Brain Targeted Drug Delivery System Prepared by : Surbhi M.Pharmacy II sem Submitted to : Dr. Anupama Diwan MAGIC BULLET : CONCEPT OF PAUL EHRLICH Brain Targeting: Challenges Blood brain barrier (BBB): Brain is tightly segregated from  the circulating blood by a unique membranous  barrier. The brain and spinal cord are lined with a layer of special endothelial cells that lack fenestrations and are sealed with tight junctions that greatly restrict passage of substances from the  bloodstream. These endothelial cells, together with perivascular elements such as  astrocytes and pericytes, constitute the BBB.  Rate-limiting factor in determining permeation. The factors affecting particular substance to cross BBB Drug related factors at the BBB Concentration at the BBB and the size, Flexibility, Conformation, Ionization (nonionized form penetrates BBB) Lipophilicity of the drug molecule, Cellular enzyme stability and cellular sequestration, Affinity for efflux mechanisms (i.e. P-glycoprotein), Hydrogen bonding potential (i.e. charge), Affinity for carrier mechanisms, and Effect on all of the above by the existing  pathological conditions Transport Mechanisms Several specialized transport mechanisms of solute transfer across endothelial cells and into the brain interstitium are also present within the BBB Carrier system for monosaccharides, monocarboxylic acid, neutral amino acids, basic amino acid, acidic amino acids, amines, purine bases, nucleosides, vitamins and hormones. The more lipophilic substances that are present in the blood can diffuse passively directly through the lipid of the cell membrane and enter the endothelial cells and brain by this means.  Strategies for Brain Targeting Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. Neurosurgical or Invasive Strategies BBB disruption :Disruption of BBB by osmotic means (Hyperosmolar solutions),  Intraventricular drug infusion Intracerebral Implants: Biodegradable implants, Physiologic based Strategies Psuedo nutrients eg L-dopa Cationic antibodies.These undergo Absorption mediated trancytosis through BBB owing  to positive charge. Chimeric peptides.

1. Brain Targeted Drug
Delivery System
Prepared by :
Surbhi
M.Pharmacy II sem
Submitted to :
Dr. Anupama Diwan
4/18/2019 1Apeejay Stya University

2. What is Drug targeting !
• Drug targeting is the ability of the drug to
accumulate in the target organ or tissue
selectively quantitatively,
independent of
the site & method of
its administration.
4/18/2019 2Apeejay Stya University

3. Need of Targeted Drug Delivery
Systems
The main complications currently associated
with systemic drug administration are:
Even biodistribution of pharmaceuticals
throughout the body
The lack of drug specific affinity toward a
pathological site
The necessity of a large total dose of a drug to
achieve high local concentration
Non-specific toxicity and other adverse
side-effects.
4/18/2019 3Apeejay Stya University

4. MAGIC BULLET : CONCEPT OF PAUL
EHRLICH
MAGIC BULLET
Drugs would be targeted by virtue of groups
having affinity for specific cells
A ligand would confer specificity on a
non-specific reagent
4/18/2019 4Apeejay Stya University

5. MAGIC BULLET: Two components
The first one recognizes and binds the target
The second one provides a therapeutic action in
this target
(a) drug
(b) targeting moiety
(c) pharmaceutical carrier
Currently, the concept of magic bullet includes a
coordinated behavior of three components:
4/18/2019 5Apeejay Stya University

6. Drug targeting may resolve many of these problems !
4/18/2019 6Apeejay Stya University

7. The
principal
schemes
of drug
targeting
include
Direct application of a drug into the affected zone,
Passive drug targeting (spontaneous drug
accumulation in the areas with leaky vasculature,
or Enhanced Permeability and Retention-EPR-effect)
Physical targeting (based on abnormal pH value
and/or temperature in the pathological zone)
Magnetic targeting (or targeting of a drug
immobilized on paramagnetic materials under the
action of an external magnetic field)
Targeting using a specific vector molecules
(ligands having an increased affinity toward the
area of interest).4/18/2019 7Apeejay Stya University

8. Advantages1
Drug
administration
protocols may be
simplified
2
Drug quantity
may be greatly
reduced as well
as
the cost of
therapy
3
Drug
concentration in
the
required sites
can be sharply
increased
without
negative effects
on non-target
compartments.
4/18/2019 8Apeejay Stya University

9. Antibodies
Lectins and other proteins
Lipoproteins
Hormones
Charged molecules
Polysaccharides
Low-molecular-weight
ligands
polymers
microcapsules
microparticles
Nanoparticles
lipoproteins
liposomes
micelles
4/18/2019 9Apeejay Stya University

