Comprehensive Strategies for Effective Brain Drug Delivery

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Comprehensive Strategies for Effective Brain Drug Delivery

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I. IntroductionMany neurotherapeutics are failed in treating Central Neuron System (CNS) because many

drugs do not penetrate the brain sufficiently. Brain drug delivery is very challenging because

there are barriers which separate the brain from its blood supply. These barriers act as controller

the transport of compounds. Those barriers are the highly restricted endothelium of the brain

capillary bed, i.e., blood-brain-barrier (BBB) and the protective layer of choroid plexus i.e.,

blood-cerebrospinal fluid barrier (BCSFB).

BBB is a major bottleneck in developing brain drug delivery and the most prominent factor

limiting the future growth of neurotherapeutics (Pardridge, 2005). Internally brain is protected

from harmful substances and noxious chemicals by BBB. BBB is a highly strengthened

membrane system of capillary endothelial cells which allow the supply of proper nutrients for

proper function (Alam et al., 2010). Endothelial cells in BBB guarantees brain homeostatis,

prevent free diffusion of hydrophilic molecules into the brain, and allow exact control over the

substances that leave and enter the brain (Risau, 1995). Complex endothelial junctions between

endothelial cells are mainly responsible for the barrier function and provide a high electrical

resistance of 1500-2000 cm2 compared to 3.33 cm2 in other body tissue (Crone and

Christensen, 1981).

The blood-cerebrospinal fluid barrier is another barrier after BBB that is systemically

administered drug encounters before entering the CNS. While BBB is considered to be localized

at the level of endothelial cells within CNS microvessels, the BCSFB is established by choroid

plexus epithelial cells (Engelhardt and Sorokin, 2009). Similar to endothelial barrier, the

morphological correlate of the BCSFB is found at the level of unique tight junctions between the

choroid plexus epithelial cells inhibiting diffusion of water-soluble molecules across this barrier.

Besides its barrier function, choroid plexus epithelial cells have a secretory function and produce

cerebrospinal fluid. Choroidal epithelium has appeared as a complex organ with many additional

functions such as neuroendocrine signaling, neuroimmune, and neuroimflammatory response.

Figure 1 shows blood-cerebrospinal fluid barrier (BCSFB).


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Figure 1 The Blood Cerebrospinal Fluid Barrier (source: http://www.ncbi.nlm.nih.gov/bookshelf)

Additionally, circumventricular organ (CVO) are present adjacent to the brain ventricles in

some regions of central neuron system (CNS). Circulamventricular organs have an incomplete

blood-brain barrier. In CVO, BBB capillary endothelial tight junctions are absent. These brain

sites are unique because 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 relative surface area of tight BBB capillaries is very less

compared to the area of tight BBB capillaries (5000:1) (Begley, 2004).

II. Endogenous Blood-Brain Barrier TransportersDifferent from peripheral capillaries that permit relatively free exchange of substance

across cells, the BBB vigorously limits transport into the brain. BBB not only acts as physical

barrier, but also a biochemical barrier that secrete certain enzymes, like peptidases along with

several cytosolic enzymes that help effluxing drugs from the endothelial cells back into the blood

which is a protective action toward the brain microenvironment (Bernacki et al., 2008). BBB is


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often the rate-limiting factor in determining permeation of drugs into the brain. Small molecules

generally cross the BBB in pharmacogically significant amount if the molecular mass of drug is

less than 400 500 Da and drug forms less than 8 10 hydrogen bonds with solvent water

(Pardridge, 2005).

The anatomical basis of the BBB is the brain microvascular endothelial barrier. The brain

microvasculature consists of four cells, include endothelial cells, the pericyte, which shares the

basement membrane with the endothelial cell, the astrocyte foot process, which invests about 90-

98% of the brain surface of the microvasculature, and the nerve endings that end directly on the

vascular surface. Although all four cells contribute to the functioning of the microvasculature in

brain, the permeability properties of the BBB are controlled only by the capillary endothelial

cells (Pardridge, 2007).

