brain targeted drug delivery-aim approches

1. Brain targeted drug
delivery
Presented By
Sujitha Mary
M Pharm
St Joseph College Of Pharmacy
1

2. AIM
 To emphasize on drug delivery to brain by using various
approaches.
 To study the Blood – Brain barrier.
 To study different approaches to bypass the BBB and to
deliver therapeutics into the brain.
2

3. INTRODUCTION
 Drug delivery to the brain is the process of passing
therapeutically active molecules across the Blood Brain Barrier
for the purpose of treating brain maladies. This is a complex
process that must take into account the complex anatomy of the
brain as well as the restrictions imposed by the special junctions
of the Blood Brain Barrier.
 In response to the insufficiency in conventional delivery
mechanisms, aggressive research efforts have recently focused
on the development of new strategies to more effectively deliver
drug molecules to the CNS.
 Various routes of administration as well as conjugations of
drugs, e.g. with liposomes and nanoparticles are considered.
3

4. APPROACHES
 To bypass the BBB and to deliver therapeutics into the
brain, thre different approaches are currently used
4

5. 5

6. Invasive Approches
 It includes
6

7. Convection-enhanced delivery
 The general principle of CED involves the stereotactically guided
insertion of a small-caliber catheter into the brain parenchyma.
 Through this catheter, infusate is actively pumped into the brain
parenchyma and penetrates in the interstitial space.
 The infusion is continued for several days and the catheters are
removed at the bedside.
 CED has been shown in laboratory experiments to deliver high
molecular weight proteins 2 cm from the injection site in the brain
parenchyma after as little as 2 h of continuous infusion
 Limitations: Some areas of the brain are difficult to saturate fully with
infusate, particularly — infiltrated tissues surrounding a cavity.
7

8. Pharmacological Approach
 The pharmacological approach to crossing the BBB is based on the
observation that some molecules freely enter the brain, e.g. alcohol,
nicotine and benzodiazepine.
 This ability to passively cross the BBB depends on the molecular size
being less than 500 D, charge (low hydrogen bonding capabilities) and
lipophilicity (the more lipophilic, the better the transport).
 This approach consists of modifying, through medicinal chemistry, a
molecule that is known to be active against a CNS target to enable it to
penetrate the BBB
8

9.  Modification of drugs through a reduction in the relative
number of polar groups increases the transfer of a drug
across the BBB. Lipid carriers have been used for transport,
and there are successful examples of both these
approaches.
 Limitations: The modifications necessary to cross the BBB
often result in loss of the desired CNS activity. Increasing the
lipophilicity of a molecule to improve transport can also result
in making it a substrate for the efflux pump P- glycoprotein
(P-gp).
9

10. Physiological approach
 Among all the approaches used for increasing brain delivery of
therapeutics, the most accepted method is the use of the
physiological approach which takes advantage of the transcytosis
capacity receptors expressed at the BBB. The of specific low
density lipoprotein receptor related protein (LRP) is the most
adapted for such use with the engineered peptide compound
(EPiC) platform incorporating the advanced withAngiopep peptide
in new the most promising data in the clinic.
Eg. Receptor-mediated transcytosis
10

11. 11

12. PRODRUGS
Prodrug is lipid soluble (pharmacologically inactive compounds)
cross the BBB
metabolized within the brain
converted to the parent drug
Esterification or amidation of hydroxy-, amino-, or carboxylic acid-
containing drugs, may greatly enhance lipid solubility and,
hence, entry into the brain
12

13. WHAT TO DO AND WHY
 Drug covalently linked to an inert chemical moiety.
 Improve physicochemical property such as solubility and membrane
permeability.
 Prodrug is cleaved by hydrolytic or enzymatic processes.
 Examples levodopa, gaba, niflumic acid, valproate
Heroin, a diacyl derivative of morphine, is a notorious example that
crosses the bbb about 100 times more easily than its parent drug just
by being more lipophilic
 Limitations of the prodrug
•. The increased molecular weight of the drug that follow from lipidation.
• Adverse pharmacokinetics
13

14. DRUG CONJUGATES
 Lipidization of molecules generally increases the volume of distibution.
 Chemical approaches include lipophilic addition and modification of
hydrophilic drugs ( e.g. Nmethylpyrimidium 2 carbaldoxime chloride)
 Example:
Glycosylated analogs of various opioid compounds
Antioxidant + pyrrolopyrimidines – increase access
For Ganciclovir : to hydroxymethyl group + 1methyl 1,4
dihydronicotinate- increase transport
For small drugs: use of fatty acids like N docosahexaenoyl(DHA)
increase uptake
For Casomorphin is a heptapeptide , able to pass the BBB.
14

