BRAIN TARGETING DRUG DELIVERY SYSTEM:

AN OVERVIEW

OMOTOSO, KAYODE SUNDAY

010702027

14TH APR, 2011

 TABLE OF CONTENT
 INTRODUCTION

 THE BLOOD BRAIN BARRIER

 APPROACHES TO CNS DRUG DELIVERY

 CONCLUSION.
 INTRODUCTION
 Inspite 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)

 TheBBB represents an insurmountable barrier for the

majority of drugs. (Cornford, 1985; Hawkins and
Davis, 2005)
 CONT’D
 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 cont’d
 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 cont’d

 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 cont’d
 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 The Brain
system supplying the CVOs contains Microvasculature
fenestrated endothelial cells instead
of epithelial tight junction (Cottrell
and Ferguson, 2004).
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, 2004)
APPROACHES cont’d
 APPROACHES cont’d
INVASIVE METHODS
 Generally, only low molecular weight, lipid-soluble 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 cont’d
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 cont’d

 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 cont’d
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 cont’d

 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 cont’d
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 cont’d

 The basic mechanism is diffusion.

 Useful in the treatment of different CNS

diseases e.g. brain tumour, Parkinson’s
Disease etc. (Menei et al, 1994; Benoit et
al, 2000)
 APPROACHES cont’d
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 cont’d
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 cont’d

 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., N-methylpyridinium-2-
carbaldoxime chloride; 2-PA). Higush et al, 1975;
1976.
 APPROACHES cont’d

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 cont’d
 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 cont’d

 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 cont’d

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 cont’d
 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 cont’d
Monoclonal Antibodies

 Monoclonal antibodies for targeting are usually

prepared by hybridoma technology.
 APPROACHES cont’d
 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 cont’d

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 cont’d
 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 cont’d

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 cont’d
 Nanoparticles can be designed from albumin
attached with apoliprotein E (Apo E-albumin
nanoparticles).

 After IV administration, Apo E-albumin

nanoparticles are internalized into the brain
capillary endothelial cells by transcytosis and
release into brain parenchyma. (Park, 2009).
 APPROACHES cont’d

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 cont’d
 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.