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Tumor targeting and brain specific delivery



• It is an abnormal mass of tissue which is a classic sign

of inflammation.
 It is a fluid-filled lesion that may or may not be formed

by an abnormal growth of neoplastic cells that appears
enlarged in size.

 The term cancer refers to a new growth which has the
ability to invade tissues, metastasize (spread to other
organs) and which may eventually lead to the patient’s
death if untreated.



Growth of cancer cells



Drug targeting to tumor
 Drug targeting to tumor have been divided into categories of

“passive” and “active”.

• PASSIVE TARGETING: Passive targeting can differentiate
between normal and tumor tissues and has the advantage of
direct permeation to tumor tissue. Drug administered passively
in the form of prodrug or inactive form, when exposed to tumor
tissue, becomes highly active.

• Nanoparticles follow the biological mechanisms such as ERS
(Enhanced Retention System).

• Size should be below 100 nanometers in diameter and drug
accumulates around the tissue.



Active targeting



Targeted Therapies available in
tumor treatment

Many different targeted therapies have been approved
for use in cancer treatment. These are:

• Hormone therapies,
• Signal transduction inhibitors,
• Gene expression modulator,
• Apoptosis inducer,
• Angiogenesis inhibitor,
• Immuno therapies,
• Toxin delivery molecules



Treatment with targeted molecular therapy

• It is a type of personalized medical therapy designed to treat cancer by
interrupting unique molecular abnormalities that drive cancer growth.

• Targeted therapies are drugs that are designed to interfere with a specific
biochemical pathway that is central to the development, growth and
spread of that particular cancer.

Treatment with Immunotherapy
• Immunotherapy is designed to repair, stimulate, or enhance the immune

system’s responses using patients’ own immune systems to fight
cancer. It uses the body’s own immune system to:

• Target specific cancer cells, thereby potentially avoiding damage to
normal cells.

• Make cancer cells easier for the immune system to recognize and

• Prevent or slow tumor growth and spread of cancer cells.
Example: vaccine therapy



Treatment with Gene therapy
• Cancer is caused by changes in our genes.

• Gene therapy is designed to modify cancer cells at the
molecular level and replace a missing or bad gene with
a healthy one.

• The new gene is delivered to the target cell via a ‘vector,’
which is usually an inactive virus or liposome, a tiny fat



Antibody directed enzyme prodrug therapy
 First injection—- the monoclonal Ab is given ( with

enzyme attached)
 Second injection ( hours later)—–a second drug (the

pro drug) is given
 Activation—- the prodrug comes into contact with the

enzyme and drug then able to destroy the cancer cells
 Selectivity—–enzyme Ab conjugate doesnot attach to

normal cells. And drug doesnot affect them



Stimuli Responsive drug release
• The tumor microenvironment differs from the

normal cells microenvironment

• Advantage of the difference in pH, temperature
and presence of enzymes is used to release the
drug in tumor microenvironment.

• The rapid release of drug from its carrier is key to
the therapeutic efficacy of dosage form



Limitations of tumor targeting
• Cancer cells can become resistant to them. Resistance can occur in two

• The target itself changes through mutation so that the targeted therapy

no longer interacts well with it.
• The tumor finds a new pathway to achieve tumor growth that does not

depend on the target.

The most common side effects seen with targeted therapies are :
• Diarrhea and liver problems, such as hepatitis and elevated liver

• Skin problems (rash, dry skin, nail changes, hair depigmentation)

• Problems with blood clotting and wound healing
• High blood pressure.



Future perspectives
• For cancer therapies, the ideal targeted drug

delivery system is the one that delivers the drug
only to the target tumor.

• As tumors may not be eradicated by just aiming at
one target, it may also be necessary to
simultaneously aim at multiple targets. Thus, it
may be worthwhile to develop “magic shotgun”
strategies that deliver multiple drugs, and/or
deliver the drug to multiple targets



Brain specific drug
delivery system



 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.



 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

 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

e.g. with liposomes and nanoparticles are considered.



Some routes of direct administration to the brain are non-invasive
such as transnasal route whereas others involve entry into the
CNS by devices and needles such as in case of intrathecal and
intracerebroventricular is considered along with sustained and
controlled release delivery.

