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