Brain Drug Delivery

Question 1

How can liposomes be delivery into the brain?

Answer 1

Attaching PEG modified liposomes can target them to the BBB.
Peg creates a longer half life so therefor rested circulation time

Question 2

What should the characteristic of nanoparticles be to cross the BBB?

Answer 2

For efficient transcytosis across the BBB, particles have to be less than 100-200nm.
Polybutylcyaboacrylate coated with Tween 80 have been successful.
Tween 80 promotes binding of apolipopoprotein E to the surface of the particle which assissts transportation across the BBB by end oxytocin’s

Question 3

What flow rate is required for conventional enhanced delivery (CED)?

Answer 3

0.1-10 micro litre / min

Question 4

What is the risk with conventional enhanced delivery (CED)?

Answer 4

Reflux risk.
Potential for toxic side effects owing to possible ventricular or subacrachnoid space leakage at rate above 3 microlitre/min.
Reducing infusion rate can reduce the chance of reflux

Question 5

What is the most well known implantable drug delivery for the brain?

Answer 5

Gliadel Wafer used for Glioblastoma brain tumours

Question 6

What is gliadel wafer made from and how is it planted in the tumour?

Answer 6

200mg died dhaoed biodegradable wafer containing 3.8% w/w of the chemotherapeutic agent carmustine (mustard gas). Active ingredient is dissolved in dichloromethane. Spray drives into microsphere varying in size from 1 to 20 micrometer. The microspheres are compressed into wafers and then placed in resection cavity
Carmustine released over a 5 day period.
Polymer matrix degrades after 6-8 weeks.

Question 7

What is another type of impantable drug delivery into the brain?

Answer 7

The polymer milirods - small biodegradable rods which can be implanted in a solid tumour, around a solid tumour and into the resection cavity.

Question 8

What is brain drug delivery a big challenge?

Answer 8

Because of the Blood Brain Barrier (BBB).
Allows a selective access to essential nutrients and signalling molecules from the vascular compartment
Restricts entry of foreign bodies

Question 9

Describe the anatomy of the BBB

Answer 9

Created by tight junctions formations between endothelial cells which form the capillaries of the brain and spinal cord microvasculature.

Question 10

What is the role of BBB?

Answer 10

CNS needs to maintain a stable internal fluid environment surrounding neurons
Prevent macromolecules from entering
Functions as a protective barrier that shields the CNS from neurotoxic substances that circulate in the blood.

Question 11

What kind of molecules are able to pass the BBB?

Answer 11

Only low MW, electrically neutral, hydrophobic molecules

Some lipid soluble molecules

Question 12

What are the factors that restrict the entry of compounds into the CNS?

Answer 12

A High polar surface area (PSA) greater than 80 A2
Tendency to form more than 6 hydrogen bonds
Presence of a number of rotatable bonds
A MW in excess of 450Da
A high affinity of binding to plasma proteins with a low off rate

Bases which carry a positive charge have more likely of penetration of the BBB, As interacts with negative phospholipid heads of the cell membrane

Question 13

What strategies are there to overcome the BBB?

Answer 13

Modification of the drugs chemical structure
Disruption of the BBB
Drug solubilisation/encpsulation in nano or microparticles
Bypass the BBB - CED and implantable drug delivery

Question 14

What can be done to modify the drugs chemical structure to allow for crossing of the BBB?

Answer 14

Lipophilic modification - correlated with CNS permeability. Point modification with one or two fatty acid residues per protein molecule. Remains water soluble but also acquires lipophilic anchors that can target cell surfaces

Prodrugs - Pharmacologically active compounds that are chemically modified to be inactive until they are activated inside the target tissue by a single activating step. Water-soluble drugs attached to lipid-soluble carriers by cleavable bonds may be carried across the BBB and released into the brain. Esterification or amidation of hydroxy-, amino-, and carboxylicacid containing drugs enhances their lipid solubility and, as a result, their transport to the brain

Vector mediated drug delivery - Some natural peptides can effectively pass the BBB
1. Insulin - Conjugation of insulin with the anticancer drug, methotrexate, resulted in receptor mediated endocytosis of the conjugate to brain tumour cells
Insulin fragments were also used for delivery of a model peptide across the BBB
The short serum half-life and hypoglycemic effect of insulin are likely to limit the suitability of insulin as a carrier for CNS drug delivery

2. Transferin - Conjugation of transferrin with mutated diphtheria toxin resulted in a considerable increase in brain tumour response by reduction in tumour volume
   Transferrin is limited as a vector as its receptors are almost saturated under physiologic conditions so can be used as vectors.

Question 15

Describe disruption of the BBB

Answer 15

One of the most invasive strategies for CNS drug delivery
Ð Used in conjunction with systemic administration
Ð Associated with a high risk of adverse effects
Ð Only used in extreme cases of rapidly growing high grade gliomas
Ð A variety of techniques that transiently disrupt the BBB have been investigated
Ð Osmotic disruption
Ð Biochemical disruption
Ð Ultrasound

Question 16

Describe osmotic disruption of the BBB.

Answer 16

o pening of the BBB tight junctions using hypertonic solutions of mannitol, arabinose, lactamide, saline, urea etc.
o Approved for administration to patients
♣ Intracarotid injection of mannitol has become the choice in both preclinical and clinical studies
• Injection into the carotid artery
o Initiates endothelial cell shrinkage and opening of BBB tight junctions for a period of a few hours thereby permitting the delivery of antineoplastic agents to the brain

Ð Toxic side-effects are often observed with hyperosmotic BBB disruption
Ð 25% increase in the permeability of the tumour microvasculature
Ð Compared to a 10-fold increase in the permeability of normal brain endothelium

Question 17

Describe biochemical disruption of the BBB

Answer 17

Ð Based on the observation that some substances can selectively open only brain tumour capillaries leaving normal brain capillaries unaffected
Ð Vasoactive leukotrienes
Ð Vasoactive amines
Ð Cereport
È RMP-7, bradykinin B2 agonist
Ð The effect of Leukotrienes was shown to be related to the abundance of g-glutamyl transpeptidase (g-GTP) in normal capillaries and its decreased amount in tumours
Ð Results in the reduction of the enzymatic barrier in tumour endothelial cells, and in the elevated effect of leukotrienes
Ð The effect of Cereport is mediated specifically through bradykinin B2 receptors
Ð The effects of the drug occur rapidly, within minutes of initiation of the infusion
Ð Restoration of the barrier begins almost immediately upon termination of infusion
Ð Complete within 2–5 min

Question 18

How is ultrasound used to disrupt the BBB?

Answer 18

Ð Sonication of the brain, applied in the presence of an ultrasound contrast agent injected intravenously increased the number of
Ð Vesicles
Ð Vacuoles fenestration
Ð Channel formation
Ð Reversible openings of the BBB tight junctions

Ð Enhanced uptake of drug into the tumour and, especially, the area of the brain immediately around the tumour boundary is important
Ð This is the area that tumour cells infiltrate, often escaping detection, surgery, and therapeutic levels of antineoplastic agents

Question 19

What are the risks with disruption of the BBB?

Answer 19

Ð Passage of plasma proteins into the brain
Ð Altered glucose uptake
Ð The expression of heat shock proteins
Ð Microembolism, and abnormal neuronal function