BBB L3 Flashcards
What is a ‘trojan’?
disguise molecule that fools the BBB into uptake - typically using endogenous molecules such as Transferrin, Lipoproteins to target their respective receptors
What are the two factors that clearance of drugs is dependent upon from the brain?
1) Size of the drug - if larger = longer time to clear
2) if taken up/bound by cells/neurones
1) What is the cause for 80% of malignant brain tumours?
2) neurones can divide - true or false?
- gliomas e.g. glioblastoma
N.B name of tumour derived from type of cell
FALSE - neurons only cell (in humans) that cannot divide
What is the median survival of patients with glioblastoma multiform?
12-18 months - very fast progressing
Define and describe metastases
The origination of a cancer from a primary peripheral site e.g. skin, breast, lung, prostate, colon and travelled to a secondary site via the blood to the form a secondary tumour
Give an example of a metastasis from a peripheral site that exists in the brain - and describe how it does this.
Breast cancer cells can release enzymes that are capable of degrading the BBB - hence gain access and metastasise in the brain tissue
a) Name molecular targets to inhibit glioma growth and proliferation, whilst describing the purpose behind the reason to target these sites
b) Have these methods had success in treatment of brain tumours? Why?
a) 1) Target growth factor receptor - as only small amount needed to allow tumour growth. Hence, reduce growth factor slightly = significant affect on growth rate of tumour
2) Intracellular signalling pathway e.g. P53 - for apoptosis -hence if can up-regulate this = cause apoptosis - i.e. “cell suicide”
3) Block cell division/proliferation by inhibiting DNA replication e.g. with use of chemotherapeutics
b) NO - due to the difficulty of crossing the BBB
Describe the function of cDNA, siRNA, and Chemotherapeutics in treatment of brain tumours
cDNA - used to cause up-regulation and expression of P53 - inducing apoptosis of brain tumour cells
siRNA - to knockdown expression of growth factor receptors = slows tumour growth
Chemotherapeutics e.g. Vincristine, Vinblastine, Paclitaxel, Daunorubicin, Doxorubicin, Irinotecan –> all act to prevent cell division and/or disrupt DNA synthesis
Why don’t the cDNA, siRNA, and chemotherapy methods work as of yet for brain tumours?
Physical barrier:
Large hydrophilic drugs (RNA, DNA), cannot go through tight junctions, and hydrophilic drugs are not recognized by the barrier i.e. barrier is of lipid nature.
Metabolic barrier:
RNA and DNA = degraded by nucleases in endothelial cells and in plasma i.e. degraded by the metabolic enzymes that exist in the BBB but N.B: degraded nucleic acids are recycled and re-used by the endothelia.
Transport barrier:
large lipophilic drugs = substrates for BBB efflux transporters, which stop the drugs from entering the brain i.e. arrive at efflux pump – kicked out – all of chemotherapeutic agents are subject to this.
What two problems d chemotherapeutics need to overcome?
1) Efflux transporters at the BBB
2) Efflux transportes at the tumour site
i. e. even if the molecule can surpass the ‘first line of defence’ at the BBB, the tumour cell also has it’s own efflux transporters that are able to kick-out the drug
Name the three common efflux transporter families
1) BCRP (Breast Cancer Resistant Protein)
2) MRP 1,3,5
3) P-Glycoprotein
Give two examples of chemotherapeutic agents from each of the following efflux transporter families:
BCRP (Breast Cancer Resistant Protein)
MRP 1,3,5
P-Glycoprotein
BRCP - Methotrexate, Irinotecan
MRP 1,3,5 - Daunorubicin, Doxorubicin
P-Glycoprotein - Paclitaxel, Vincristine
What are the advantages of using nanoparticles for delivery of drugs?
Can encapsulate drug in order to:
a) Avoid metabolic barrier and efflux transporter barrier
b) Carry relatively large cargo to neurones
c) Carry variety of different drug types (almost all) = dependent on type of nanoparticle
d) High molecular weight drugs delivered i.e. large and complex drugs
What are the disadvantages of using nanoparticles to deliver drugs?
a) Toxicity of the nanoparticle itself
b) Accumulation of nanoparticle by liver and spleen
c) Not only target brain i.e. will enter other organs = off-target effects
d) Clinical trials needed for both the therapeutic drug and nanoparticle itself = makes trials costly and time consuming – i.e. testing nanoparticle = almost like having to test entirely separate drug.
what is the size of major types of nanoparticles?
<200 nm