Drug delivery to the brain

Question 1

what is a brain tumour?

Answer 1

abnormal tissue growth inside the brain - malignant or benign

which exerts pressure onto the brain causing problems

Question 2

whats glioblastoma (GBM)?

Answer 2

aggressive stage IV brain cancer
progresses rapidly and difficult to cure

Question 3

whats the treatment for glioblastoma (GBM)?

Answer 3

removal via surgery followed by chemotherapy (temozolomide) and radiation therapy

12-15month survival rate

Question 4

why can temozolomide be given for brain cancer?

Answer 4

as the drug crosses the BBB

Question 5

what is the limiting step for drug delivery to the brain?

Answer 5

the drug crossing the BBB

Question 6

what is the role of the blood brain barrier?

Answer 6

plays a key role on maintaining brain function
allows selection access to essential nutrients and signalling molecules
restrict entry of foreign bodies (e.g. drugs/pathogens)

Question 7

what treatment plans require drug transport across the BBB?

Answer 7

depression
severe pain
epilepsy
GBM

Question 8

why do imaging agents require drug transport across the BBB?

Answer 8

accurate diagnosis of neuropathology
monitoring of disease progression
localised for surgical intervention
introduction of therapeutic agents

Question 9

how is the BBB composed?

Answer 9

Question 10

how does the structure of capillaries in general differ from capillary in the brain?

Answer 10

astrocytes
pericytes
tight junctions
mitochondria

Question 11

why is the BBB needed?

Answer 11

to maintain a extremely stable internal fluid environment surrounding neurones for the CNS- protective barrier shielding the CNS from neurotoxic substances/macromolecules

Question 12

what drugs characteristics allow passing of the BBB?

Answer 12

low MW
electrically neutral molecules
hydrophobic

Question 13

how do lipid-soluble molecules pass the BBB?

Answer 13

passively diffuse with no energy needed

Question 14

what factors restrict the entry of compounds into the CNS?

Answer 14

highly polar surface area (PSA) >80A^2
form <6 hydrogen bonds
presence of rotatable bonds
MW >450 Da
high affinity/binding to plasma proteins

Question 15

do bases or acids penetrate the BBB more? and how?

Answer 15

bases (positively charged) have an advantage of acids

due to their cationic interactions with negatively charged phospholipid head group of the cell membrane

Question 16

overall what are the possible ways to enhance drug influx through the BBB?

Answer 16

-modification of the drugs chemical structure
-disrupt the BBB
-drug solubilisation/encapsulation in nano/microparticles
-bypass the BBB
-conventional enhanced delivery
-implantable drug delivery devices

Question 17

how can you modify the drug to allow enhanced drug influx through the BBB?

Answer 17

1. lipophilic drug modification
2. prodrugs
3. vector-mediated drug delivery

Question 18

how are lipophilic drug modification used to cross the BBB?

Answer 18

Question 19

how are prodrugs used to cross the BBB?

Answer 19

Question 20

how can vector-mediated drugs be used to cross the BBB?

Answer 20

Question 21

what are some natural peptides used for vector mediated drug delivery?

Answer 21

natural peptides
-insulin
-transferrin

Question 22

how does insulin help vector mediated drugs to cross the BBB?

Answer 22

1.conjugating insulin with anticancer drugs e.g. methotrexate
-allows passage thru the receptor mediated endocytosis
2. insulin fragments

Question 23

what can limit the suitability of insulin as a vector mediated carrier?

Answer 23

short serum half-life =the drug may not reach the brain in time

hypoglycaemic effect of insulin

Question 24

how does transferrin help vector mediated drugs to cross the BBB?

Answer 24

conjugated transferrin with mutated diphtheria toxin = increase brain tumour response by reducing tumour pressure by reducing tumour volume

Question 25

what can limit the suitability of transferrin as a vector mediated carrier?

Answer 25

saturation of the receptors

Question 26

what monoclonal antibody binds to transferrin receptor? and what does this mean?

Answer 26

OX26 conjugation of OX26 to fibroblasts growth factor = 80% reduction in strokes to the brain

Question 27

what is one of the most invasive strategy for CNS drug delivery? and why?

Answer 27

Direct Brain Admission disruption of the BBB due to high risk of adverse effects

Question 28

what are the methods used to disrupt the BBB?

Answer 28

1. osmotic disruption 2. biochemical disruption 3. ultrasound

Question 29

how does osmotic disruption disrupt the BBB?

