The document summarizes various approaches for brain targeted drug delivery to bypass the blood-brain barrier (BBB). It discusses the invasive approach using intracerebroventricular infusion and convection-enhanced delivery. The pharmacological approach modifies drug properties for passive diffusion. The physiological approach uses receptor-mediated transcytosis. Non-invasive approaches include prodrugs, drug conjugates, monoclonal antibodies, receptor-mediated transport, liposomes, nanoparticles, and colloidal carriers coated with surfactants to mimic LDL transport across BBB. The goal is to develop safe and effective strategies for delivering therapeutics to the brain.

1. Department of Pharmaceutics
SREE SIDDAGANGA COLLEGE OF PHARMACY
BRAIN TARGETED DRUG
DELIVERY SYSTEM
By:
Sathish HT
2nd Sem M Pharm
Under the Guidance of:
Dr. PAshok Kumar M. Pharm Ph.D.

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.

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.

4. Schematic representation of the transport of molecules across the BBB.

5. APPROACHES
• To bypass the BBB and to deliver
therapeutics into the brain, thre different
approaches are currently used —
Physiolog
ical
approach
Pharmaco
-logical
approach
Invasive
approach

7. Invasive Approach
1) Intracerebro-
ventricular infusion
2) Convection-
enhanced
delivery
3) polymer or
microchip
systems
( Implants)
It includes……………

8. Intracerebro- ventricular infusion

9. Convection-enhanced delivery
(CED)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.

10. Intra-cerebral injection or use of implants

11. 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

12. Cont
….
• 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).

13. 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

14. NON INVASIVE
APPROACH
CHEMICAL
PRODRUGS
DRUG
CONJUGATES
BIOLOGICAL
MONOCLONAL /
CATIONIC
ANTIBODIES
CONJUGATES
RECEPTOR /
VECTOR
MEDIATED
APROTONIN /
CHIMERIC
PEPTIDES AS
CARRIER
COLLOIDAL
NANOPARTICLES
LIPOSOMES
B

15. 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

16. 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:
 Adverse pharmacokinetics.
 The increased molecular weight of the drug that follow from lipidation.
 VARSHA, A., OM B., KULDEEP R., & RIDDHI, P. B. P. (2014). Poles apart Inimitability of Brain Targeted
Drug Delivery system in Middle of NDDS. International Journal of Drug Development and Research 6(4)15-27.

17. 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
Casomorphin is a heptapeptide , able to pass the BBB.

18.  Drug transfered via amino acid transporter (LAT1):
 Melphalan for brain cancer
 Alpha methyl dopa for high blood pressure
 Gabapentin for epilepsy
 Ldopa for parkinsonism
 Transport via organic acid transporter(MCT)
salicyclic acid, lactate, acetate, propionate
 Choline transporter( for choline, thiamine)
 Nucleoside transporter(purine bases like adenine guanine)
anticancer agent, antiviral agent, 3 azidodeoxythymide
 Amine transporter: for mepyramine
 Peptide transporters: for glutathione, peptide harmones,
growth factor, enkephalins, t vasopressin , arginine
CARRIER MEDIATED TRANSPORT
 Pardridge, W. M. (2003). Blood-brain barrier drug targeting: the future of brain drug development.
Molecular interventions, 3(2),90.
Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92

19. 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.
VECTOR BRAIN SPECIFICITY PHARMACOKINETICS
HIGH YIELD
COUPLING
CLEAVABILITY
RETENTION OF
AFFINITY AFTER
CLEAVAGE
INTRINSIC
RECEPTOR
LINKER
DRUG

20. CHIMERIC PEPTIDES AS CARRIER
DRUG VECTOR
MODIFIED
PRODUCT
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

21.  Begley David J., Bradbury Michael W. , Kreuter Jörg “Targeting Macromolecules to the Central Nervous
System” The Blood–Brain Barrier and Drug Delivery to the CNS, Ulrich Bickel(e.d.) , 2000 by Marcel
Dekker,Inc., 8.

22. 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:
 control degradation of drug
 Prevent harmful side effects
 increase the availability of the drug at the disease site.
 slowly degrade, react to stimuli and be site-specific
 Advantages:
 Prolong the existence of the drug in systemic circulation
 Improves the bioavailability especially of poorly soluble
drugs.
 Both hydrophilic and lipophilic drugs can be incorporated.
 Delays elimination of rapidly metabolizable drugs and thus
function as sustained release systems.

