Drug delivery to the brain Flashcards

1
Q

what is a brain tumour?

A

abnormal tissue growth inside the brain - malignant or benign

which exerts pressure onto the brain causing problems

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2
Q

whats glioblastoma (GBM)?

A

aggressive stage IV brain cancer
progresses rapidly and difficult to cure

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3
Q

whats the treatment for glioblastoma (GBM)?

A

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

12-15month survival rate

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4
Q

why can temozolomide be given for brain cancer?

A

as the drug crosses the BBB

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5
Q

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

A

the drug crossing the BBB

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6
Q

what is the role of the blood brain barrier?

A

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)

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7
Q

what treatment plans require drug transport across the BBB?

A

depression
severe pain
epilepsy
GBM

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8
Q

why do imaging agents require drug transport across the BBB?

A

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

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9
Q

how is the BBB composed?

A
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10
Q

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

A

astrocytes
pericytes
tight junctions
mitochondria

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11
Q

why is the BBB needed?

A

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

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12
Q

what drugs characteristics allow passing of the BBB?

A

low MW
electrically neutral molecules
hydrophobic

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13
Q

how do lipid-soluble molecules pass the BBB?

A

passively diffuse with no energy needed

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14
Q

what factors restrict the entry of compounds into the CNS?

A

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

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15
Q

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

A

bases (positively charged) have an advantage of acids

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

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16
Q

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

A

-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

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17
Q

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

A
  1. lipophilic drug modification
  2. prodrugs
  3. vector-mediated drug delivery
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18
Q

how are lipophilic drug modification used to cross the BBB?

A
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19
Q

how are prodrugs used to cross the BBB?

A
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20
Q

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

A
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21
Q

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

A

natural peptides
-insulin
-transferrin

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22
Q

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

A

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

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23
Q

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

A

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

hypoglycaemic effect of insulin

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24
Q

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

A

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

25
Q

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

A

saturation of the receptors

26
Q

what monoclonal antibody binds to transferrin receptor?

and what does this mean?

A

OX26

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

27
Q

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

A

Direct Brain Admission

disruption of the BBB

due to high risk of adverse effects

28
Q

what are the methods used to disrupt the BBB?

A
  1. osmotic disruption
  2. biochemical disruption
  3. ultrasound
29
Q

how does osmotic disruption disrupt the BBB?

A

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

30
Q

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

A

mannitol, Arabinose, lactamide saline, urea etc.

mainly intracarotid injection of mannitol is used

31
Q

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

A

antineoplastic agents to the brain

32
Q

how does biochemical disruption disrupt the BBB?

A

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

33
Q

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

A

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

34
Q

cereport BBB restored period

A

2-5 mins after infusion

35
Q

how does ultrasound disrupt the BBB?

A

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

36
Q

what are the risk factors of disruption of the BBB?

A

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

37
Q

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

A

encapsulate/solubilise the nano/micro-particle

38
Q

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

A

as they are subject to degradation by blood proteins/enzymes

39
Q

how can drug carriers be targeted?

A

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

40
Q

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

A

liposomes

41
Q

why are drugs encapsulated into liposomes?

A

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

42
Q

how can we further increase liposomes encapsulated drugs circulation time?

A

PEG-coat the liposome surface

43
Q

how are liposomes used to target the BBB?

A

attaching an immunoreactive moiety to PEG-modified liposomes

e.g. transferrin

44
Q

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

A

poly(butyl)cyanoacrylate (PBCA) coated with Tween 80

allowing surface protein binding, assisting transportation across the BBB by endocytosis

45
Q

how can nanoparticles be used to overcome the BBB?

A

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

46
Q

what increases nanoparticles transportation? and how?

A

coat polysorbate 80

increasing permeability by the surfactant
slightly toxic

47
Q

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

A

bypassing the BBB

48
Q

how does CED work?

A

drugs delivered through several catheters directly to/surrounding the tumour

using a pump with a positive pressure and constant flow of the drug

49
Q

when is CED treatment used?

A

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

50
Q

CED delivery treatment summary

A

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

51
Q

what is the disadvantage of CED?

A

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

52
Q

whats the difference between injection and CED?

A
53
Q

what is implantable drug delivery?

A

bypasses the BBB

used for treatment of recurring GBM

54
Q

how does implantable drug delivery work?

A

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

55
Q

what are the disadvantages of implantable drug delivery devices?

A

issues with wound healing
severe side effects

56
Q

what are the advantages of implantable drug delivery devices?

A

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

57
Q

what are implantable drug delivery devices made from?

A

active ingredient and polymer dissolved in dichloromethane

must be biodegradable

58
Q

how are implantable drug delivery devices made?

A

spray dried method

59
Q

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

A

6-8 weeks