15. CARRIER MEDIATED
TRANSPORT
 Peptide transporters: for glutathione, peptide harmones, growth factor,
enkephalins, t vasopressin , arginine
 Amine transporter: for mepyramine
 Nucleoside transporter(purine bases like adenine guanine) anticancer
agent, antiviral agent, 3 azidodeoxythymide
 Choline transporter( for choline, thiamine)
 Transport via organic acid transporter(MCT) salicyclic acid, lactate,
acetate, propionate
 Drug transfered via amino acid transporter (LAT1):
Ldopa for parkinsonism
Gabapentin for epilepsy
Alpha methyl dopa for high blood pressure
Melphalan for brain cancer 
15

16. RECEPTOR / VECTOR MEDIATED
 Conjugation of drug to transport vector is facilitated with chemical
linkers avidin–biotin technology, polyethylene glycol linkers.
 vector such as the Monoclonal antibody Mab
 Portals of entry for large molecular drug attached to endogenous RMT
ligands
VECTO
R
DRUG
LINKE
R
BRAIN
SPECIFICIT
Y
HIGH
YIELD
COUPLING
CLEAVABILITY
PHARMAC
OKINETICS
RETENTION OF
AFFINITY AFTER
CLEAVAGE
INTRINSIC
RECEPTOR
16

17. CHIMERIC PEPTIDES AS
CARRIER
 Conjucated proteins may be endogenous peptides, monoclonal
antibodies, modified protein, cationized albumin etc.
 Chimeric peptides are transported to brain by various pathways like
peptide specific receptor.
E.g. Insulin and transferrin by transcytosis
Conjugation of drug with antibodies e.g. OX-26, 8D3 Mab
antibody to red transferrin receptor
DRUG
VECTOR
MODIFIED
PRODUCT
17

18. COLLOIDAL
 The vesicular systems are highly ordered assemblies of one or several
concentric lipid bilayer formed, when certain amphiphillic building blocks
are confronted with water 
 Coated with surfactants like polyoxyethylene/propylene, PEG
AIM:
 slowly degrade, react to stimuli and be site-specific
 increase the availability of the drug at the disease site.
 Prevent harmful side effects
 control degradation of drug
Advantages
 Delays elimination of rapidly metabolizable drugs and thus function as
sustained release systems.
 Both hydrophilic and lipophilic drugs can be incorporated.
 Improves the bioavailability especially of poorly soluble drugs.
 Prolong the existence of the drug in systemic circulation
18

19. NANOPARTICLES
• Size 1-1000 nm
• includes both nanocapsules, with a core-shell structure (a
reservoir system) and nanospheres (a matrix system)
• Materials used: polyacetates, acrylic copolymers, poly(lactide),
poly(alkylcyanoacrylates) (PACA), poly(D,L-lactide-co-glycolide
Radiolabeled polyethylene glycol coated hexadecylcyanoacrylate
nanospheres targeted and accumulated in a rat gliosarcoma.
Polyoxyethylene sorbitan monooleate coated nanoparticles
containing drug easily cross BBB. 
Polysorbate coated nanoparticles can mimic LDL to cross BBB. )
Mechanisms of transport Adhesion Fluidization of BBB endothelium
by surfactants Opening of tight junction Transcytosis /
Endocytosis Blockage of glycoprotein
19

20.  Mechanisms of transport
Adhesion
Fluidization of BBB endothelium by
surfactants
Opening of tight junction
Transcytosis / Endocytosis
Blockage of glycoprotein
20

21. MECHANISM OF
TRANSPORT(ENDOCYTOSIS)
21

22. TARGETTING
Due to this coating the particles adsorb apolipoproteins E or A-
1 from the blood
: The coating of polyalkylcyanoacrylate or poly-lactic-co-
glycolic acid (PLGA) nanoparticles with polysorbate 80 or
poloxamer 188.
Interact with the LRP1 or with the scavenger receptor followed
by transcytosis across the blood-brain barrier into the brain.
22

23.  for the treatment of glioblastomas are presently in Clinical
Phase I. Human serum albumin nanoparticles conjucated
with antibodies(OX26/R17217) against transferrin receptor
e.g. For lopera
 Cell penetrating peptide(trans activating transduction protein
) modified liposome i.e. Tat-LIP having positive charge
transported via adsorptive mechanism. E.g. for caumarin
 These particles loaded with doxorubicin mide, 5-florouracil(5-
FU) 
 Human serum albumin nanoparticles conjucated with
antibodies(29B4) against insulin receptor e.g. for targeting
loperamide
23