10. Brain Targeting: Challenges
• Blood brain barrier (BBB): Brain is tightly segregated
from the circulating blood by a unique membranous barrier.
• The brain and spinal cord are lined with a layer of special
endothelial cells that lack fenestrations and are sealed with
tight junctions that greatly restrict passage of substances
from the bloodstream.
• These endothelial cells, together with perivascular elements
such as astrocytes and pericytes, constitute the BBB.
• Rate-limiting factor in determining permeation.
4/18/2019 10Apeejay Stya University

11. Characteristics of the BBB
(1)tight junctions that
seal the pathway
between the capillary
(endothelial) cells
(2) the lipid nature of the
cell membranes of the
capillary wall which
makes it a barrier to
water-soluble molecules
(3), (4), and (5) represent
some of the carriers and
ion channels
(6) The
'enzymatic barrier 'that
removes molecules from
the blood
(7) the efflux pumps
which extrude fat-
soluble molecules that
have crossed into the
cells .
4/18/2019 11Apeejay Stya University

12. Schematic view of BBB
4/18/2019 Apeejay Stya University 12

13. The factors affecting particular substance
to cross BBB
• Drug related factors at the BBB
• Concentration at the BBB and the size,
• Flexibility,
• Conformation,
• Ionization (nonionized form penetrates BBB)
• Lipophilicity of the drug molecule,
• Cellular enzyme stability and cellular sequestration,
• Affinity for efflux mechanisms (i.e. P-glycoprotein),
• Hydrogen bonding potential (i.e. charge),
• Affinity for carrier mechanisms, and
• Effect on all of the above by the existing pathological
conditions4/18/2019 13Apeejay Stya University

14. The Physicochemical
Characteristics of Drugs
• Log Po/w of the therapeutic agent, the rule of 2 is generally
accepted i.e. the value of log Po/w nearing 2 is considered
optimal.
• However, increasing the lipophilicity with intent to increase
permeability would increase the volume of distribution (Vd)
and also the rate of oxidative metabolism by cytochrome
P450
• Peripheral factors including systemic enzymatic stability,
• Plasma protein binding affinity,
• Uptake of the drug into other tissues,
• Clearance rate, and
• Effects of existing pathological conditions are also
important.
4/18/2019 14Apeejay Stya University

15. • The lipophilicity of a given drug is inversely related to the
degree of hydrogen bond formation that occurs with
surrounding water.
• The presence of certain chemical moieties in drug like
terminal amide, primary amines or amides and hydroxyl
group favors hydrogen bond formation resulting in a
decreased lipophilicity.
• Thus for a compound to be transported through the BBB,
the cumulative number of hydrogen bonds should not go
beyond 810.
• Therefore for small drugs increasing lipophilicity i.e.
decreasing hydrogen bonds has a positive impact on
capillary permeability and drug transfer to the brain and
for large drug molecules with molecular weight above 400
Da or for those with strong polarity, the
capillary permeability will remain low regardless of
the lipophilicity
4/18/2019 15Apeejay Stya University

16. Transport Mechanisms
• Several specialized transport mechanisms of
solute transfer across endothelial cells and
into the brain interstitium are also present
within the BBB Carrier system for
monosaccharides, monocarboxylic acid, neutral
amino acids, basic amino acid, acidic amino acids,
amines, purine bases, nucleosides, vitamins and
hormones.
• The more lipophilic substances that are present
in the blood can diffuse passively directly
through the lipid of the cell membrane and enter
the endothelial cells and brain by this means.
4/18/2019 16Apeejay Stya University

17. • These solutes, and in many cases their
metabolites, are actively removed from the CNS
by efflux transporters.
• Various efflux transport pathways like P-
glycoprotein and active organic acid present in
choroids plexus may also be active in brain
endothelial cells efflux systems are present in
the BBB to remove unwanted substances.
• On the other hand the presence of the tight
junctions and the lack of aqueous
pathways between cells greatly restrict the
movement of polar solutes across the cerebral
endothelium
4/18/2019 17Apeejay Stya University

18. • The molecules that can freely diffuse through
this capillary endothelial membrane can passively
cross the BBB, and this ability is closely
related to their lipid solubility (lipophilicity/
hydrophobicity).
• Practically all drugs currently used to treat
brain disorders are lipid-soluble and can readily
cross the BBB following oral administration.
• The BBB also has an additional, enzymatic aspect
solutes crossing the endothelial cell membrane
are subsequently exposed to numerous
degrading enzymes within these cells.
4/18/2019 18Apeejay Stya University

