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Lab 3 > Drug delivery to brain > Flashcards

Drug delivery to brain Flashcards

1
Q

What is a brain tumour?

A

Any abnormal tissue growth inside the brain; whether malignant (cancerous) or benign

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2
Q

How do brain tumours cause problems?

A

by the pressure they exert on the normal brain

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3
Q

What is a glioblastoma?

A

An aggressive (stage IV), cancerous brain tumour that progresses rapidly and is difficult to cure

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4
Q

What does treatment of glioblastoma involve?

A

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

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5
Q

How much distance of original resection is required for glioblastoma tumours to recur?

A

within 3cm of original resection

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6
Q

What is the average survival rate with a glioblastoma?

A

12 to 15 month survival rate

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7
Q

What is the survival rate after 5 years of a glioblastoma?

A

<3% :(

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8
Q

What is the limiting step in the development of new treatments for diseases of the CNS?

A

drug delivery to the brain: the presence of the BBB which restricts drug delivery to CNS

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9
Q

What does the BBB do?

A

maintains brain function:
- Allows selective access to essential nutrients and signalling mols from vascular compartment
- Restricts entry of foreign bodies i.e. drugs

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10
Q

What are examples of disorders that require drug transport across the BBB?

A

depression, severe pain, epilepsy, GBM

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11
Q

Efficient delivery of imaging agents across the BBB is necessary for what purposes? 4

A
  • Accurate diagnosis of neuropathology
  • Monitoring disease progression
  • Localization for surgical intervention,
  • Introduction of therapeutic agents
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12
Q

why can you not just treat glioblastoma by pulling it out?

A

not just a solid tumour, also has fingers going into important functional brain tissue

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13
Q

What structures form the blood brain barrier?

A
  • capillaries: tight junctions between endothelial cells
  • fenestrations: openings to allow drugs in and out
  • tight junctions: physical barrier to drugs
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14
Q

in brain capillary, fenestrations are much tighter, why?

A

Blood comes in, pumped around, dynamic. Then want it to pass through and get to brain tissue (which will be all around this vessel).

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15
Q

Why does the CNS need a BBB?

A
  • CNS must maintain an extremely stable internal fluid environment surrounding the neurons
  • maintains reliable synaptic communication between nerve cells
  • protective barrier shielding CNS from neurotoxic substances in blood
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16
Q

What macromolecule does the BBB also prevent from entering the brain?

A

proteins: content of CSF when compared to plasma is very low and markedly different from that of plasma

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17
Q

BBB is very selective
What molecules can cross the BBB passively?

A
  • low MW
  • neutral
  • hydrophobic

(wide range of lipid soluble mols too)

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18
Q

What characteristics of a drug RESTRICT its entry into the CNS?

A

high PSA >80 A2
>6 HBDs
a number of rotatable bonds in molecule
MW >450 Da
high affinity to plasma proteins w low off-rate

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19
Q

Why does having >6 HBDs restrict entry into CNS?

A

increases the free energy requirements of moving from aqueous phase -> lipid of cell membrane

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20
Q

Which better penetrate the BBB: bases or acids? Why?

A
  • bases
  • positive charge means they can interact w negatively charged phospholipid head groups of the cell membrane
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21
Q

What are the 4 possible approaches for enhancing drug influx across the BBB?

A

Modification of the drug’s chemical structure

Disruption of the BBB

Drug solubilisation/encapsulation in nano or microparticles

Bypass the BBB

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22
Q

What are 2 strategies that bypass the BBB?

A

Convection Enhanced Delivery

Implantable drug delivery devices

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23
Q

What 3 techniques comprise the drug modification approach to overcome the BBB?

A
  • lipophilic drug modification
  • prodrugs
  • vector-mediated drug delivery
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24
Q

What does lipophilicity correlate with?

A

CNS permeability

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25
Q

What is lipophilic drug modification?

A

modify drug w lipophilic moiety

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26
Q

What is the best application for lipophilic drug modification?