24. 24

25. OTHER APPROACH:
 Photodynamic therapy (PDT), Photofrin along with iron oxide
nanoparticles which is used to target tumor cells. In this, iron oxide is
used as contrast agent to get improved magnetic resonance imaging
(MR
 Trojan horses coated with sugar layer, is another modern approach
containing magnetized, iron-containing nanoparticles
• Advantages of using nanoparticles for CNS targeted drug delivery
 The use of biodegradable materials ---allows sustained drug release at
the targeted site after injection
 small size --- penetrate into even small capillaries ---taken up within
cells ----drug accumulate at the targeted sites
 protect drugs against chemical and enzymatic degradation.
• Limitations of using nanoparticles for CNS targeted drug delivery
 small particles size and large surface area result in limited drug loading
and burst release.
 small size and large surface area ----particle-particle aggregation--
physical handling of oparticles difficult in liquid and dry forms. 
25

26. LIPOSOMES
 lipid based vesicles are microscopic (unilamellar or multilamellar)
vesicles
 Lipid soluble or lipophilic drugs get entrapped within the bilayered
membrane whereas water soluble or hydrophilic drugs get entrapped in
the central aqueous core of the vesicles
 • Advantages
 reduced toxicity and increased stability of entrapped drug via
encapsulation (eg.Amphotericin B, Taxol).
 could encapsulate macromolecules like superoxide dismutase,
haemoglobin, erythropoietin, interleukin-2 and interferon-g. 
 suitable for delivery of hydrophobic, amphipathic and hydrophilic drugs
and agents.
Limitation :
 Leakage and fusion of encapsulated drug / molecules
 High production cost , Short half-life , Low solubility , Less stability
26

27. Mechanism: receptor/adsorptive mediated transport
 liposome coated with mannose reaches brain tissue where
mannose coat assists transport
 Addition of sulphatide (a sulphate ester of galactocerebroside)
to liposome increases availability 
TARGETING
A non viral supercoiled plasmid DNA is
encapsulated in an interior of an 85nm liposome
Liposome surface is conjucated with 1000-
2000 strands of 2000 dalton peg to form
pegylated liposome
Tips of 1-2 % peg strands are conjucated with a
peptidomimetic Mab(HIR/TR) to form pegylated
immunoliposomeS
Transfer via RMT
27

28. 28

29. MONOCYTES
 Used as a Torjan Horse
 Ideal endogenous carriers
 Express certain receptors involved in receptor mediated
endocytosis upon interaction with suitable ligands
29

30. MISCELLANEOUS
TECHNIQUE
IONTOPHORETIC
DELIVERY
INTRANASAL
DELIVAERY
30

31. INTRANASAL DELIVERY
 Drug delivered intranasally are transported along olfactory
sensory neurons to yield significant concentrations in the CSF
and olfactory bulb and then enter into other regions of brain by
diffusion(facilitated by perivascular pump)
 DIFFICULTIES : enzymatic activity, low pH nasal epithelium,
mucosal irritation or large variability caused by nasal pathology
(common cold)
 THE OLFACTORY PATHWAYS: the olfactory nerve pathway
(axonal transport) and the olfactory epithelial pathway. •
 AXONAL TRANSPORT (slow route) : Agent enters the olfactory
neuron via endocytotic or pinocytotic mechanisms travels to the
olfactory bulb compounds pass paracellularly across the
olfactory epithelium into the perineural space continues to the
subarachnoid space & in direct contact with the CSF.
31

32.  AXONAL TRANSPORT (slow
route)
Agent enters the olfactory neuron via
endocytotic or pinocytotic mechanisms
travels to the olfactory bulb
compounds pass paracellularly across
the olfactory epithelium into the
perineural space
continues to the subarachnoid space &
in direct contact with the CSF.
32

33. 33

34. IONTOPHORETIC DELIVERY
 Iontophoresis is the introduction of ionised molecules into
tissues by means of an electric current
 biologically active agent is transported by means of
iontophoresis and/or phonophoresis directly to the CNS
using the olfactory pathway to the brain and thereby
circumventing the BBB and is known as transnasal
iontophoretic delivery .
34

35. 35

36. CONCLUSION
 The treatment of brain diseases is particularly challenging
because the delivery of drug molecules to the brain is often
precluded by a variety of physiological, metabolic and
biochemical obstacles that collectively comprise the BBB, BCB
and BTB.
 Drug delivery directly to the brain interstitium has recently been
markedly enhanced through the rational design of polymer-
based drug delivery systems.
 Substantial progress will only come about, however, if
continued vigorous research efforts to develop more therapeutic
and less toxic drug molecules are paralleled by the aggressive
pursuit of more effective mechanisms for delivering those drugs
to their brain targets.
36