 Among the three main approaches to drug delivery to the CNS –
systemic administration, injection into CSF pathways, and direct
injection into the brain, the greatest developments is anticipated
to occur in the area of targeted delivery by systemic

 Overcoming the difficulty of delivering therapeutic agents to
specific regions of the brain presents a major challenge to
treatment of most brain disorders. The brain (central nervous
system) is protected by barriers which control the entry of
compounds into the brain, thereby regulating brain homeostasis.
Brain is tightly segregated from the circulating blood by a unique
membranous barrier – the Blood Brain Barrier (BBB).



 The blood–brain barrier (BBB) is a highly selective

permeability barrier that separates the circulating blood
from the brain extracellular fluid (BECF) in the central
nervous system (CNS).

 BBB is a unique membranous barrier that tightly
segregates the brain from the circulating blood .

 The blood-brain barrier acts very effectively to protect
the brain from many common bacterial infections.

 The blood-brain barrier is composed of high density cells
restricting passage of substances from the bloodstream
much more than endothelial cells in capillaries elsewhere
in the body.



Structure of BBB
 Capillaries of brain are lined with a layer of special

endothelial cells that lack fenestrations and are sealed
with tight junctions

 These tight junctions called zona occludens .
 The tight junctions produced by the interaction of

several transmembrane proteins such as occludin and
claudin that project into and seal the paracellular

 The interaction of these junctional proteins is complex
and effectively blocks an aqueous route of free diffusion
for polar solutes from blood along these potential
paracellular pathways and thus denies these solutes free
access to brain interstitial (extracellular) fluid .



Ependymal cells lining the cerebral ventricles and
glial cells are of three types

 Astrocytes form the structural framework for the neurons
and control their biochemical environment.

Astrocytes foot processes or limbs that spread out and
abutting one other, encapsulate the capillaries are closely
associated with the blood vessels to form the BBB.

 Oligodendrocytes are responsible for the formation and
maintenance of the myelin sheath, which surrounds axons
and is essential for the fast transmission of action
potentials by salutatory conduction.



 Microglias are blood derived mononuclear macrophages.
The tight junctions between endothelial cells results in a
very high trans-endothelial electrical resistance of 1500-
2000 Ω.cm2 compared to 3-33 Ω.cm2 of other tissues
which reduces the aqueous based paracellular diffusion
that is observed in other organs.

 Small hydrophilic molecules such as amino acids, glucose,
and other molecules necessary for the survival of brain
cells use transporters expressed at the luminal (blood) and
basolateral (brain) side of the endothelial cells.



 Larger and/or hydrophilic essential molecules such as
hormones, transferrin for iron, insulin, and lipoproteins use
specific receptors that are highly expressed on the luminal
side of the endothelial cells. These receptors function in the
endocytosis and transcytosis of compounds across the BBB.

 Small lipophilic molecules can diffuse passively across the
BBB into the brain but will be exposed to efflux pumps
(Pglycoprotein [P-gp].



Diseases related to BBB
 Meningitis
 Brain abscess
 Epilepsy
 Multiple sclerosis
 Neuromyelitis optica
 Late-stage neurological
 trypanosomiasis (Sleeping sickness)
 Progressive multifocal leukoencephalopathy (PML)
 Alzheimer’s Disease, etc.





Functions of BBB
 The BBB acts very effectively to protect the brain from many common bacterial


 Infections of the brain that do occur are often very serious and difficult to

 Antibodies are too large to cross the blood–brain barrier, and only certain
antibiotics are able to pass.

 The blood–brain barrier becomes more permeable during inflammation.

 This allows some antibiotics and phagocytes to move across the BBB. However,
this also allows bacteria and viruses to infiltrate the BBB.

 An exception to the bacterial exclusion is the diseases caused by spirochetes,
such as Borrelia, which causes Lyme disease, and Treponema pallidum, which
causes syphilis. These harmful bacteria seem to breach the blood–brain barrier
by physically tunneling through the blood vessel walls.



