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Getting into the Brain: Approaches

to Enhance Brain Drug Delivery
Article in CNS Drugs February 2009
Source: PubMed

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Shraddha Bhadada

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nn72-7047/09/000i-Xi35/S49.95/0
72-7047/09/0001-X135/S49.95/0
O 2009 ACHS Dato Information av. All ftghts reserved

Getting into the Brain

Approaches to Enhance Brain Drug Delivery
Mayur M. Patel, Bhoomika R. Goya, Shraddim V. Bfiadada, ]ay S. Bhatt and
Avani F. Amin
Institute of Pharmacy, Nirma University of Science and Technology, Ahmedabad, India

Contents
Abstract
1. Approaches to Enhance Brain Drug Delivery
1.1 Chemical Delivery Systems
1.1.1 Upid-iviediated Transport (Upidization of Smaii Moiecules)
1.1.2 Prodrug Approach
1.1.3 Lock-in System
1.2 Bioiogica! Deiivery Systems
1.2.1 Adsorptive-Mediated Transcytosis
1.2.2 Carrier-Mediated Transport
1.2.3 Receptor-Mediated Transport
1.2.4 Active Efflux Transport
1.2.5 Peptide Vector Strategies
1.3 Disruption of the Blood Brain-Barrier (BBB)
1.3.1 Osmotic Disruption of the BBB (Hyperosmotic Shoci<)
1.3.2 Biochemicai Disruption of the BBB (Administration of Vasoactive Substances)
1.3.3 BBB Disruption by Alkylgiycerols
1.4 Molecular Trojan Horses for Brain Drug Deiivery
1.5 Drug Delivery Approach
1.5.1 Drug Delivery via Catheters and Pumps
1.5.2 Drug Deiivery from Microspheres
1.5.3 Drug Delivery from Biodegradabie Wafers
1.5.4 Drug Delivery from Colioidai Drug Carrier Systems
1.5.5 Drug Delivery from Biologicai Tissues
1.5.6 Drug Delivery from Microchips
1.6 Other Alternative Routes/Methods
1.6.1 Intranasal Drug Delivery to the Brain
1.6,2 Convection-Enhanced Diffusion
1.6,3 Intrathecal/lntraventricuiar Drug Deiivery to the Brain
2. Conciusion

Abstract

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Being the most delicate organ of the body, the brain is protected against
potentially toxic substances by the blood-brain barrier (BBB), which restricts the
entry of most pharmaceuticals into the brain. The developmental process for new
drugs for the treatment of CNS disorders has not kept pace with progress in
molecular neurosciences because most of the new drugs discovered are unable to
cross the BBB. The clinical failure of CNS drug delivery may be attributed largely
to a lack of appropriate drug delivery systems. Localized and controlled delivery

36

Patcl et al.

of drugs at their desired site of action is preferred because it reduces toxicity and
increases treatment efficiency. The present review provides an insight into some
of the recent advances made in the lield of brain drug delivery.
The various strategies that have been explored to increase drug delivery into
the brain include (i) chemical delivery systems, such as lipid-mediated transport,
the prodrug approach and the lock-in system; (ii) biological delivery systems, in
which Pharmaceuticals are re-engineered to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium; {iii} disruption
of the BBB. for example by modification of tight junctions, which causes a
controlled and transient increase in the permeability of brain capillaries; (iv) the
use of molecular Trojan horses, such as peptidomimetic monoclonal antibodies to
transport large molecules (e.g. antibodies, recombinant proteins, nonviral gene
medicines or RNA interference drugs) across the BBB; and (v) particulate drug
carrier systems. Receptor-mediated transport systems exist for certain endogenous
peptides, such as insulin and transferrin. enabling these molecules to cross the
BBB (il vivo.
The use of polymers for local drug delivery has greatly expanded the spectrum
of drugs available for the treatment of brain diseases, such as malignant tumours
and Alzheimer's disease. In addition, various drug delivery systems (e.g. liposomes, microspheres. nanoparticles. nanogels and bionanocapsules) have been
used to enhance drug delivery to the brain. Recently, microchips and biodegradable polymers have become important in brain tumour therapy.
The intense search for altemative routes of drug delivery (e.g. intranasal drug
delivery, convection-enhanced diffusion and intrathecal/intraventricular drug
delivery systems) has been driven by the need to overcome the physiological
barriers of the brain and to achieve high drug concentrations within the brain. For
more than 30 years, considerable efforts have been made to enhance the delivery
of therapeutic molecules across the vascular barriers of the CNS. The current
challenge is to develop drug delivery strategies that will allow the passage of drug
molecules through the BBB in a safe and effective manner.

