Drug delivery to the brain Flashcards
what is a brain tumour?
abnormal tissue growth inside the brain - malignant or benign
which exerts pressure onto the brain causing problems
whats glioblastoma (GBM)?
aggressive stage IV brain cancer
progresses rapidly and difficult to cure
whats the treatment for glioblastoma (GBM)?
removal via surgery followed by chemotherapy (temozolomide) and radiation therapy
12-15month survival rate
why can temozolomide be given for brain cancer?
as the drug crosses the BBB
what is the limiting step for drug delivery to the brain?
the drug crossing the BBB
what is the role of the blood brain barrier?
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)
what treatment plans require drug transport across the BBB?
depression
severe pain
epilepsy
GBM
why do imaging agents require drug transport across the BBB?
accurate diagnosis of neuropathology
monitoring of disease progression
localised for surgical intervention
introduction of therapeutic agents
how is the BBB composed?
how does the structure of capillaries in general differ from capillary in the brain?
astrocytes
pericytes
tight junctions
mitochondria
why is the BBB needed?
to maintain a extremely stable internal fluid environment surrounding neurones for the CNS- protective barrier shielding the CNS from neurotoxic substances/macromolecules
what drugs characteristics allow passing of the BBB?
low MW
electrically neutral molecules
hydrophobic
how do lipid-soluble molecules pass the BBB?
passively diffuse with no energy needed
what factors restrict the entry of compounds into the CNS?
highly polar surface area (PSA) >80A^2
form <6 hydrogen bonds
presence of rotatable bonds
MW >450 Da
high affinity/binding to plasma proteins
do bases or acids penetrate the BBB more? and how?
bases (positively charged) have an advantage of acids
due to their cationic interactions with negatively charged phospholipid head group of the cell membrane
overall what are the possible ways to enhance drug influx through the BBB?
-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
how can you modify the drug to allow enhanced drug influx through the BBB?
- lipophilic drug modification
- prodrugs
- vector-mediated drug delivery
how are lipophilic drug modification used to cross the BBB?
how are prodrugs used to cross the BBB?
how can vector-mediated drugs be used to cross the BBB?
what are some natural peptides used for vector mediated drug delivery?
natural peptides
-insulin
-transferrin
how does insulin help vector mediated drugs to cross the BBB?
1.conjugating insulin with anticancer drugs e.g. methotrexate
-allows passage thru the receptor mediated endocytosis
2. insulin fragments
what can limit the suitability of insulin as a vector mediated carrier?
short serum half-life =the drug may not reach the brain in time
hypoglycaemic effect of insulin
how does transferrin help vector mediated drugs to cross the BBB?
conjugated transferrin with mutated diphtheria toxin = increase brain tumour response by reducing tumour pressure by reducing tumour volume
what can limit the suitability of transferrin as a vector mediated carrier?
saturation of the receptors
what monoclonal antibody binds to transferrin receptor?
and what does this mean?
OX26
conjugation of OX26 to fibroblasts growth factor = 80% reduction in strokes to the brain
what is one of the most invasive strategy for CNS drug delivery? and why?
Direct Brain Admission
disruption of the BBB
due to high risk of adverse effects
what are the methods used to disrupt the BBB?
- osmotic disruption
- biochemical disruption
- ultrasound
how does osmotic disruption disrupt the BBB?
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
what are some examples of hypertonic solutions used to disrupt the BBB?
mannitol, Arabinose, lactamide saline, urea etc.
mainly intracarotid injection of mannitol is used
when do we use osmotic disruption to the BBB? (an example)
antineoplastic agents to the brain
how does biochemical disruption disrupt the BBB?
based on some substances can selectively open brain tumour capillaries
(peptides, cytokines, chemokines, etc)
what are some examples used for biochemical disruption of the BBB?
vasoactive leukotrienes - decrease g-GTP = more leukotrienes
vasoactive amines
cereport - b2 receptors closed in (2-5 mins)
cereport BBB restored period
2-5 mins after infusion
how does ultrasound disrupt the BBB?
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
what are the risk factors of disruption of the BBB?
passage of plasma proteins into the brain
altered glucose uptake
the expression of heat shock proteins
micro embolism, and abnormal neuronal function
how can we provide the CNS with drugs with low hydrolytic stability?
encapsulate/solubilise the nano/micro-particle
why can’t low hydrolytic stability drugs cross the BBB into the CNS?
as they are subject to degradation by blood proteins/enzymes
how can drug carriers be targeted?
using encapsulate/solubilise the nano/micro-particle to facilitate receptor-mediated transport
what can you encapsulate drugs into, to cross the BBB?
liposomes
why are drugs encapsulated into liposomes?
prolongs the time of drug circulation in the bloodstream
reduces side effects
enhances therapeutic effects of CNS agents
how can we further increase liposomes encapsulated drugs circulation time?
PEG-coat the liposome surface
how are liposomes used to target the BBB?
attaching an immunoreactive moiety to PEG-modified liposomes
e.g. transferrin
give an example of nanoparticles that can reach the CNS by passing the BBB? and how does it work?
poly(butyl)cyanoacrylate (PBCA) coated with Tween 80
allowing surface protein binding, assisting transportation across the BBB by endocytosis
how can nanoparticles be used to overcome the BBB?
by bypassing P-glycoprotein efflux system
the penetrate deep into the brain tissue & accumulate more in brain tissue than within capillaries
what increases nanoparticles transportation? and how?
coat polysorbate 80
increasing permeability by the surfactant
slightly toxic
what is convection enhanced drug (CED) delivery used for?
bypassing the BBB
how does CED work?
drugs delivered through several catheters directly to/surrounding the tumour
using a pump with a positive pressure and constant flow of the drug
when is CED treatment used?
-chemotherapy
e.g. for anti-GBM drugs that don’t pass the BBB
-recombinant proteins
CED delivery treatment summary
intracranial catheters
flow rates 0.1-10microlitre/min
depends on patient gradient
directly to the brain extracellular space
what is the disadvantage of CED?
reflux of the drug reduces the volume of drug distribution, reducing the infusion rate can reduce the reflux
whats the difference between injection and CED?
what is implantable drug delivery?
bypasses the BBB
used for treatment of recurring GBM
how does implantable drug delivery work?
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
what are the disadvantages of implantable drug delivery devices?
issues with wound healing
severe side effects
what are the advantages of implantable drug delivery devices?
used when near most of the resection is possible
- treat deep-seated tumours
what are implantable drug delivery devices made from?
active ingredient and polymer dissolved in dichloromethane
must be biodegradable
how are implantable drug delivery devices made?
spray dried method
how long does it take for the polymer-drug matrix take to degrade?
6-8 weeks