A
  • proteins modified w fatty acid residues
  • point modification w 1-2 fatty acid residues per protein molecule
  • remains water soluble but also acquires lipophilic anchors that can target cell surfaces
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27
Q

What is: Pharmacologically active compounds that are chemically modified to be inactive until they are activated inside the target tissue by a single activating step?

A

prodrugs

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27
Q

What is: Pharmacologically active compounds that are chemically modified to be inactive until they are activated inside the target tissue by a single activating step?

A

prodrugs

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28
Q

What 3 deficient properties of a CNS drug could prodrugs intend to improve?

A

Membrane permeability

Stability

Water solubility

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29
Q

How do prodrugs for overcoming the BBB work?

A
  • Water-soluble drugs attached to lipid-soluble carriers by cleavable bonds carried across BBB, released into brain
  • released + processed prodrug then ‘trapped’ as it cannot exist BBB
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30
Q

How do we chemically modify drugs to make a CNS prodrug?

A

Esterification/ amidation of hydroxy-, amino-, and carboxylic acid containing drugs enhances lipid solubility thus transport to brain

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31
Q

simple example:
How was morphine formulated into a prodrug to improve its brain uptake?

A
  • OH replaced w methyl increasing lipid solubility
  • add another acidic group to molecule to increase brain uptake
  • heroin (morphine prodrug) rapidly metabolised to 6-acetyl-morphine then to morphine, which interacts with opioid receptor
  • morphine due to being more polar is ‘trapped’ as it cannot diffuse back across BBB
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32
Q

What is vector-mediated drug delivery?

A

Link a non-transportable drug with a vector to the BBB which act as molecular Trojan horses

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33
Q

What types of molecules is vector-mediated drug delivery used for?

A

proteins, DNA, small molecules, micro- and nanocarriers

Will stay in and slowly release drug over time
–The choice of a vector moiety and type of linker is crucial for success

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34
Q

What natural molecules can effectively pass the BBB and are hence used in vector-mediated drug delivery?

A

natural peptides:

  • insulin
  • transferrin
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35
Q

What are examples of insulin being used in vector-mediated drug delivery? What is its limitations?

A
  • Conjugation of insulin with the anticancer drug, methotrexate, resulted in receptor mediated endocytosis of the conjugate to brain tumour cells
  • insulin fragments also used for delivery of peptides but short half-life + hypoglycemic effect limits its suitability

no major sucess yet

36
Q

What is are examples of transferrin being used in vector-mediated drug delivery? What is its limitation?

A
  • conjugation to mutated diphtheria toxin resulted in increase in brain tumour response by reduction in tumour volume
  • however limited use as receptors are saturated under physiologic conditions
37
Q

What strategy is designed to overcome transferrin’s limitation? Give an example.

A
  • antibody for transferrin’s receptors
  • mab OX26 binds to receptor’s extracellular domain shown to pass BBB
  • single IV injection conjugated to fibroblast GF produced 80% reduction in stroke volume in brain of rats with a significant improvement of neurological deficit
38
Q

What is the most invasive approach to overcoming the BBB?

A

disruption of BBB

39
Q

What is disruption of the BBB used in conjunction w?

A

systemic administration, there it’s an adjunct and efficacious as one

40
Q

What is the nature of the side-effect profile of disrupting the BBB? What is the consequence of its use?

A
  • Associated with a high risk of adverse effects
  • Only used in extreme cases of rapidly growing high grade gliomas
41
Q

What are the 3 techniques that comprise the disruption of the BBB approach?

A
  • Osmotic disruption
  • Biochemical disruption
  • Ultrasound (main)
42
Q

How does osmotic disruption work?

A
  • Open BBB tight junctions using hypertonic solutions of mannitol, arabinose, lactamide, saline, urea etc
  • Initiates endothelial cell shrinkage and opening of BBB tight junctions for a period of a few hours allowing drug entry
43
Q

How is osmotic disruption done in clinical trials?

A

intracarotid injection of mannitol (into carotid artery)

44
Q

By how much did the median survival of patients with primary CNS lymphoma improve w the use of osmotic disruption?

A

increased from 17.8 to 44.5 months

45
Q

What is the additional benefit that was observed w osmotic disruption?

