BBB Drug Delivery Flashcards
___ % of small molecules and ____% of biologics do NOT enter the BBB
98%; 100% (biologics = large molecule pharmaceuticals–hormones, peptides, monoclonal antibodies)
2 key props of drugs that pass the BBB
1) passive permeability
2) LOW affinity to P-gp
P-gp role in Drug permeability
P-gp dramatically affects drug distribution and is a key determining of drug resistance to chemotherapeutic, anti-epileptics, morphine etc.
Strategies to overcome the BBB: 2 categories
1) bypassing or disruption of BBB (i.e. change BBB)
2) Drug modification and delivery systems to allow passage THROUGH BBB (i.e. change drug)
Methods that change the BBB (disrupt/bypass)
intrathecal and intracerebroventricular delivery
focused ultrasound disruption
intranasal drug delivery
Methods that change the drug to pass the BBB
production of lipophillic drugs (lipidization);
inhibition of P-gp;
use of pre-existing BBB transport systems to deliver hydrophilic compounds to the brain (molecular trojan horse);
nanoparticles
Intrathecal drug delivery
a catheter placed in lumbar/low thoraic spinal cord with a pump under the skin
chronically pump drugs into sub-arachnoid space
Intrathecal drug delivery–downsides
diffusion through this route is affected greatly by the nature of the drug and by the infusion rate
some stay local, some travel to the brain;
diffusion into the brain can be very limited
Common intrathecal drugs
for pain, spasticity or dystonia
morphine (opioid aginist)
ziconotide (N-type Calcium channel blocker)
baclofen (GABA-B agonist)
Target of intrathecal drugs
primarily the dorsal horn of the SC
Intraventicular drug delivery–what is it
infusion of drug into later ventricles to be distributed in the CSF
Example of intraventricularly delivered drug
infusion of recombinant lysosomal enzymes for the treatment of Batten disease (lysosomeal storage disease) in pediatrics (children with battens have cognitive and motor impairment and early fatality–this treatment increases lifespan)
Intraventicular drug delivery downsides
Complications can be very serious; only use it for very serious issues
Focus Ultrasound (FUS) for drug delivery: method
drug and bubbles (inert gas) injected into blood stream; bubbles vibrate at same frequency as US –> breaks tight junctions allowing drugs into system
FUS drug can be carried…
- in the bubbles
- on the surface of the bubbles
- or along with the bubbles
Low frequency FUS
expand and contract of TJs –> loosening TJs
High frequency FUS
bubbles burst –> disrupts BBB and releases cotransported drugs –> drugs can enter BBB
Uses fo FUS (focused ultrasound)
Experimental use–brian tumors, delivery of bilogics un neurodegenerative conditions
FUS: Downsides
Concerns about whether long-term ad repeated BBB disruption may cause more issues than FUS drug delivery solves (benefit to detriment ratio)
Intranasal Drug delivery: 2 pathways
olfactory nerve/pathway
trigeminal nerve/pathway
Intranasal drug delivery: mechanism
drugs that cross the nasal mucosa are transported into 1) perineural olfactory –> olfactory bulb OR 2) in the trigeminal space –> the pons
from there the drugs are transported with CSF flow
Intranasal drug delivery: movement through perivascular space
approx. 5% of drug is transported through the perivascular space; rhythmic contraction of adjacent blood vessels contribute to movement/distribution of the drug
Intranasal: advantages
- provides a direct route to the brain circumventing the BBB
- bypasses GI and hepatic first pass metabolism
- decreases system exposure (and possible related side effects)
Intranasal: limitation
nasal bioavailability is poor for hydrophilic and large molecules or biologics–similar to factors that decrease BBB permeability
drug diffusion is limited to the ependymal surface of the brain (i.e. drugs don’t travel far)
Reasons for limited Intranasal bioavailability
Rapid clearnace by nasal epithelim/mucus and tight junctions b/t epithelial cells that limit paracellular trasnsports
Intranasal: permeability enhancers
Increase drug nasal residence time and improve passage through nasal mucosa–liposomes, gel formulations, nanoparticles
Permeability enhancers, enzyme inhibitors and mucoadhesive substances
Drugs administered intranasally
- IN naloxone –pre-hospital intervention for opioid OD
- IN benzos–tested for acute treatment of seziures for its rapid action and convenient admin
- IN insulin–imporves memory, anxiety, mood in those with mild-cognitive impairment and AD (w/o peripheral effects on blood sugar)
Focused ultrasounds Intranasal delivery (FUSIN)
IN therapies adn focused US + microbubbles
bubbles expand and contract due to US frequency to increase permeability of blood vessels at focused target/location
result: drugs taken up via IN will have increased permeability at their tissue of interest
Chemical modifications of small molecules: why
BBB permeability is inversily proportional to molecular weight of the compound and the number of H bonds that it forms with water (polar surface area)
increased permeability with decreased polar surface area (make chemical changes to decrease polar SA)
For each pair of H-bonds permeability of a drug decreases ___-fold
10
increases free energy requirement for passing from aqueous phase (blood) to lipid enviro (cell memb)
To pass through the BBB need a MW under ___ and less than ___ H-bonds
MW <400 DA
H-bonds <8
Strategies to improve BBB permeability include
- modification of groups that form H-bonds
- lipidation of molecules (this is also increase uptake at other organs and binding to plasma proteins)
Downside of lipidation
-Increases drug uptake at other organs–decreasing overall plasma concentration of the drug
-may increase removal by P-gp
-may attach to plasma proteins (ex. albumin)
due to theses reasons it isn’t often successful
Potential strategies to inhibit drug efflux by P-gps: 3 methods
- modified small molecule (P-gp nonsubstrate)
- coadministration with competitor P-gp substrate
- coadminstration with non-competitive inhibitor
Inhibiting P-gp efflux: modified small molecule (P-gp nonsubstrate)
make the drug less recognizable to P-gp
but that can change drug specificity, etc.