Figure 2 The Brain Microvasculature

The endogenous transporters of the BBB are expressed on the luminal and abluminal

membranes of the brain capillary epithelial cell. The transporters can be classified into three

categories, carrier mediated transport (CMT), active efflux transport (AET), and receptor-

mediated transport (RMT). CMT and AET systems are responsible for the transport of small

molecules between blood and brain, whereas the RMT systems are responsible for the transport

across the BBB of certain endogenous large molecules.


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Table 1 Description of several receptors responsible for the transport of molecules through BBB under

receptor-mediated transport system

Transport System Receptors Molecules

Receptor-mediated transport(RMT)

Insulin receptor (INSR)Transferrin receptor (TFR)

Insulin-like growth factorreceptors (IGF1R & IGF2R)

InsulinTransferrin

Insulin-like growth factor(IGF1R & IGF2R)

Table 2 Description of carrier mediated transport system with several different transporters and endogenous

molecules to be transported

Transport System Transporters Molecules Use

Carrier mediatedtransport (CMT)

LAT1 (Large neutralamino acid transporter 1)

Large and smallneutral amino acids

In parkinsonism,hypertension, and in

delivery ofantieptileptic drug

MCT1 (Monocarboxylicacid transporter 1)

Lactate, pyruvate,ketone bodies and

monocarboxylic aciddrugs like probenecid

In treatment of goutand urinary

incontinence

CNT2 (Concentrativenucleoside transporter 2)

Purine nucleosidesand certain pyrimidine

nucleosides as uridine

In delivery of severalanticancer and

antiviral drugs


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Table 3 Classification of active efflux transporter system (based on energy dependence) with transporters and

drug molecules to be transported

Transport System Classification TransportersD

rug moleculesActive effluxtransporter (AET)

Energy and Na+dependent transporters

(luminal membrane)

ABCB1 (Adenosinetriphosphate-binding

cassette transporter,subfamily B, member

1)

In targeting ofantitumor drugs like

doxorubicin,paclitaxel to brain

ABCC (Adenosine

triphosphate-bindngcassette transporter,

subfamility C)

Anticancer drugs

Na+

and Cl-dependent

low affinity system

ATA2 (Acidic

aminoacid transporter2)

Small neutral amino

acids like L-alanine,L-glycine, L-proline

It has been investigated that 100% of large-molecule pharmaceutics, including peptides,

recombinant proteins, monoclonal antibodies, RNA interference (RNAi)-based drugs and gene

therapies, do not cross the BBB. And also more than 98% of small molecules do not cross the

BBB either. Only 5% or 7000 drugs in the comprehensive medicinal chemistry that treats the

CNS disorders. That drugs which treat CNS disorders are limited to three conditions: depression,

schizophrenia, and insomnia.D

ue to these circumstances, development of BBB drug deliverytechnologies would be a high priority in the pharmaceutical industry and in the academic

sciences. The BBB drug delivery problem can be solved but requires new approaches and new

strategies.

Drugs which are administered into brain can be delivered in several methods, such as

1) Direct delivery system2) Direct central neural system (CNS) system3) Chemistry based approach4) Novel approach for brain targeting5) Biotechnology based approach


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III. Direct Delivery SystemDirect delivery system of brain drug delivery can be conducted by several methods, such as

intraventricular delivery and intra-arterial delivery.

III.1. Intravenous Delivery SystemDrugs can be directly injected into the cerebrospinal fluid intraventricularly. This method

guarantee the drug to reach the specific site on brain and avoid first-pass effect. This approach

has an impressive potential to deliver drugs to almost all neurons in brain because neurons in

brain are well connected with the blood vessels. In addition, the drug bioavailability through

intravenous is highly affected by the half life of the drug in plasma, rapid metabolism, and level

of non-specific binding to plasma proteins (Alam et al., 2010).

Several drugs have shown a theurapeutic effect in clinical trials when this drug

administration was applied. Large reduction in stroke volume can be achieved by intravenous

administration of neurotrophins such as brain-derived neurotrophic factor (BDNF) (Zhang and

Pardridge, 2001). The gene expression was found to be effective when delivered intravenously

from external source to brain (Shi et al., 2001).

