrophilic molecules - carrier mediated for small molecules (amino acids, glucose).
Transporters - receptor-mediated transcytosis for large molecules such as hormones.
Endocytosis - lipophilic Molecules crosses by transcellular diffusion (e.g. benzodiazepines and barbiturates).
Passive diffusion.
What are the essential physical properties for a good absorption and permeability?
Lipophilicity.
Molecular weight.
Hydrogen bonding.
Polar surface area.
Charge.
Pharmacokinetics properties.
What are the 4 strategies for CNS drug delivery?
Invasive techniques.
Pharmacological approaches.
Physiological methods.
Miscellaneous.
What are some invasive techniques for CNS drug delivery?
Intra-cerebro-ventricular (ICV) infusion:
This method can be used for glycolpeptide antibiotics (Vancomycin) or aminoglycoside antibiotics (gentamicin).
Intra-cerebral injection of implants (biodegradable carrier plus pharmaceutical molecules).
Convection enhanced delivery (CED):
Inserting a small diameter catheter into the tumour.
Disruption of the BBB:
Osmotic disruption which shrinks the endothelial cells and disrupting the tight junctions.
The disruption can be also the outcome during inflammation, hypertension and hypoxia.
What are the shortcomings for the invasive procedures?
The techniques are not cost effective and include anesthesia and hospitalization.
It may lead to the spread of tumor cells.
Another outcome could be a permeant damaged in the brain tissue.
What are some pharmacological approaches for CNS drug delivery?
Chemical drug delivery:
Involves increasing the drug lipophilicity by forming a prodrug to enhance CNS penetration.
Once the prodrug is inside the brain, it will be cleaved enzymatically yielding.
A less lipophilic / active drug molecules which will be trapped in the brain.
What are some physiological approaches for CNS drug delivery?
Nanoparticles:
Adjusting the particle size (1-100nm) and drug - polymer ratio.
Coating with surfactant, cell penetrating peptides or antibodies.
Liposomes:
Liposomes are lipid vesicles that have an aqueous core encircled by a lipid bilayer used for CNS drug delivery via passive diffusion.
Targeted CNS delivery can be achieved by exploitation of endogenous pathway via binding with specific receptors (insulin or lipoprotein and transferrin receptors) which will facilitate drug delivery via endo/transcytosis.
What are some miscellaneous approaches for CNS drug delivery?
Intranasal drug delivery:
The nasal mucosa offer direct delivery of the drug molecules to the CNS.
This is a non invasive method which allows the drug to enter the CNS through or along the olfactory /trigeminal neural pathways.
Requires high solubility.
pH and isotonicity are essential for successful drug delivery.
Improper administration can send the drug to the lung or stomach.
Image-guided focused ultrasound:
Injection of drug loaded microbubbles followed by exposure to ultrasound radiation to achieve temporarily disruption of the BBB and hence enhancing drug delivery to the brain.