Inhibiting P-gp efflux: coadministration with competitor P-gp substrate
Often inhibit BBB too well –> dangerous (other molecules can also enter the brain)
Inhibiting P-gp efflux: coadminstration with non-competitive inhibitor
Often still get efflux due to redundancy –> P-gp-like transporters may be upregulated when P-gp is blocked
First gen: P-glycoprotein inhibitors
Cyclosporin A; Verapamil
competitive inhibitors with unacceptable toxicity due to low affinity for P-gp, needed high conc)
2nd gen: P-glycoprotein inhibitors
Valspodar (cyclosporin A analogue)
- Better tolerability than 1st gen but unpredicatble pharmacokinetic and interactions with other transporters
- toxicity due to inhibition of cytochrome P450
3rd gen: P-glycoprotein inhibitors
Tariquidar, laniquidar, zosuquidar (anthranilamide derivatives–chosen thru rational drug design)
non-competitive inhibitors with higher potency and specificity for P-gp. Lower affinity for C450 enzymes
BUT tariquidar + 3 anticancer drugs phase 3 clinical trial cancelled due to unexpected toxicity
Molecular Trojan Horses: mechanism
brain transport vectors (that include endogenous peptides, modified proteins and monoclonal antibodies) that target specific receptor/transport systems in the brain capillary endothelium and undergo receptor-mediated transcytosis through the BBB–molecules attach to the trojan horse and are co-transported into the brain
Molecular trojan horses-possible vectors
endogenous peptides, modified proteins, and monoclonal antibodies
the drug will attach to one of these for transport into the brain
note: you can transport antibodies on antibodies as well
Example of Molecular trojan horse in AD
Anti-A-beta antibody that binds with high affinity to plaques attaches to Fab fragment of the anti-TfR antibody
When attached to fab, it can be endocytosied and transferred across BBB –> antibody can enter brain and then target A-beta plaques
Cell-penetrating peptides (CPPs)
short ampipathic and/or cationic sequences with an adsorptive-mediated mechanism–i.e. can attach to negatively charged space of endothelium
Used as molecule trojan horses
Cell-penetrating peptides (CPPs) : downsides
CPPs lack speciificity and therefore can accumulate within the endothelial cells (and be taken up in other tissues)
EPiC technoology
Engineered peptide-compounds technology
A synthetic peptide, angiopep2, that is able to bind LRP-1, is conjugated to drugs for delivery into brain by LRP-1 (molecular trojan horse)
Note: LRP-1 = low-density lipoprotein receptor-relaed protein 1
EPiC technology: why LRP-1
LRP-1 is one of the most abundant receptors expressed in the BBB and has a very fast recycling rate
Makes LRP-1 the ideal receptor (hard to saturate, high brain distribution)
EPiC technology Example: ANG1005
novel taxane derivative of angiopep2 conjugated with 3 molecules of paclitaxol (chemotherapy drug)
Positive results in phase 3 trials
Why ANG1005
LRP-1 receptor is also highly expressed in brain tumours –> passes BBB and taken up in higher conc in tumour (due to large number of LRP-1 receptors there)
Liposomes
one or more lipid bilayer of amphiphilic lipids delimiting an internal aqueous compartment loaded with drugs
Liposomes bypass P-gp
Cationic liposomes
contain positively charged lipids and undergo absorptive-mediated endocyotsisi and internalization in endosomes
Polymeric nanoparticles
- solid colloidal particle composed of biodegradable polymers
- drugs can be sequestered on their surface or within them
- Liposomes bypass P-gp
Common polymers for Polymeric nanoparticles
polylactic acid (PLA)
Polyglycolides (PGA)
Polylactide-co-glycolides (PLGA)
Liposomes and nanoparticles bypass the ____
p-glycoprotein–b/c too big for P-gp binding site
Advantages of nanoparticles over liposomes
- smaller number of excipients are used for their production
- simpler manufacturing process
- higher physical stability and longer plasma half-life
- more efficient sustained drug release
- can be multifunctionalized more easily to improved delivery and target engagement
How can you multifunctionalize nanoparticles and liposomes and why
- by attaching targeting peptides, cationic molecules, or targeting antibodies
- for improved delivery and target engagement
