OMOTOSO, KAYODE SUNDAY 01070202714TH APR, 2011

INTRODUCTION THE

BLOOD BRAIN BARRIER CNS DRUG DELIVERY

APPROACHES TO CONCLUSION.

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). 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)

Despite

The

BBB represents an insurmountable barrier for the majority of drugs. (Cornford, 1985; Hawkins and Davis, 2005)

BBB

is a major bottleneck in developing brain drug delivery and the most prominent factor limiting the future growth of neurotherapeutics (Pardridge, 2005). methods that can enhance drug delivery to the brain are therefore of great pharmaceutical importance.

General

Our

aim here is to review the various drug delivery strategies that have been developed to circumvent the BBB.

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)

The

presence of tight junction, few endocytic vesicles and efflux transporters (e.g. Pglycoproteins) in the CNS capillaries form the barrier that occlude the free uptake of into the interstitium. ( Nabeshima, 1975; Lewin, 1980; Habgood et al, 2000) a result, a significant number of CNS diseases have poorly met therapy. (Pardridge, 1995)

As

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.

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

To

overcome the multitude of barriers restricting CNS drug delivery of potential therapeutic agents, numerous drug delivery strategies have been developed. strategies generally fall into one or more of the following categories: invasive, noninvasive or miscellaneous techniques. (Misra et al, 2003; Kabanov and Batrakova, 2004)

These

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)

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.

Useful

in cerebral lymphoma, malignant, glioma and disseminated CNS germ cell tumours. (Torchilin, 2001; Rosler et al, 2001) effects include physiological stress, transient increase in intracranial pressure and unwanted delivery of anticancer agents to normal brain tissues.

Side

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. suitable for sites close to the ventricles.

Only

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.

INTRACEREBRAL IMPLANTSEntails

delivery of drugs directly into the brain parenchymal space. can be administered by:

Drugs

Direct injection via intrathecal catheter. (Benoit et al,

2000) Control release matrices. (Yang et al, 1989) Microencapsulated chemicals. (Nathelie et al, 2004)

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)

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)

Chemical Methods The

main premise for the chemical methods remains the use of prodrugs. prodrug approaches were explored for a variety of acid containing drugs, like levodopa . (Bodor et al, 1987)

Such

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-2carbaldoxime chloride; 2-PA). Higush et al, 1975; 1976.

Biological ApproachesChimeric 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.

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.

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)

Cationic Proteins Cationic

protein is suited method for protein and peptides delivery based on isoelectric point to the brain. transport of large molecule drugs is not possible e.g proteins. (Pardridge, 2002).

BBB

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

Various

Monoclonal Antibodies Monoclonal

antibodies for targeting are usually prepared by hybridoma technology.

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.

Liposomes Liposomes are

non-toxic, biocompatible and biodegradable lipid body carrier made up of animal lipid like phospholipids, sphingolipids, etc. benefits of carrying hydrophilic, lipophilic, as well as amphoteric drug molecules either entrapped inside it or its micellar surface.

They have

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 receptormediated transcytosis or by absorptivemediated transcytosis. (Schnyder and Huwyler, 2005).

Nanoparticles Nanoparticles

have attracted interest in targeting drug molecules to brain. employed for the development of nano drug delivery system in the treatment of CNS disorders include polymeric nanoparticles, nanospheres, nanosuspensions, etc. enter into the brain by crossing the BBB by various endocytotic mechanisms.

Nanosystems

Nanoparticles

Nanoparticles

can be designed from albumin attached with apoliprotein E (Apo E-albumin nanoparticles). IV administration, Apo E-albumin nanoparticles are internalized into the brain capillary endothelial cells by transcytosis and release into brain parenchyma. (Park, 2009).

After

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.

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)

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.