23. 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)
 Polysorbate coated nanoparticles can mimic LDL to cross BBB.
 Polyoxyethylene sorbitan monooleate coated nanoparticles containing drug
easily cross BBB.
 Radiolabeled polyethylene glycol coated hexadecylcyanoacrylate
nanospheres targeted and accumulated in a rat gliosarcoma.
• Mechanisms of transport
Adhesion
Fluidization of BBB endothelium by surfactants
Opening of tight junction
Transcytosis / Endocytosis
Blockage of glycoprotein

24. Mehmood, Y., Tariq, A., & Siddiqui, F. A. (2015). Brain targeting Drug Delivery System: A
Review. International Journal of Basic Medical Sciences and Pharmacy (IJBMSP), 5(1),32-40.
MECHANISM OF TRANSPORT(ENDOCYTOSIS)

25. • TARGETTING:
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
 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
 Cell penetrating peptide(trans activating transduction protein )
modified liposome i.e. Tat-LIP having positive charge transported
via adsorptive mechanism. E.g. for caumarin
The coating of polyalkylcyanoacrylate or poly-lactic-co-glycolic
acid (PLGA) nanoparticles with polysorbate 80 or poloxamer
188.
Due to this coating the particles adsorb apolipoproteins E or A-
1 from the blood
Interact with the LRP1 or with the scavenger receptor followed
by transcytosis across the blood-brain barrier into the brain.

26.  Babu, A., Templeton, A. K., Munshi, A., & Ramesh, R. (2014). Nanodrug delivery systems: a promising technology
for detection, diagnosis, and treatment of cancer. Aaps Pharmscitech, 15(3), 709-721.

27. • 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 (MRI).
 Trojan horses coated with sugar layer, is another modern approach containing
magnetized,
iron-containing nanoparticles
• Advantages of using nanoparticles for CNS targeted drug delivery
 protect drugs against chemical and enzymatic degradation.
 small size --- penetrate into even small capillaries ---taken up within cells ----drug
accumulate at the targeted sites
 The use of biodegradable materials ---allows sustained drug release at the
targeted site after injection
• Limitations of using nanoparticles for CNS targeted drug delivery
 small size and large surface area ----particle-particle aggregation-- physical
handling of nanoparticles difficult in liquid and dry forms.
 small particles size and large surface area result in limited drug loading and burst
release.
 Avhad, P. S., Patil, P. B., Jain, N. P., & Laware, S. G. (2015). A Review on Different Techniques for
Brain Targeting. International Journal of Pharmaceutical Chemistry and Analysis, 2(3),143-147.
 Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal
of Pharma Research & Review, 2(6),36-44.

28. 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
 suitable for delivery of hydrophobic, amphipathic and hydrophilic
drugs and agents.
 could encapsulate macromolecules like superoxide dismutase,
haemoglobin, erythropoietin, interleukin-2 and interferon-g.
 reduced toxicity and increased stability of entrapped drug via
encapsulation (eg.Amphotericin B, Taxol).
 Limitation :
 High production cost , Short half-life , Low solubility , Less stability
 Leakage and fusion of encapsulated drug / molecules
 Sometimes phospholipid undergoes oxidation and hydrolysis
 Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems:
Molecular Basis of Targeted Drug Delivery, 1,508.

29. 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
TARGETING
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
 Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat
brain diseases. Neurobiology of disease, 37(1),48-57.

30.  Sercombe, L., Veerati, T., Moheimani, F., Wu, S. Y., Sood, A. K., & Hua, S. (2015). Advances and challenges of
liposome assisted drug delivery| NOVA. The University of Newcastle's Digital Repository.

31. MONOCYTES
• Used as a Torjan Horse
• Ideal endogenous carriers
• Express certain receptors involved in receptor mediated
endocytosis upon interaction with suitable ligands
CARRIER MONOCYTE BBB DRUG
 Vyas, S. P., & Khar, R. K. (2012). Targeted and Controlled Drug Delivery-Novel Carrier Systems: Molecular
Basis of Targeted Drug Delivery, 1,508.

32. MISCELLANEOUS
TECHNIQUE
INTRANASAL
DELIVAERY
IONTOPHORETIC
DELIVERY
C

33. 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.

34. Antosova, Z., Mackova, M., Kral, V., & Macek, T. (2009). Therapeutic application of peptides and proteins: parenteral
forever?. Trends in biotechnology, 27(11), 628-635.
INTRANASAL DELIVERY
Example: Small molecules like cocaine,cephalein & protein like inulin

35. 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
 Roy Sandipan (2012) “Strategic Drug Delivery Targeted to The Brain” Pelagia Research Library., 3(1),76-92
 Singh, S. B. (2013). Novel Approaches for Brain Drug Delivery System-Review. International Journal of
Pharma Research & Review, 2(6),36-44.

36.  Zorec, B., Préat, V., Miklavcic, D., & Pavselj, N. (2013). Active enhancement methods for intra-and
transdermal drug delivery: a review. Zdravniski Vestnik, 82(5).

37. 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.

38. ANY QUESTIONS ?

39. THANK YOU