A
  • 25% increase in the permeability of the tumour microvasculature
  • Compared to a 10-fold increase in the permeability of normal brain endothelium
46
Q

What observation is biochemical disruption based on?

A

some substances can selectively open only brain tumour capillaries leaving normal brain capillaries unaffected

47
Q

What substances are used in biochemical disruption? 3

A

Vasoactive leukotrienes

Vasoactive amines

Cereport

48
Q

What is Cereport?

A

a nonpeptide known as RMP-7, bradykinin B2 agonist

49
Q

What was the effect of leukotrienes in biochemical disruption shown to be related to?

A

abundance of g-glutamyl transpeptidase (g-GTP) in normal capillaries and its decreased amount in tumours

50
Q

What is the result of biochemical disruption?

A

-> reduction of enzymatic barrier in tumour endothelial cells, and in elevated effect of leukotrienes

51
Q

What is the effect of Cereport mediated specifically through?

A

bradykinin B2 receptors (as it’s an agonist)

52
Q

How fast is biochemical disruption and how quickly does it reverse?

A
  • drug effects occur rapidly within mins of infusion initiation
  • barrier restores 2-5 upon termination
53
Q

How does using ultrasound to disrupt the BBB work?

A

Sonication of brain, applied in presence of ultrasound contrast agent injected IV

increases num of:
- vesicles,
- vacuoles fenestration,
- channel formation,
- reversible openings of the BBB tight junctions

54
Q

Which area of the tumour is important to deliver drug to and why?

A

area of the brain immediately around the tumour boundary = where tumour cells infiltrate, often escaping detection, surgery, and therapeutic levels of antineoplastic agents

Have to debulk first to remove pressure

55
Q

What are the risk factors associated w disruption of the BBB?

A
  • Passage of plasma proteins into the brain
  • Altered glucose uptake
  • The expression of heat shock proteins
  • Microembolism, and abnormal neuronal function
56
Q

Disruption of the BBB often used as an adjunct therapy to ?

A

pharmacological treatments of CNS disorders is efficacious

57
Q

Lecture 2…….

Strategies to overcome the BBB include?

A

Drug solubilisation/encapsulation in nano or microparticles

58
Q

why do CNS drugs need a protective durg carrier?

A

due to their low hydrolytic activity (hide in carrier)
Subject to degradation by blood proteins or enzymes encountered in the BBB

59
Q

Drug carriers can be targeted using brain-specific vector moieties, what type of transport will take place?

A

receptor-mediated

60
Q

single unit of given drug carrier can incorporate many drug molecules, resulting in high payloads per single targeting moiety
2 benefits of this?

A

o Improved efficacy
o Low number of receptors required

61
Q

what 2 carriers can you encapsulate drugs into, to cross the BBB?

A

liposomes
nanoparticles (similar)

62
Q

why are drugs encapsulated into liposomes? 3

A
  • Prolongs time of drug circulation in bloodstream
  • Reduces adverse effects
  • Enhances therapeutic effects of CNS agents
63
Q

why are conventional liposomes not good for drug delivery to brain?

A

theyre cleared rapidly form circulation by reticuloendothelial system

64
Q

what type of liposomes remain in circ with half life as long as 50h in humans and are therefore suitable for drug delivery to brain 😊?

A

PEG coated long circulating liposomes

65
Q

how can we further increase liposomes encapsulated drugs circulation time?

A

Want to avoid immune system taking it out or through general PK

Adding immunoreactive moieties to PEG-modified liposomes can target them to the BBB. Maybe hang around longer

Efficient delivery of PEG-liposomes conjugated with transferrin to the cerebral endothelium was achieved in rats

66
Q

what molecules used for CNS DD usually have a cross linked core and do not disassemble upon dilution in bloodstream

A

NPs

67
Q

For efficient transcytosis across BBB, nanoparticles must be …

A

less than 100-200nm in size.
But if go smaller, have to put more NPs in, risk of tox?

