Targeted drug delivery to the brain

The central nervous (CNS)

• The CNS consists of the brain and the spinal cord and its main role is to coordinate/control body functions through a network of nerves

• The CNS is protected by a specialized structure known as the Blood Bran Barrier. The barrier tightly separates the CNS from the circulating blood. The aim is to:

  • Protect the brain from any harmful substance in the circulation ( microbes or toxins).

  • Shield the CNS and the body from the effect of chemokines.

  • Control the CNS environment and maintain homeostasis.

CNS

• This efficient barrier function belongs to the anatomy. It consists of a basement membrane lined by endothelial cells with tight junction to control the movement of substance.

• Endothelial cells with tight junction at the bottom, then the basement membrane and then astrocyte endfoot

CNS drugs

• This unique anatomy and control of molecule transport into the brain created a challenge for CNs drug delivery

• Different classes of pharmaceutical molecules target the CNS to achieve therapeutic response, these include:

  • Analgesics ( NSAID or Narcotics)

  • Anticonvulsants

  • Antiparkinsonian agents

  • Antiemetics

  • Anyxolyic, sedatives and hypnotics

  • CNS stimulants

  • General Anaesthetics

  • Antidepressant

  • Antibiotics

• Targeted drug delivery to the /CNS is not an easy task this is mainly due to the presence of the BBB which protects the CNS by providing shielding effect from harmful molecules.

How does molecules move into the brain?

• Two classes= either hydrophobic or hydrophilic

• Hydrophilic Molecules

  • Carrier mediated for small molecules (amino acids, glucose)

    • Transporters (e.g. L-Dopa, Baclofen and Valproate)

  • Receptor-mediated transcytosis for large molecules such as hormones

    • Endocytosis (e.g. donepezil and Taxol)

• Lipophilic Molecules crosses by Transcellular diffusion (e.g. benzodiazepines and barbiturates)

  • Passive diffusion (high volume of distribution and lower selectivity). Any lipophilic molecule can pass through into the CNS. It is non-specific. High volume of distribution for lipophilic molecules leading to a lower concentration into the CNS and getting to everywhere in the body. Can require an increase in dose of medication which could lead to side effects.

  • P-gp= Permeability glycoprotein. Recognises lipophilic molecules and collects them to kick them out. Prevents them getting into BBB

Medicinal drug properties for successful CNS delivery

• The essential physical properties for a good absorption and permeability Include:

• Lipophilicity

  • This is measured by Oil/water distribution coefficient or LogP.

    • If you mix water with oil in a 1:1 ratio there are two layers. Mix in potential drug molecule. Measure concentration of drug in each layer and get percentage of distribution in each layer.

    • If majority of molecule in oil layer so there is a high oil partition compared to the water layer then the drug is likely to be able to be delivered by passive diffusion

  • Optimal CNS drug permeation to the brain via passive diffusion when log P is between 1.5-2.7

    • However if molecule is lipophilic but doesn’t meet other specifications it won’t pass into the CNS

• Molecular weight

  • Due to the anatomical barrier (BBB), the CNS drug molecules should be lower than others (400-500 Da). Smaller lipophilic molecules can move by passive diffusion into BBB if they fill all criteria

• Hydrogen bonding

  • This should be kept below 5 for good CNS permeation

  • Increasing the number of H+ decreases drug penetration to the CNS

Medicinal Drug Properties for Successful CNS Delivery - Continued

• Polar surface area

  • CNS drug molecules are expected to have low PSA values ( 60-70Å)

• Charge

  • Better CNS drug penetration was evident with positively charged molecules at physiological pH(7-8).

  • Can adsorb into surface and pass by adsorption endocytosis

• Pharmacokinetic properties

  • Metabolism, permeability, protein binding etc can also affect CNS drug permeation

Factors affecting CNS Drug delivery: Physiochemical properties

• Lipophilicity

• Molecular charge

• Molecular weight

• Chemical structure

• Chemical conformation

• Polymorph= arrangement of molecules in lattice which can have effect on properties of molecules

Factors affecting CNS Drug delivery: Bio pharm. & phk. factors

• Systemic absorption

• Membrane transport

• Receptor/carriers affinity

• Distribution

• Metabolism

• Clearance rate

Factors affecting CNS Drug delivery: Dosage form factors

• Formulation & additives

• Concentration gradient

• Particle size

• Dissolution rate

Factors affecting CNS Drug delivery: Biological factors

• Physiological factors

• Cerebral blood flow

• Pathological status e.g. can change permeability of BBB

Strategies for CNS drug delivery

• Invasive Techniques

• Pharmacological Approaches

• Physiological Methods

• Miscellaneous

Invasive techniques: Intra-cerebro-ventricular (ICV) infusion

• This method can be used for glycopeptide antibiotics (Vancomycin) or aminoglycoside antibiotics (gentamicin).

