Week 11 & 12 - Drug Delivery to The Brain Flashcards
What is the purpose of the BBB
To maintain homeostasis of the CNS (brain and spinal cord)
- Protects brain from blood-borne toxins + pathogens
- Controls what can enter + leave the brain
What are the main problems with drug delivery across the BBB
Establishing a conc. gradient (from blood across BBB)
- Blood conc. is limited
- can ↑ GI tract drug conc. by ↑ drug intake
- BUT when drug diffuses from GIT to blood the conc. is ↓ due to constant blood flow (taking drug away)
- DUE to LOW CONC. in BLOOD = gradient from blood to brain is LIMITED
- even if BBB was permeable movement across BBB is limited
- can NOT force drug out of blood + across BBB down conc. gradient
What are the 4 main components of the BBB
These are physiological factors affecting drug delivery
- Special capillary construction
- Direct drainage to/from CSF
- Active Efflux Transporters (AETs)
- Metabolic / destructive enzymes
Explain how “special capillary construction” affects drug delivery across the BBB
Brain has a large network of capillaries surrounding it = good blood supply
- capillaries are very close together
- capillaires bring nutrients + remove metabolites from brain
- blood capillaries: endothelial cells are closer together = tight junctions (no large gaps) = not leaky
BBB (phospholipid bilayer) is flexible
- Polar / hydrophilic heads move = small pores are formed = how passive diffusion occurs
- Small, lipophillic molecules can diffuse through gap / pore
- Capillary is connected to astrocytes (glial cells) which is connected to neurones
Astrocytes:- repair damage to neurones + provide physical support
- make tight junctions on capillary even tighter
- release enzymes that destroy drug
- AETs
NOTE:
- Large, hydrophilic drugs can NOT pass BBB (can only pass through large gaps in normal capillaries)
- Small (<450Da), lipophilic drugs can cross BBB
- Some drugs may reach capillaries but not pass it into brain / parenchyma due to size
- When have illness may need to reduce dose as tight junction may become leaky
Explain how “direct drainage to/from CSF” affects drug delivery across the BBB
CSF circulates around the brain + spine
- removes drug + metabolites from brain tissues and INTO bloodstream
- found in subarachnoid space
- Produced in choroid plexus
- CSF is leaky (some drug can pass through it)
- drug molecules can pass to/from CSF via arachnoid granulation (point of contact with bloodstream / vessels)
- also have 4 points of contact with brain tissue
NOTE:
- Rate of drug loss from CSF is faster than rate of drug absorption from blood vessels (to CSF)
- due to efflux transporters
Explain how “Active Efflux Transporters (AETs)” affects drug delivery across the BBB
AETs pump drug molecule outside of brain cell back into blood (into venous sinus)
- requires energy (transporter converts ATP into ADP = energy produced)
AETs Found In:
- Astrocytes
- CSF
What drug properties affect its permeability across the BBB
- Size
- MUST be SMALL (< 450Da)
- in order to cross BBB by passive diffusion
- Nature
- Must be LIPOPHILIC
- HBD
- Must be <3
- the less donors = more permeable drug will be through BBB
How does diseases effect BBB permeability
Both types of stroke, brain tumors etc. can impair BBB and cause tight junctions to become leaky
- causes a change in expression in the network of proteins that hold the cells tightly together
- molecules that normally couldnt pass can now pass = hyperpermeable BBB
List the 6 main transport mechanisms through the BBB
- Paracellular
- through tight junctions between cells
- Transport proteins / transporters
- found on plasma membrane of endothelal cells
- ligand binds to receptor + is uptaken
- NOTE: exploit these transporters to deliver drugs to brain
- e.g. big, hydrophillic molecules
- Lipophillic diffusion
- small, lipophillic molecules
- Receptor-mediated Transcytosis
- molecule binds to receptor = complex forms = endocytosis occurs
- complex vesicle taken into endothelial cell, passes through cell + exocytosis occurs
- molecule is released into brain
- Adsorptive Transcytosis
- occurs due to charge