Despite considerable advances in research in the

area of brain and CNS disorders, diseases of the
CNS remain tbe world's leading cause of disabilities, accounting for more hospitalizations and prolonged care than almost all other diseases combined.
Being the most delicate organ of the body, the brain
is protected against potentially toxic substances by
the blood-brain barrier (BBB); however, the BBB
also prevents the penetration of most molecules that
have potential activity in the CNS. For drugs to be
effective against CNS diseases, they must reach the
brain by crossing the BBB. The BBB is a unique
complex endothelial barrier that segregates the cireulating blood compartment of the brain from the
2009 Adis Data Information BV. All rtghis reserved.

extracellular fluid (figure I ). The BBB consists of a

continuous layer o endothelial cells joined by complex tight junctions. The luminal plasma membrane
of the endothelial cells faces the blood compartment, wbereas tbe abluminal membrane is directed
towards the brain extracellular fluid.^''^
A common belief is that small molecules readily
cross tbe BBB; however, findings suggest that 98%
of small molecules are not able to cros.s tbe BBB and
that 100% of large molecules cannot cross the
BBB.l-^^ Limited penetration of a drug into the brain
is the rule rather than the exception. One study'-'^J
revealed that of 7000 drugs in the Comprehensive
Medicinal Cbemistry database,''^' only 5% are used
CNS Drugs 2009:23 CD

Getting into the Brain

37

Tight
junctions

Astrocyte foot
process
Capillary
endothelial cells
Fig. 1. Components of the blood-brain barrier.

for the Ireaimenl of CNS diseases (i.e. mainly depression, schizophrenia and insomnia). Another
study'^i revealed ihal although 12% of drugs are
active on the CNS. only 1% are active in the brain
for diseases other than affective disorders.
Despite aggressive research, patients experiencing fatal and/or debilitating CNS diseases, such as
brain tumours, HIV encephalopathy, epilepsy, cerebrovascular diseases and neurodegenerative disorders, far outnumber those dying of all types of
systemic cancer or beart disease. Tbe incidence of
CNS disorders in humans increases witb age; this,
along with the fact that very few drugs can cross tbe
BBB, exacerbates tbe problem of drug delivery to
tbe CNS. It is predicted that by 2020, the number of
people in tbe US aged >65 years will increase by
50%,t^l wbicb will result in a simultaneous increase
in CNS disorders. Tbis would result in an annual
expenditure in the US for Alzbeimer's disease alone
of $US0.5 trillion. Because one in every three people will experience a CNS disorder during his/her
lifetime, tbe neuropbarmaceutical market is predicted to become tbe largest sector of tbe pharmaceutical industry.'^' Although the global market for CNS
drugs compared with other classes of drugs bas
recently fallen considerably, a growth rate of approximately 500% would be required for the market
for CNS drugs to be comparable to that for cardiovascular drugS-f"^' Again, the principal reason for
this decrease is the difficulty in getting most CNS
drugs to cross the BBB. Taking into tbe considerae 2009 Adis Data Informatton BV. Allrightsreserved.