III.2. Intra-antrial Delivery SystemDelivery of therapeutics agent by nasal administration to brain has attracted many

researchers interest. There are three routes along which a drug administered into the nasal cavity

may pass through, (1) entry into systemic circulation directly from nasal mucosa, (2) entry into

the olfactory bulb via axonal transport along neurons, and (3) direct entry into brain (Graff and

Pollack, 2005). Transnasal delivery is noninvasive method of bypassing the BBB to deliver the

drug substances to the central neuron system. Many agents active in the CNS are more effective

when administered nasally and only required small dosage, self administration and do not require

sterile technique. However, this method also has several disadvantageous, such as damage of

nasal mucosa on the frequent use of this method, rapid clearance from nasal mucosa cavity by

mucociliary clearance system, and elimination of some quantity of drug absorbed systemically

via normal clearance mechanism and possibility of partial degradation to the nasal mucosa.


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Dopamine and morphine have high water solubility and lower lipid solubility. These drugs

can be transferred into the olfactory bulb following nasal administration (Dahlin et al., 2000).

IV. Direct Central Neural System (CNS) SystemBy direct injection of drug to central neural system or parenchymal space, it is possible to

achieve much higher concentration of drug in the brain (Graff and Pollack, 2005). Direct CNS

delivery systems can be conducted by several methods. On this paper, I will describe

intracerebral delivery and transcranial delivery.

IV.1. Intracerebral (intraparenchimal) DeliveryIntracerebral delivery entails delivery of drug directly into brain parenchimal space. Drugs

can be administered (1) via direct injection via intrathecal catheters, (2) by control release

matrices, (3) Mincroencapsulated chemicasls, or (4) recombinant cell. The main problem with

injection is slow movement of compounds within the brain because of the restricted diffusion

coefficient. The reason is because of the closely packed arrangement of cells in both gray and

white microenvironment. Hence a large amount of drug dosage is necessary for an appropriate

drug concentration in parenchyma. On the other hand the continuous infusion method can beapplied which uses convection enhanced diffusion phenomena to drive the drugs to a larger

tissue region.

Intracerebral implants are devices for controlled release of drugs at the target site in the

brain. Implants are made up of biodegradable/non-biodegradable polymeric materials

encapsulating drugs inside it. The basic mechanism of drug release from this device is diffusion.

Several cases which utilize this method are available where brain implants have already been

employed for curing diseases. An implant containing nerve growth factor when implanted in

brain to cure a quadriplegic patient showed better results from spinal cord damage. These

implants are implanted inside the brain surgically where they release the drug for a

predetermined level of time. In the same wat, the vapor pressure activated devices like Ommaya

reservoir pump (a dome-shaped device, with a catheter attached to the underside used to deliver


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chemotherapy) containing etoposide, an antitumor agent used for healing metastatic brain tumor

showed 100-fold more effective concentration.

Figure 3 Ommaya reservoir

IV.2. Intraventricular Delivery (Transranial Drug Delivery)Like other approaches intraventricular route also act as an approach to avoid BBB where

therapeutic agents are implanted directly into cerebral ventricle. This route is suited for

meningioma medication and metastatic cells of CSF as it distributes drugs mainly into ventricles

and subarachnoidal area of brain. Main benefit of this route is its lack of interconnection with

interstitial fluid of brain unlike intracerebral delivery. Cerebrospinal fluid (CSF) is in a free

communication with the interstitial fluid of brain, thus allowing for free movement into the

parenchyma (Lo et al., 2001). The drug achieves higher concentration in brain in comparison to


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that of its extravascular distribution. However the effectiveness of this route may be much more

limited due to low diffusion rate. Diffusion decreases logarithmically with each millimeter of

increase in distance of brain tissue. Slow intraventricular infusion is found to be very effective

when compared to bolus administration. Cytosine arabinoside is a chemotherapy agent used

mainly for treating hematological malignancies such as acute leukemia and non-hodgkin

lymphoma. When delivered by slow intraventricular infusion cytosine arabinoside was 71%

more effective as compared to when given intrathecally.

V. Chemistry Based ApproachSome chemical substances showed significant effect in transporting the drug substances

through BBB. Drug delivery using chemistry-based include the use of chimeric peptides and

cationic polymer.

V.1. Chimeric PeptideDrug 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. These chimericpeptides are formed by covalent binding of a BBB non-permeable neuropeptide with the vector.