19. • These cells also contain many mitochondria
metabolically active organelles and active
transport can significantly alter both inward and
outward transport for compounds.
• The BBB is highly efficient and makes the brain
practically inaccessible to lipid-insoluble
compounds.
• Brain-delivery of such compounds, therefore,
requires a strategy to overcome the BBB.
• Delivery of compounds such as neuropeptides or
oligonucleotides is further complicated by their
metabolic lability.
4/18/2019 19Apeejay Stya University

20. • Strategies for Brain Targeting Mechanisms for
drug targeting in the brain involve going either
"through" or "behind" the BBB.
• Neurosurgical or Invasive Strategies
 BBB disruption :Disruption of BBB by osmotic means
(Hyperosmolar solutions),
 Intraventricular drug infusion
 Intracerebral Implants: Biodegradable implants,
• Physiologic based Strategies
 Psuedo nutrients eg L-dopa
 Cationic antibodies.These undergo Absorption
mediated trancytosis through BBB owing to positive
charge.
 Chimeric peptides.
4/18/2019 20Apeejay Stya University
Strategies for Brain Targeting Mechanisms

21. • Pharmacologic Strategies :
1. Chemical Delivery system: Nanocarriers for active
targeting of the brain.
2. Liposomes
3. Polymeric micelles.
4. Polymeric nanoparticles
5. Lipid nanoparticles .
6. Biochemically by the use of vasoactive substances
such as bradykinin,
7. Localized exposure to high intensity focused
ultrasound
(HIFU).
8. Cell-penetrating peptides and
9. Brain transport vectors
4/18/2019 21Apeejay Stya University

22. • Use of Ligands:
• Ligands or homing devices that specifically bind to surface epitopes
or receptors on the target sites, can be coupled to the surface of
the long-circulating carriers.
• Certain cancer cells over express certain receptors, like
1. folic acid (over-expressed in cells of cancers with epithelial origin),
2. LDL (B16 melanoma cell line shows higher expression of LDL
receptors) and,
3. peptide receptors (such as somatostatin analogs, vasoactive
intestinal peptide, gastrin related peptides, cholecystokinin,
leutanising hormone releasing hormone).
• Attaching suitable ligands for these particular receptors on to
the nanoparticles would result in their increased selectivity.
• It was postulated that the presence of specific ligands on the
surface of nanoparticles could lead to their increased retention at
the BBB and a consequent increase in nanoparticle concentration at
the surface of BBB.
• E.g. coated nanoparticles from Brij 78, and emulsifying wax, with
thiamine ligand (linked to DSPE via a PEG spacer).
4/18/2019 22Apeejay Stya University

23. • Gene targeting technology :
• Gene therapy of the brain: Many serious disorders of the CNS that
are resistant to conventional small-molecule therapy could be
treated, even cured, with gene therapy of the brain.
• Current approach include delivery of the therapeutic gene to the
brain by drilling a hole in the head followed by insertion of the gene
incorporated in a viral vector.
• The advantage of craniotomy-based gene delivery is that the gene
can be expressed in a highly circumscribed area of the brain with an
effective treatment volume of 110 µl.
• This craniotomy based delivery does not enable the expression of the
therapeutic gene widely throughout the brain or even to a relatively
localized area such as a brain tumor, which could have a volume
greater than several milliliters.
• Viruses have been the vector of choice because the virus-coat
proteins trigger endocytosis of the virus into the target brain cell.
• The two most commonly used viral vectors are adenovirus or herpes
simplex virus (HSV).
• The problem with both these viruses is that, because they are
common, humans have a pre-existing immunity. This immunity
generates an inflammatory response.
4/18/2019 23Apeejay Stya University

24. • Immunoliposome:
• The surface of the nanocarrier is modified that triggers transcytosis
across microvascular endothelial barriers such as the BBB and then
endocytosis into target neurons or glial cells in brain. (Targeting
through the BBB and neuronal plasma membrane is accomplished
by tethering the tips of 12 of the PEG strands with a targeting
monoclonal antibody (MAb) to form an immunoliposome).
• Owing to expression of the transferrin receptor (TfR) on both the
BBB and the neuronal plasma membrane, the use of an anti-TfR MAb
causes the pegylated immunoliposome to undergo transport through
both the BBB and the neuronal plasma membrane in vivo.
• The liposomal lipids fuse with the endosomal membrane
inside neurons, which releases the plasmid into the cytosolic space of
target neurons, where it can then diffuse to the nuclear compartment.
• The only immunogenic component of the formulation is the MAb and
the immunogenecity of murine MAbs in humans can be liminated with
genetic engineering and humanization of the MAb.
4/18/2019 24Apeejay Stya University

25. Thanks for your attention!
4/18/2019 Apeejay Stya University 25