tion tbe potential size of tbe global neuropharmaceutical market and the fact that only a few drugs can
cross tbe BBB, one would predict tbat a priority for
both the pharmaceutical industry and researchers
would be tbe development of drug delivery technologies that enable drugs to cross tbe BBB.
Modern methods of CNS drug discovery consider expected pbarmacological effects only after direct
injection of tbe drug into tbe brain and not after
systemic administration, because the transport of
drugs across the BBB after systemic administration
is negligible. Tbe flow chart in figure 2 shows an
approach made some years ago to tbe development
of CNS drugs. There are two pathways by which
CNS drugs may be developed: tbrougb trial and
error or using rational drug design. Rational drug
design is based on bigb-tbrougbput screening of
tbousands of molecules and has a tendency to identify drugs witb negligible ability to cross the BBB.
Therefore, in tbe absence of parallel progress in tbe
development of CNS drug delivery strategies, the
CNS drug discovery programme invariably ends in
failure. If effective CNS drug delivery systems were
available, the drug discovery programme would be
successful.
The present review deals mainly witb the various
approaches used to get drug molecules into tbe brain
CNS
drug discovery

Trial and error

Rational drug design

High-throughput screening

CNS
dmg development

BBB transport of dnjg

is negligible

CNS
drug discovery
Programme
cessation
Slices
Fig. 2. Flow chart representing the CNS drug development approach. BBB = biood-brain barrier.

CNB Drugs 2009; 23(1)

Patd et al.

38

and will hopefully provide valuable insights for

researchers interested in rational drug design of
CNS drugs.
1. Approaches to Enhance Brain
Drug Delivery
1. ] Chemical Delivery Systems
There have been various attempts to overcome
the hmited access of drugs to the hrain by chemically modifying particular drugs. Chemical delivery
systems can be divided into three main groups,
namely lipid-mediated transport (Iipidization of
small molecules), a prodrug approach and a iock-in
system (LIS).
1.1.1 Lipid'Mediafed Transport (Lipidizafion of
Smalt Molecules)

Lipidization of a drug mainly involves the addition of lipid-like molecules by modification of the
hydrophilic moieties on the drug structure. Drug
permeability across the BBB is favoured by
lipophilicity, low molecular weight and lack of ionization at physiological pH. It is believed that lipidsoluble molecules {with a molecular weight
<5(X) Da) may cross the BBB through the small
pores that form transiently within the lipid bilayer.l">'2l
Drug transport across the BBB can also be increased by the addition of hydrophobic groups to a
molecule, which improves drug transportation
mainly by passive diffusion (figure 3). The best
example of this sort of modification is the addition
of methyl groups to various drugs in the barbiturate
class, which results in increased lipophilicity and
brain penetration in animals.l'^'"*' Morphine is converted to heroin by diacetylation of its two hydroxyl
groups, which results in the removal of two hydrogen bonds between the drug and solvent (water).
The transportation of heroin across the BBB is reported to be approximately 100-fold greater than for
its parent drug morphine owing to the lipophilic
nature of heroin.^'''1 As a general rule, the BBB
permeability of a drug decreases one log order in
magnitude for each pair of hydrogen bonds added to
ihe molecule as a polar functional group.'^'^^

2009 Adis Da+O Information BV. All rights reserved.

+}
Adsorptive* mediated
+)
Iranscylosis
Carriermediated
transport
Receptormedialed
transport
Active efflux
transport

Fig. 3. Transport mechanisms across the blood-brain barrier. P-gp

= P-giycoprotein.

Recently, with the emergence of liposomal drug

delivery as an alternative to changing the lipophilicity of a drug, the ability of the drug to cross the less
permeable and lipophilic BBB and to reach the
brain, have improved. For example, improved drug
delivery has been demonstrated for encapsulated
doxorubicin in the treatment of experimental brain
tumours.''^"'^' Similar observations were made
when liposomal doxorubicin was administered in
phase I/II clinical trials to patients with brain
tumours: patients exhibited stabilization of symptoms and increased survival
'^^^
There are certain drawbacks to the lipidization of
drugs. First, increasing the lipid solubility of a drug
will increase the permeability of the lipidized molecule across al! biological membranes in the btdy,
not just the BBB. This will affect the plasma distribution of the drug, increasing plasma clearance and
subsequently decreasing the plasma area under the
concentration-time curve (AUC). In their study of
lipidized chlorambucil, Greig et al.'--' suggested that
the plasma AUC of this formulation was reduced.
Thus, although the pharmacological activity of a
drug may be increased as a result of the greater
transfer of drug across the BBB, the increased lipid
solubility also results in increased plasma clearance,
with a subsequent reduction in the plasma AUC,
leading to a significant change in drug therapy.'^^-'1
Second, increased lipophilieiiy enhances plasma
protein binding, which could neutralize any benefits
associated with increased BBB permeability follow-

