BRAIN TARGETING DRUG DELIVERY

SYSTEM:
AN OVERVIEW

OMOTOSO, KAYODE SUNDAY

010702027
14TH APR, 2011

TABLE OF CONTENT
INTRODUCTION
THE

BLOOD BRAIN BARRIER

APPROACHES

DELIVERY
CONCLUSION.

TO CNS DRUG

INTRODUCTION
In

spite of an impressive increase CNS

drug discovery, the biggest impediment
remains the effective delivery of these
agents across the blood brain barrier
(BBB).

Despite

aggressive research, patients

suffering from fatal or debilitating CNS
diseases far outnumber those dying of all
types of systemic cancers or heart
diseases. (Ricci et al, 2006)

The

BBB represents an insurmountable

barrier for the majority of drugs.

CONTD
BBB

is a major bottleneck in developing

brain drug delivery and the most
prominent factor limiting the future
growth of neurotherapeutics (Pardridge,
2005).

General

methods that can enhance drug

delivery to the brain are therefore of great
pharmaceutical importance.

Our

aim here is to review the various drug

delivery strategies that have been
developed to circumvent the BBB.

THE BLOOD BRAIN BARRIER

The brain is shielded internally against

potentially toxic substances by the
presence of two barrier systems: the blood
brain barrier (BBB) and the blood
cerebrospinal fluid barrier (BCSFB) .
(Pardridge, 2003)

The term blood brain barrier was first

coined in 1900 by Lewandowsky.
(Brightman, 1992)

BBB contd

The presence of tight junction, few

endocytic vesicles and efflux
transporters (e.g. P-glycoproteins) in
the CNS capillaries form the barrier
that occlude the free uptake of into the
interstitium.
( Nabeshima, 1975;
Lewin, 1980; Habgood et al, 2000)

As a result, a significant number of CNS

diseases have poorly met therapy.
(Pardridge, 1995)

BBB contd

The parameters considered optimum

for a compound to transport across
the BBB are:
(a) Non-ionization.
(b) Log P value near to 2.
(c) Molecular weight less than 400
Da.
(d) Cumulative number of
hydrogen bonds
between 8 to10.

BBB contd

Additionally, circumventricular
organs (CVO) are present adjacent
to the brain ventricles in some
regions of central neuron system
(CNS).

The CVO have an incomplete

blood-brain barrier and the BBB
capillary endothelial tight
junctions are absent.

They are highly vascularised and

lack of BBB because capillary
system supplying the CVOs
contains fenestrated endothelial
cells instead of epithelial tight
junction (Cottrell and Ferguson,
2004).

The Brain
Microvasculature

APPROACHES TO CNS DRUG

DELIVERY

To overcome the multitude of

barriers restricting CNS drug
delivery of potential therapeutic
agents, numerous drug delivery
strategies have been developed.

These strategies generally fall into

one or more of the following
categories: invasive, non-invasive or
miscellaneous techniques. (Misra et
al, 2003; Kabanov and Batrakova,

APPROACHES contd

APPROACHES

contd

INVASIVE METHODS

Generally, only low molecular weight, lipidsoluble molecules and a few peptides and
nutrients can cross this barrier to any significant
extent, either by passive diffusion or using
specific transport mechanisms. (Grieg, 1987)

However, these methods entail that drugs are

administered directly into the brain tissue.
(Wang, et al, 2002; Graff and Pollank, 2005)

APPROACHES

contd

Biochemical BBB Distruption

(Neuwelt, 1989)
Temporary breakdown of the BBB by
sugar solution (mannitol).

The endothelial cells shrink opening

the tight junctions. (Miller, 2002)

The effects last for 20-30min during

which drugs diffuse freely.

APPROACHES

contd

Useful in cerebral lymphoma,

malignant, glioma and disseminated
CNS germ cell tumours. (Torchilin,
2001; Rosler et al, 2001)

Side effects include physiological

stress, transient increase in
intracranial pressure and unwanted
delivery of anticancer agents to
normal brain tissues.

APPROACHES contd

INTRAVENTRICULAR INFUSION

Used extensively in clinical trials.

Infusion is done using a plastic

reservoir (Ommaya reservoir)
implanted SC in the scalp and
connected to the ventricles within
the brain via an outlet catheter.

Only suitable for sites close to the

ventricles.

APPROACHES contd

Continuous infusion may be

necessary for drugs that need to be
at elevated levels for a long period.

Gilbert (2007) developed a new and

useful device and method for the
needle-free delivery of drugs with
minimal trauma to the tissue.

The Ommaya Reservoir

APPROACHES contd

INTRACEREBRAL IMPLANTS

Entails delivery of drugs directly

into the brain parenchymal space.

Drugs can be administered by:

Direct injection via intrathecal catheter.

(Benoit et al, 2000)

Control release matrices. (Yang et al,
1989)
Microencapsulated chemicals. (Nathelie
et al, 2004)

APPROACHES contd

The basic mechanism is

diffusion.