- positively charged molecule adsorbs to surface of negatively charged membrane
- molecule is engulfed (endocytosis)
- exocytosis of molecule
- phosphate group of phospholipid bilayermembrane = -ive
- AETs / efflux pumps
- removes drug out of brain (across BBB) into blood
- known as ABC-binding cassette (ABC)
- require energy (transporter converts ATP into ADP)
What are the strategies used to deliver hydrophillic drugs
- Conventional Strategies
- Unconventional Strategies
What are the 3 conventional pharmaceutical stratergies for enhancing drug delivery across the BBB
a.k.a. pharmaceutical / chemical
- REMOVE HYDROGEN bonding sites
- makes drug less polar - CONJUGATE drug to LIPID MOLECULES
- add acyl (hydrocarbon) chains to drug
- makes drug more lipophillic
- CAUTION: can ↑ drug size - Create a LIPID SOLUBLE PRODRUG
- conjugate drug to lipophilic molecule = inactive prodrug
- enzymes cleave lipophilic molceule = active prodrug formed
NOTE:
- Changes shouldnt alter drug action
- Changes shouldn’t increase drug size >450Da
- Can increase SE as increased permeation to other tissues (due to lipophilicity)
What are the 2 unconventional pharmaceutical stratergies for enhancing drug delivery across the BBB
- Transiet (temporary) Disruption of BBB
(Opening tight junctions)- dangerous (homeostatsis of BBB can be impacted) BUT effective
DONE VIA using:
1. Vasoactives = vasodilation of arteries = leaky capillaires
2. Hyperosmolar Mannitol = absorbs water from endothelial cell = cell shrinks = junctions open
- dangerous (homeostatsis of BBB can be impacted) BUT effective
- Advanced delivery systems
- Blocking active efflux pumps (AET)
- Invasive routes (ICV injection and IC implants)
- Hijack special biology (nanocarriers and transport systems)
- Nose to brain route
Blocking AETs
Advanced delivery systems
CONJUGATE drug to a SECOND MOLECULE (= prodrug) to prevent loss of drugs from brain into blood
- many drugs are substrates for AETs
- BUT when conjugated AETs UNABLE to RECOGNISE the prodrug = drug is able to remain in brain for longer
Explain the 2 “Invasive routes”
Advanced delivery systems
- Intracerebroventricular Injections (ICV)
- introduces drug into ventricles in CSF or parenchyma
- used in brain tumours, cancers
DRAWBACKS:- Have metabolic enzymes in CSF = drug metabolised
- Have efflux pumps in CSF = drug pumped back into blood (into venous sinus)
- Have extra barrier lining the ventricles (lipiad gilal sheaths)
- Diffusion from CSF to brain is much slower than diffusion from CSF into blood
- Intracerebal Implants
- implant directly into parenchyma
- used for altered cells (deliver drugs to surrounding cells)
- e.g. to prevent reoccurance of cancer in safety margin (healthy tissue surrounding mass) after surgical removal of a tumour mass - can be matrix or reservoir (slow release of drug)
DRAWBACKS:- Parenchymal bleeding
- Poor diffusion of drug from implant to parenchyma
- Metabolic enyzmes
- Efflux pumps
- Implant could migrate to ventricles = CSF becoems leaky
What are the 2 ways to “Hijack special biology”
Advanced delivery systems
- Exploit transport systems
- some nutrients e.g. amino acids are taken up by LAT1 transporters into brain
- drugs like L-dopa have similar structure to amino acid = can be taken up via this transporter
DONE VIA:- DESIGN DRUG that has SIMILAR STRUCTURE to natural NUTRIENT
- CONJUGATE natural NUTRIENT to DRUG
- CONJUGATE drug to large carrier molecule (e.g. mAb, peptides) which targets receptror e.g. TfR (for large hydrophillics)
- conjugated with weak conavlent bonds (disulfide ~ S-S) = after drug is uptaken it can be cleaved + released
- Nanocarriers
ACTIVE TARGETTING:
- drug is loaded inside core of drug-carrying liposome
- ligand / molecule (e.g. mAb) is conjugated to liposome / nanocarrier
- ligand binds to receptor = endocytosis of entire structure
PASSIVE TARGETTING:
(only in cancer)
- if have tumour = impaired capillaires = big gaps
- gaps allow nanoparticle through
- in healthy capillaries nanoparticle would NOT be able to pass
- cancer vasculature have enhanced permation + retention (due to inefficent lymphatic drainage system) = drug will remain there for long time