 To bypass the BBB and to deliver therapeutics into the

brain, three different approaches are currently used —

➢ invasive approach
➢ pharmacological approach
➢ physiological approach



Invasive Approach
 It includes
➢ intracerebro ventricles infusion
➢Convection enchanced delivery
➢Polymer or microchip systems (implants)



1.Intra-cerebro-ventricular (ICV) infusion

 One strategy for bypassing the BBB .
 injection or intraventricular infusion of drugs directly into

the CSF.
 Drugs can be infused intraventricularly using an Ommaya

reservoir, a plastic reservoir implanted subcutaneously in
the scalp and connected to the ventricles

 Drug solutions can be subcutaneously injected into the
implanted reservoir and delivered to the ventricles by
manual compression of the reservoir through the scalp.

 Eg; Glycopeptide and aminoglycoside antibiotics used in



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



3.Intra-cerebral injection or use of implants
 Both the bolus injection of chemotherapy agents and

the placement of a biodegradable, chemotherapeutic
impregnated, wafer into a tumour resection cavity, rely
on the principle of diffusion to drive the drug into the
infiltrated brain..



4.Disruption of the BBB Osmotic disruption:
 Disruption of the BBB can open access of the brain to

components in the blood by making the tight junction
between the endothelial cells of the brain capillaries
leaky. Different techniques are used to disrupt the tight

 The osmotic shock causes endothelial cells to shrink,
thereby disrupting the tight junctions. Intracarotid
administration of a hypertonic mannitol solution with
subsequent administration of drugs can increase drug
concentration in brain and tumour tissue to reach
therapeutic concentration.



 MRI-guided focused ultrasound BBB disruption
technique: Ultrasound has been shown to be capable of
BBB disruption. The combination of microbubbles . This
technique has been shown to increase the distribution of
Herceptin in brain tissue by 50% in a mice model

 Application of bradykinin-analogue: There is evidence of
the opening of the tight junctions to occur by activation of
bradykinin B2 receptors through a calcium-mediated



Limitations of invasive approach
 All these approaches are relatively costly, require

anaesthesia and hospitalization, and are non-patient
friendly. These techniques may enhance tumour
dissemination after successful disruption of the BBB.
Neurons may be damaged permanently from
unwanted blood components entering the brain.



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



 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

 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
Pglycoprotein (P-gp).



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 of specific receptors expressed
at the BBB. The low density lipoprotein receptor related
protein (LRP) is the most adapted for such use with the
engineered peptide compound (EPiC) platform
incorporating the Angiopeptide in new the most advanced
with promising data in the clinic.
Eg. Receptor-mediated transcytosis



Other Non-invasive Approaches
 Lipophilic Analogs
 Prodrugs
 Receptor/Vector Mediated Drug Delivery
 Carrier Mediated Drug Delivery
 Intra nasal DDS



Lipophilic Analogues

 CNS penetration is favored by low molecular weight,
lack of ionization at physiological pH, and
lipophilicity. Delivery of poorly lipid-soluble
compounds to the brain requires some way of getting
past the BBB.

 There are several possible strategies, such as transient
osmotic opening of the BBB, exploiting natural
chemical transporters, highdose chemotherapy, or
even biodegradable implants.



 Prodrugs are pharmacologically inactive compounds.

 chemical change is usually designed to improve some
deficient physicochemical property–(solubility and
mem. permeability)

 Examples: levodopa, GABA, Niflumic acid, valproate
or vigabatrin



Colloidal drug carriers

 Its an promising approach

 Colloidal carriers include
➢ nanoparticles

• Coating with surfactants like
e g: polyoxypropylene, polyethylene glycol,




Nano particles
These are submicron drug carrier systems that are made

from a broad number of materials such as
 polyalkylcyano acrylates(PCAS)
 Polyacetates
 Polysaccharides& co-polymers

Polysorbate coated nanoparticles can mimic LDL to
cross the BBB




 Need to target therapeutics to specific brain regions or
cell types.

 Need to improve understanding of BBB transport

 Need for in vivo evaluation of brain drug

 Need to identify new brain drug targeting systems. •
Need to speed development and application of
molecular imaging probes and targeted contrast



 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.

 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



 State briefly on targeted drug delivery system. What

are their limitation and explain briefly different
approaches available for targeting of drugs to brain

( 5m- 2 times)

 Explain the concept of targeted drug delivery sytem.
Describe active drug targeting in detail. (5M)

 Explain the advantage of drug targeting with examples



 S.P Vyas and R.K Khar controlled drug delivery system
 Encyclopedia of controlled delivery system
 Drug delivery to the brain from wikipedia.



Thank you