CNS Drug Delivery

Question 1

Briefly desribe the stucture of the Blood-Brain Barrier (BBB).

Answer 1

• Tight junctions forms a seal that prevents any movement of molecue or ion
• Astrocytic foot processes sheath the brain-facing side of the vessels & release nutrients to make sure that the endothelial cell is tight & is functional. (I.e. letting the right rhings in & keeping the bad stuff out)
• Pericyte responsible for tight function formation & vesicle trafficking amongst endothelial cells. Also, they reduce the CNS immune effects that can disrupt the BBB and reduce the expression of molecules that increase BBB vascular permability.

Question 2

List TWO potential routes of drug transport across the BBB.

Answer 2

1. Transcellular passive permeability
2. Mediated transporters:
   (a) Carrier mediated transporters (CMT)
   (b) Receptor mediated transporters (RMT)

Question 3

Why is the paracellular route of drug transport across the BBB practically non-existant?

Answer 3

• Because of the tight junctions that prevent paracellular movement

Question 4

Lise the FIVE physicochemical properties that an ideal CNS drug candidate should possess for optimal passive permeability.

Answer 4

• MW (Da)​
  
  • < 450
• Log P
  
  • 1 - 3
• H-bond donors
  
  • ​< 3
• H-bond acceptors
  
  • ​< 7
• Polar Surface Area (PSA)
  
  • ​< 60 - 90

Question 5

The ideal Log P for BBB permeability is between 1 - 3. So why is the following picture depicting drugs with optimal conditions for lipophilicity still have poor CNS uptake?

Answer 5

• Good penetration requires certain physicochemical properties for optimal passive permeability. BUT, it does not guarantee absorption.
• Those drugs (depicted in yellow) have ideal Log P values, but they are also substrates of efflux transporters (e.g. P-gp, BCRP, MRP)
• Efflux transporters are expressed on the blood-facing side of the endothelium that actively exlude compunds from the brain endothelial cell.

Question 6

How can essential endogenous compounds (such as nutrients) access the brain?

Answer 6

• There are ACTIVE transport pumps that recognise these endogenous materials & takes them in.
• They involve:
  
  • Carrier mediated transporters (CMT)
    
    • LAT1; GLUT-1; MCT1
  • Receptor-mediated transporters (RMT)
    
    • Transferrin receptor; Insulin receptor
    • Generally for larger compounds
    • Once the receptor recognises the compound, the entire receptor-compound complex becomes internalised within a vesicle to be transferred to the brain.

Question 7

Name FOUR approaches for enhancing CNS drug delivery.

Answer 7

1. Optimisation of medicinal chemistry
2. Osmotic disruption
3. Chemical modification
   
   1. Lipidisation
   2. Utilisation of carrier-mediated transporters
   3. Utilisation of receptor-mediated transporters
4. Inhibition of active efflux transporters

Question 8

Briefly explain the Osmotic disruption technique used for enhancing CNS drug delivery.

Answer 8

• It involves an intracarotid administration of hyperosmotic (25% w/v) mannitol solution
  
  • Causes water (from blood) from the brain endothelial cells to move out to the vessels to try to correct the hyperosmotic solution.
• This leads to:
  
  • Shrinking of endothelial cells forming the BBB
  • Disruption of interendotheliala Tight Junctions
  • Opening of the paracellular route

Question 9

What is an advantage and disadvantage of osmotic disruption of the BBB?

Answer 9

• Advantage:
  
  • Enhances the entry of chemotherapeutic agents that are usually substrates of efflux transporters (such as P-gp or BCRP)
• Disadvantage:
  
  • Intracarotid administation requires surgery
  • Risks of infection that can possibly induce a seizure
  • Other unwanted plasma proteins and materials can also cross over.

Question 10

What are THREE approahces of chemical modification (not optimising medicinal chemistry) for enhancing CNS drug delivery?

Answer 10

1. Lipidisation
2. Utilisation of carrier-mediated transporters
3. Utilisation of receptor-mediated transporters

Question 11

Explain, using an example in practice, the idea behind lipidisation to enhance BBB permeability.

Answer 11

• Lipidisation is a chemical modification approach that converts hydrophilic compounds into lipophilic compounds.
  
  • Due to the lipophilic nature of the BBB.
  • E.g) The only difference b/w the structure of heroin and morphine are the two acetoxy groups on heroin that increases its lipophilicity so that it has much more rapid BBB penetration. These acetoxy groups are later cleaved so it returns to Morphine in the brain.
• An example in practice involves NAX 5055
  
  • Galanin (neuropeptide with anticonvulsant properties) is only effective if it is administered into cerebral ventricles
  • NAX 5055 involves lipidisation of the native Galanin peptide that increases BBB permeability and high affinity.

Question 12

Use an example to briefly descrip the utilisation of carrier-mediated transporters for enhancing BBB delivery.

Answer 12

• Various carrier-mediated transport (CMT) systems are present at the BBB to ensure CNS access of vitamins
• L-dopa (pro-drug) has been designed to a mimic Phenylalanine, a subtrate of the Large neutral amino acid transporter (LAT1)
• This L-dopa is then able to cross the BBB via LAT1 and be metabolised to dopamine.

Question 13

Explain tha concept of the “Trojan horse” approach in enhancing BBB permeability, using an example.

Answer 13

• Utilisation of receptor-mediated transporter
• The drug is attached to a monoclonal antibody that has an affinity for a receptor-mediated transporter (such as Human insulin receptor [HIR] and Transferrin receptor [TR].
• The binding of the monoclonal antibody to the RMT triggers transport across the BBB.

Question 14

What is this and how can it enhance BBB permeability?

Answer 14

• This is a PEGylated immunoliposome.
• It utilises a receptor-medaited transporter approach for enhancing BBB permeability.
• It contains monoclonal antibodies that have an affinity for receptors on the brain (such as human insulin receptor ot transferrin receptor) that increases penetration in the brain.
• It also contains PEG groups that improves its half-life by rendering it invisible to the immune defence.
• It also has a liposome that acts as the drug carrier.
• An example would be the GDNF plasmid DNA under the influence of tyrosine hydroxylase promoter (pTHpro-GDNF) that decreases the rotations per minute in mice with parkinsons.

Question 15

What is the significance of cyclosporin in enhancing BBB permeability?

Answer 15

• Cyclosporin can inhibit the function of P-gp at the BBB
• P-gp is an active efflux transporter.
• Therefore, various compounds have been designed to a similar structure as cyclosporin to inhibit P-gp at the BBB to increase permeability.
• BUT, these compournds have not necessarily been approved b/c efflux transporters re meant to protect the brain
  
  • Therefore, there’s an oppurtunity for short-acting p-Gp inhibitors.