Brain delivery and nanomedicines Flashcards
List Types of neurological diseases that lead to disability death or morbidity
Sleep disorder Pain and migraines Depression Schizo Alzheimer's epilepsy CNS tumour Stroke
Describe the BBB
Blood vessels (epithelial cells) with by tight junctions, that only allows lipid soluble molecules that pass out of the cells and active transport.
What % of drug pass the BBB
2%
98% of drugs cannot pass
How does the BBB differ from other blood barriers
- Increase mitochondria
- Lack of fenestrations
- Minimal pinocytotic activity
- Presence of tight junctions
comprised of 2 plasma membranes in series; the luminal and the abluminal membranes separated by about 0.3μm of endothelial cytosol
Circumventricular organ vs tight BBB
The relative SA of the permeable fenestrated capillaries of CVO compared to tight BBB capillaries is 1: 5000, making these high permeability areas unable to influence the bulk composition of the brain extracellular fluid and an unrealistic route for drug entry into the brain
Describe the pathway across the BBB
- Paracellular aqueous transport through the tight junctions
- Transcellular lipophilic pathways
- Transport proteins
- Receptor mediated transcytosis
- Adsorption transcytosis
How optimal PK drug properties for BBB penetration
- Increase lipophilicity correlation with BBB permeability
- p-gp efflux can limit amount accumulation in the brain parenchyma
- Lipidisation can potentially increase BBB transport
- MW<500 Da
- LogP between -0.5-6
- polar SA <70A
- Reduced hydrogen bonding potential
What strategies are used to overcome the BBB
Invasive: -Intra-cerbro-ventricular infusion -Convection-enhanced delivery -Intracerebral injection or use of 23implants. -Modulation of BBB >Invasive, expensive, low therapeutic efficacy and hugely traumatic
Non-invasive
-Osmotic opening
-MRI focused ultrasound BBB disruption.
>Unsuccessful, short-lived effects
How is the BBB overcome
Optimise PK properties
Lipidisation: remove polar groups, halogenations
Prodrugs
How are ICV infusions used to optimise drug transport to the brain.
Works like a slow infusion and the drugs travels via the parenchyma.
However diffusion is Low
works if target receptor are located near the ependymal surface of the brain
How does CED delivery help with drug delivery to the brain?
Stereotactically guided insertion of small-caliber catheter into the brain parenchyma.
Infusate pumped over several days and catheters removed
delivers high MW protein 2cm from injection to brain parenchyma as little as 2h
Correct catheter placement vital
Intracerebral injection or use of implants
- Bolus injection of chemotherapeutics
- Wafers: diffusion of high conc drugs
What modulations of the BBB can be used
- Osmotic opening of the BBB
- Shunts
- Biodegradable implants
- Ultrasound and electromagnetic radiation
How is the osmotic opening utilised
- 30 mins window
- Infusion of 25% mannitol into the cartoid artery with rate of 4-8ml over 30 sec
- Osmotically pulls water out of the epithelial cells leading to shrinking and disengagement of protein of the TJ
MRI- guided focused ultrasound BBB disruption MOA
Ultra sounds capable of disrupting BBB
microbubble of ultrasound agents (optison) with 2-6 micro meter