Useful in the treatment of

different CNS diseases e.g. brain
tumour, Parkinsons Disease etc.
(Menei et al, 1994; Benoit et al,
2000)

APPROACHES contd

NON-INVASIVE APPROACHES
A variety of non-invasive brain drug delivery
methods have been investigated, that make
use of the brain blood vessel network to gain
widespread drug distribution.
Noninvasive techniques usually rely upon
drug manipulations which may include
alterations as prodrugs, lipophilic analogues,
chemical drug delivery, carrier-mediated
drug delivery, receptor/vector mediated drug
delivery etc. (Byrne et al, 2002)

APPROACHES contd

Chemical Methods

The main premise for the chemical

methods remains the use of prodrugs.

Such prodrug approaches were

explored for a variety of acid
containing drugs, like levodopa .
(Bodor et al, 1987)

APPROACHES contd

Lipidization of molecules generally

increases the volume of distribution, the
rate of oxidative metabolism by enzymes
and uptake into other tissues, causing an
increased tissue burden. (Han and
Amidon, 2000; Wu et al, 2002)

Chemical approaches for delivering drugs

to the brain include lipophilic addition and
modification of hydrophilic drugs, (e.g., Nmethylpyridinium-2-carbaldoxime
chloride; 2-PA). Higush et al, 1975; 1976.

APPROACHES contd

Biological Approaches
Chimeric Peptide

Drug substances which are not

transported through BBB are
combined with a transport vector to
form an easily transportable or fused
molecule. The conjugated proteins
may be endogenous peptides,
monoclonal antibodies (mAbs),
modified protein, etc.

APPROACHES contd

The chimeric are transported to

brain by various transportation
pathways like peptide-specific
receptor. E.g. insulin and transferrin
which undergo trancytosis by their
insulin and transferrin receptor
present at BBB.

APPROACHES contd

The vector itself should have

pharmacological activity, for example
insulin and secondly, the interaction
between peptide vectors with its
binding receptor site must be highly
specific for targeting drug to brain.
(Sood and Panchagnula, 2000;
Vandermeulen and Klok, 2003)

APPROACHES contd

Cationic Proteins

Cationic protein is suited method for

protein and peptides delivery based
on isoelectric point to the brain.

BBB transport of large molecule

drugs is not possible e.g proteins.
(Pardridge, 2002).

APPROACHES contd

This method offers an additional benefit for

delivering them by making them charged into
cationic form, which can go through brain
easily by electrostatic interaction with anionic
functional groups exists on brain surface.

Various cationic proteins have been reported

to penetrate the BBB including avidin, histone,
protamine, and cationized polyclonal bovine
immunoglobulin (Brasnjevic et al., 2009).

APPROACHES contd

Monoclonal Antibodies

Monoclonal antibodies for targeting are

usually prepared by hybridoma
technology.

APPROACHES contd

Combining malenoma (tumor) cells

with antitumor antibodies against a
particular type of antigens found on
malignant cells in animals like rat.
But instead of using mAb directly for
brain targeting, they are modified
structurally to get genetically
engineered monoclonal antibodies.

APPROACHES contd

Liposomes

Liposomes are non-toxic, biocompatible

and biodegradable lipid body carrier made
up of animal lipid like phospholipids,
sphingolipids, etc.

They have benefits of carrying hydrophilic,

lipophilic, as well as amphoteric drug
molecules either entrapped inside it or its
micellar surface.

APPROACHES contd

The surface modified liposomes can

be employed to encapsulate drug
molecules to diseased tissue or organ
directly.

The basic mechanism is by coupling

with brain drug transport vector via
receptor-mediated transcytosis or by
absorptive-mediated transcytosis.
(Schnyder and Huwyler, 2005).

APPROACHES contd

Nanoparticles

Nanoparticles have attracted interest in

targeting drug molecules to brain.

Nanosystems employed for the

development of nano drug delivery
system in the treatment of CNS disorders
include polymeric nanoparticles,
nanospheres, nanosuspensions, etc.

Nanoparticles enter into the brain by

crossing the BBB by various endocytotic
mechanisms.

APPROACHES contd

Nanoparticles can be designed from

albumin attached with apoliprotein E
(Apo E-albumin nanoparticles).

After IV administration, Apo Ealbumin nanoparticles are

internalized into the brain capillary
endothelial cells by transcytosis and
release into brain parenchyma.
(Park, 2009).

APPROACHES contd

Intra Nasal Drug Delivery

After nasal delivery drugs first reach

the respiratory epithelium,
compounds can be absorbed into the
systemic circulation by Tran cellular
and Para cellular passive absorption,
carrier-mediated transport, and
absorption through trancytosis.

APPROACHES contd

When a nasal drug formulation is

delivered deep and high enough into
the nasal cavity, the olfactory
mucosa may be reached and drug
transport into the brain and/or CSF
via the olfactory receptor neurons
may occur. (Chieny et al, 1989;
Yamada, 2004)

CONCLUSION
Even though a lot of strategies have been
developed to deliver drug into brain to treat
brain tumors and other abnormalities treatment,
none of them have showed to be suitable in each
and every case of CNS disorders.
This is due to the brain physiology which
presents unique challenges, made up of tight
regulation of what can enter the brain space and
limited distribution of substances along
extracellular fluid flow pathways.