68
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) nanoparticles coated with Tween 80 have successfully delivered a wide range of drugs to the CNS
–Tween 80 promotes binding of apolipoprotein E to the surface of the particle, which assists transportation across the BBB by endocytosis

69
Q

how can nanoparticles be used to overcome the BBB? MoA

A

Bypassing of the P-glycoprotein efflux system is suggested as a mechanism for enhanced transport of CNS drugs incorporated into the nanoparticles

70
Q

Nanoparticles - where do they accumulate to more, and where to less?

A

penetrate deeper into brain tissue
–Accumulate more + localised to brain tissue
–less in capillary endothelial cells of BBB

71
Q

what increases nanoparticles transportation? and how? (surfactant)

A

coated with polysorbate 80 -> elevated transport across BBB due to
–Increased permeability induced by surfactant
–Possibility of toxic effect

72
Q

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

A

to bypass the BBB and increase transport of therapeutics in and around brain tumors

73
Q

in CED, how is the drug delivered?

A

through one to several catheters placed stereotactically directly within the tumour mass / around tumour or the resection cavity

A pump provides positive pressure and constant flow of the drug

74
Q

what type of drugs in CED used to administer?

A

Most anti-glioblastoma multiforme (GBM) drugs effective in vitro do not cross the BBB.

anti-GBM drugs directly to tumour thus circumvents problem with BBB penetration

75
Q

CED uses fine intracranial catheters with flow rates of…

A

0.1-10ul/min
− Depends on development of pressure-gradient.

  • Infusate distributes directly into the brain extracellular space
    − Tendency to follow anatomical boundaries.
    − Catheter tip position v important!
76
Q

how does CED differ to injection in terms of time in therapeutic window??

A

CED in there longer

77
Q

whats the difference between injection and CED?

A

CED: homogenous, distributes over large vols regardless of size of therapeutic, and possible to control tissue conc of therapeutic

Injection: heterogenous, over small vols, dependant on size and source conc of therapeutic agent

78
Q

Drugs of various types can be delivered using CED, such as?

A

–Chemotherapeutics
–Recombinant proteins

Catheters with one opening at their tips have primarily been used with CED

79
Q

problem with CED?

A

-Problems with homogenous and reproducible distribution of the drugs
–Prone to reflux of the infusates

80
Q

what limits the distribution vol even if infuion vol increased, in CED?

A

Reflux
–>Potential for toxic SE due to possible ventricular/ subacrachnoid space leakage at rates above 3 μl/min
Reducing infusion rate may reduce chance of reflux
better to deliver drugs at varying flow rates: >/= 5 μl/min to maximize tissue vol for drug delivery

Reflux-Preventing Catheters currently being investigated

81
Q

Infusates been formulated as monodispersed NPs in solutions of 3% sucrose or 3–6% polyethene glycol
Liposomes and their contents been successfully delivered through X
formulation of infusates is an important parameter to consider in X

for which technique?

A

CED

82
Q

what is implantable drug delivery used for?

A

Provide localised delivery of a chemotherapeutic agent directly into the resection cavity and the site of the cancer

83
Q

main problem with implantable DDD such as the Gliadel wafer for recurring GBM?

A

Associated with severe side effects
–Risk Vs Beneft?
Issues with wound healing
–Infection
Suitable for patients where a near gross total resection is possible
–Difficult to treat deep-seated tumours

84
Q

what is the gliadel wafer (implantable DDD)?

A

200mg disc-shaped, biodegradable wafer containing 3.85% w/w of chemo agent Carmustine

API + polymer dissolved in dichloromethane
Spray dried into microspheres varying in size from 1- 20μm
microspheres then compressed into wafers.

85
Q

how does implantable drug delivery work?

A

Following the surgical resection of a primary brain tumour, up to 8 wafers implanted in resection cavity
Carmustine is released form them over a five-day period
The polymer matrix degrades over a period of 6-8 weeks

86
Q

what are the advantages of implantable drug delivery devices?

A

provide localised drug dleivery

87
Q

name the implantable DDD:

Small biodegradable rods 2mm diameter, 6mm long
–Implanted into resection margin
–Provide site specific controlled release of
chemotherapeutic drugs
–Directly into the tumour over a sustained
period of time
–Reduced systemic toxicity

A

ChemoSeed

Lab 3 (21 decks)

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