Answer 29

endothelial cell shrinkage causing the opening of BBB tight junctions using hypertonic solutions of mannitol, Arabinose, lactamide saline, urea etc. mainly intracarotid injection of mannitol is used

Question 30

what are some examples of hypertonic solutions used to disrupt the BBB?

Answer 30

mannitol, Arabinose, lactamide saline, urea etc. mainly intracarotid injection of mannitol is used

Question 31

when do we use osmotic disruption to the BBB? (an example)

Answer 31

antineoplastic agents to the brain

Question 32

how does biochemical disruption disrupt the BBB?

Answer 32

based on some substances can selectively open brain tumour capillaries (peptides, cytokines, chemokines, etc)

Question 33

what are some examples used for biochemical disruption of the BBB?

Answer 33

vasoactive leukotrienes - decrease g-GTP = more leukotrienes vasoactive amines cereport - b2 receptors closed in (2-5 mins)

Question 34

cereport BBB restored period

Answer 34

2-5 mins after infusion

Question 35

how does ultrasound disrupt the BBB?

Answer 35

sonication of the brain, in the presence of ultrasound contrast agents injected through IV increasing the numbers of... vesicles, vacuoles fenestrations, channel formations, reversible opening of tight junctions

Question 36

what are the risk factors of disruption of the BBB?

Answer 36

passage of plasma proteins into the brain altered glucose uptake the expression of heat shock proteins micro embolism, and abnormal neuronal function

Question 37

how can we provide the CNS with drugs with low hydrolytic stability?

Answer 37

encapsulate/solubilise the nano/micro-particle

Question 38

why can't low hydrolytic stability drugs cross the BBB into the CNS?

Answer 38

as they are subject to degradation by blood proteins/enzymes

Question 39

how can drug carriers be targeted?

Answer 39

using encapsulate/solubilise the nano/micro-particle to facilitate receptor-mediated transport

Question 40

what can you encapsulate drugs into, to cross the BBB?

Answer 40

liposomes

Question 41

why are drugs encapsulated into liposomes?

Answer 41

prolongs the time of drug circulation in the bloodstream reduces side effects enhances therapeutic effects of CNS agents

Question 42

how can we further increase liposomes encapsulated drugs circulation time?

Answer 42

PEG-coat the liposome surface

Question 43

how are liposomes used to target the BBB?

Answer 43

attaching an immunoreactive moiety to PEG-modified liposomes e.g. transferrin

Question 44

give an example of nanoparticles that can reach the CNS by passing the BBB? and how does it work?

Answer 44

poly(butyl)cyanoacrylate (PBCA) coated with Tween 80 allowing surface protein binding, assisting transportation across the BBB by endocytosis

Question 45

how can nanoparticles be used to overcome the BBB?

Answer 45

by bypassing P-glycoprotein efflux system the penetrate deep into the brain tissue & accumulate more in brain tissue than within capillaries

Question 46

what increases nanoparticles transportation? and how?

Answer 46

coat polysorbate 80 increasing permeability by the surfactant slightly toxic

Question 47

what is convection enhanced drug (CED) delivery used for?

Answer 47

bypassing the BBB

Question 48

how does CED work?

Answer 48

drugs delivered through several catheters directly to/surrounding the tumour using a pump with a positive pressure and constant flow of the drug

Question 49

when is CED treatment used?

Answer 49

-chemotherapy e.g. for anti-GBM drugs that don't pass the BBB -recombinant proteins

Question 50

CED delivery treatment summary

Answer 50

intracranial catheters flow rates 0.1-10microlitre/min depends on patient gradient directly to the brain extracellular space

Question 51

what is the disadvantage of CED?

Answer 51

reflux of the drug reduces the volume of drug distribution, reducing the infusion rate can reduce the reflux

Question 52

whats the difference between injection and CED?

Answer 52

Question 53

what is implantable drug delivery?

Answer 53

bypasses the BBB used for treatment of recurring GBM

Question 54

how does implantable drug delivery work?

Answer 54

using microspheres compressed into wafers into a resected tumour site that are biodegradable providing a localised delivery of a chemotherapy agent directly into the resection cavity of the cancer

Question 55

what are the disadvantages of implantable drug delivery devices?

Answer 55

issues with wound healing severe side effects

Question 56

what are the advantages of implantable drug delivery devices?

Answer 56

used when near most of the resection is possible - treat deep-seated tumours

Question 57

what are implantable drug delivery devices made from?

Answer 57

active ingredient and polymer dissolved in dichloromethane must be biodegradable

Question 58

how are implantable drug delivery devices made?

Answer 58

spray dried method

Question 59

how long does it take for the polymer-drug matrix take to degrade?

Answer 59

6-8 weeks