After formation of such peptides, they are transported to brain by various transportation

pathways like peptide-specific receptor. For example, insulin and transferrin are the two

circulating peptides which undergo trancytosis by their insulin and transferrin receptor present at

BBB. There are two principles that should be considered in this administration method, firstly

the vector itself should have pharmacological activity, for example insulin a natural peptide has

its own transport mechanism. Secondly, the interaction between peptide vectors with its binding

receptor site must be highly specific for targeting drug to brain.

V.2. Cationic ProteinsCationic 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. Proteins are generally


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have high molecular weight, therefore they are not able to cross the BBB because of their large

size (Pardridge, 2002). 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. After cationization they easily enter by

using the transcellular adsorptive-mediated endocytosis pathways. Cationization is a process

which improves the net positive charge on the polypeptide by modifying the free carboxyl

groups of acidic amino acid residues on a polypeptide.

Various cationic proteins have been reported to penetrate the BBB including avidin,

histone, protamine, and cationized polyclonal bovine immunoglobulin (Brasnjevic et al., 2009).

VI. Novel Approach for Brain TargetingVI.1. Liposomes

Liposomes are defined as non-toxic, biocompatible and biodegradable lipid body carrier

made up of animal lipid like phospholipids, sphingolipids, etc. They have benefits of carrying

hydrophyilic, lipophilic, as well as amphoteric drug molecules either entrapped inside it or its

micellar surface.

There are several advances technology in liposomal technology. The surface modifiedliposomes can be employed to encapsulate drug molecules to diseased tissue or organ directly.

The basic mechanism by which these liposomes achieve brain concentration by crossing BBB is

by coupling with brain drug transport vector via receptor-mediated transcytosis or by absorptive-

mediated transcytosis. Cationic liposome have shown to cross the BBB easily through absorptive

mediated transcytosis (Schnyder and Huwyler, 2005). The finding proved that liposomes with

additional sulphatide groups, such as sulphate ester of galactocerebrocides increased the crossing

ability across BBB.

VI.2. Nanoparticles Nanoparticles have attracted interest in targeting drug molecules to brain. Nanodelivery

systems have impressive potential to facilitate the drug movement across barriers, such as BBB.


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Nanosystems employed for the development of nano drug delivery system in the treatment of

CNS disorders include polymeric nanoparticles, nanospheres, nanosuspensions, etc.

The correct mechanism of barrier opening by nanoparticles still open to question. But the

delivered nanoparticles enter into the brain by crossing the BBB by various endocytotic

mechanisms. Nanoparticles can be designed from albumin. Albumin nanoparticles is attached

with apoliprotein E (Apo E-albumin nanoparticles). After intravenous administration, Apo E-

albumin nanoparticles are internalized into the brain capillary endothelial cells. This is followed

by transcytosis and release into brain parenchyma and the subsequent appearance of these

particles in the cytoplasm of neurons. This observation provides a strong evidence of a

mechanism enabling the direct delivery of the albumin-bound drugs to the central neuronal

targets (Park, 2009).

VII. Biotechnology Based ApproachVII.1. Monoclonal Antibodies for Targeting

Monoclonal antibodies for targeting are usually prepared by hybridoma technology by

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 braintargeting, they are modified structurally to get genetically engineered monoclonal antibodies.

VII.2. Application of Genomics in Brain Drug DeliveryThe word genome corresponds to the total D NA contained in an organism in a cell.

Therefore genomics is described as the study related with structure and function of genome.

Common of the CNS disorders (e.g. Alzheimer;s disease, cerebral AIDS, stroke, brain cancer)

that have not been beneficially treated by small molecule therapy could be cured with large

molecule pharmaceuticals, which do not cross the brain capillary endothelial wall. There drugs

are transported through the BBB using gene technologies.

The most prominent application of genomics is in identifying the different molecular

vectors, carriers, transporters which express on the membranes of blood-brain barrier and helps

in transporting the drug molecules and peptides to brain microenvironmenment.


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VIII.ConclusionEven 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. To obtain capable drug delivery we must

take into account the interaction between drug and biological environment, changes of drug in

cell receptors that occur with progression of disease, mechanism and site of drug action, multiple

drug administration, and pathobiology of the disease.

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Comprehensive Strategies for Effective Brain Drug Delivery

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