  • For large molecules that can’t get into the BBB by any other route

  • Diffusion of drug through a pump intrathecally into the CSF fluid

  • Or can be injected into a pre implanted reservoir which connects to ventricles 

• Intra-cerebral injection of implants (biodegradable carrier plus pharmaceutical molecules).

  • Direct injection into ventricles using a needle. Requires a special formulation with a biodegradable carrier loaded with the pharmaceutical molecule which allows slow release

• Can be used for meningitis to get large concentration of antibiotic into brain

Invasive techniques: Convection enhanced delivery

• Inserting a small diameter catheter into the tumour

• Anti-cancer drug injected through catheter

Invasive techniques: Disruption of the BBB

• Causing osmotic disruption which shrinks the endothelial cells and disrupting the tight junctions to allow molecules to pass through

• The disruption can be also the outcome during inflammation, hypertension and hypoxia

• The shortcomings for the invasive procedures include:

  • The techniques are not cost effective and include anaesthesia and hospitalization.

  • It may lead to the spread of tumour cells

  • Another outcome could be a permeant damaged in the brain tissue

• First picture shows tight junctions not allowing anything to pass, second picture shows tight junctions opening

Pharmacological approaches: Chemical drug delivery

• Involves increasing the drug lipophilicity by forming a prodrug to enhance CNS penetration.

• Once the prodrug is inside the brain, it will be cleaved enzymatically yielding a less lipophilic / active drug molecules which will be trapped in the brain.

• E.g. Ganciclovir, Benzylpenicillin and Zidovudine, Levodopa, GABA and Morphine

• Figure on left:

  • Drug on its own cannot pass as it does not fulfil any criteria.

  • So it is attached to a promoiety to make it more lipophilic. It becomes a prodrug and crosses the BBB. 

  • Once it has crossed it goes through enzymatic transformation and the active drug is released

• Figure on right: Drug is attached to NADH, making it inactive

  • In circulation it will go to brain and metabolised at the same time

  • If it goes to the liver it will go through metabolism, cleaving the NADH moiety, leaving the active molecule which is excreted via kidney

Physiological Methods (Nanoparticles and Liposomes)

• Nanoparticles is another approach for targeted CNS delivery this involve

  • Adjusting the particle size (1-100nm) and drug - polymer ratio

  • Coating with surfactant, cell penetrating peptides or antibodies can enhance CNS penetration

Physiological Methods (Nanoparticles and Liposomes)

Liposomes are lipid vesicles have an aqueous core encircled by a lipid bilayer used for CNS drug delivery via passive diffusion (Taxol, Amphotericin B and Rivastigmine).

Targeted CNS delivery can be achieved by exploitation of endogenous pathway via binding with specific receptors (insulin or lipoprotein and transferrin receptors) which will facilitate drug delivery via endo/transcytosis

Brand Name	Active Pharmaceutical Ingredient (API)	Application
AMBISOME (Liposome)	Amphotericin B	Antifungal
CASELYX (Liposome)	Doxorubicin	Brain Tumour
ARICEPT (Liposome)	Donepezil	Alzheimer’s Disease
AUROSHELL ( Nanoparticles)	Gold coated silica NPs	Solid Tumours

Miscellaneous approaches: Intranasal drug delivery

• Intranasal drug delivery, the nasal mucosa offer direct delivery of the drug molecules to the CNS

• This is a non invasive method which allows the drug to enter the CNS through or along the olfactory /trigeminal neural pathways.

• Requires high solubility to deliver 20-30ul

• pH and isotonicity are essential for successful drug delivery

• Improper administration can send the drug to the lung or stomach

Miscellaneous approaches: Image-guided focused ultrasound

• Injection of drug loaded microbubbles followed by exposure to ultrasound radiation to achieve temporarily disruption of the BBB and hence enhancing drug delivery to the brain