CNSDfugs2009;23Cl)

Getting into- the Brain

ing lipidization.f**' Third, lipidization will increase

the molecular weight of a drug. Drugs that have a
molecular weight >400-500 Da are unahle to cross
the BBB in a pharmacologically significant amount.
Fischer et a\S^'*^ reported that BBB permeability
decreases exponentially with an increase in the molecular size of a drug. If the size of a drug is
increased from 52 A (molecular weight, 200 Da) to
105 A (molecular weight, 450 Da), its BBB permeability decreases 100-fold.["'
1.1.2 Prodrug Approach

The transport of drugs across the BBB can he

increased using the prodrug approach.i^'^' The design
and use of prodrugs helps overcome any pharmaceutical and/or pharmacokinetic prohlems associated
with the parent drug molecule. Modification of the
properties of the prodrug can increase its affinity for
the receptor target and improve its residence time.
The prodrug is then converted at the site of action hy
either a chemical reaction or enzyme activity to a
physiologically active compound. A typical example of the prodrug approach is the amidation or
esterification of amino, carboxyl and hydroxyl
groups, which increases their lipid solubility, thus
causing higher uptake in the brain. Subsequent hydrolysis of these groups leads to the release of the
active drug into the hrain. Alternative prcxlrug formation could include the coupling of the active drug
with lipid moieties, such as fatty acids, glycerides or
phospho lipids.
Prodrugs of acid-containing CNS drugs, such as
niflumic acid, valproate, levodopa, vigabatrin and
GABA, have heen prepared by coupling these drugs
with diglycerides or modified diglycerides.!-''! Although increased lipophilicity facilitates drug transport across the BBB, it also enhances the efflux
process, which, in turn, results in poor tissue retention. Furthermore, if, in addition to its conversion to
parent drug, the prodrug is metabolized by other
pathways, there is the possibility of toxicity as a
result of the production of these other metabo1.1.3 Lock-In System

In addition to the lipidization or attachment of

hydrophobic groups, chemical modification of a
2009 Ad!s Data Informotion flV. Allrightsreserved.

39

drug moiety can also increase its transport across the

BBB. The LIS requires multichemieal or enzymatic
transformations for release of the active drug.'-^' In
this system, two types of bioremovable moieties are
usually introduced to convert the drug into an inactive precursor: a targetor moiety and a mtKJificr
function. The targetor moiety is responsihle for
targeting, site specificity and lock in. whereas the
modifier function serves as a lipophilizer that protects against certain functions, or fine tunes which
molecular properties are necessary to prevent premature, unwanted metabolic conversions. Once the
lipophilic compound of the LIS enters the hrain, it is
converted into lipid-insoluhle moieties and, hence,
cannot leave the brain (i.e. it is locked in).
The LIS concept evolved from the prodrug concept and the only difference hetween the two systems is that although the prodrug contains one or
more modifier function moieties, it does not contain
targetor moieties.t^' Another type of LIS is based on
a dihydropyridine<->quaternary pyridinium ion redox system, which is chemically analogous to the
NAD+<->NADH coenzyme system. The active drug
is transformed to a 1,4-dihydropyridine moiety-containing conjugate, which is a type of LIS and is more
lipophilic than the parent drug. When administered
systemically in animals, the conjugated drug has
been found to be distrihuted extensively throughout
the body, including the hrain.^-^^ Upon oxidization in
the body, the unstable dihydropyridine derivative
forms a hydrophilic polar quaternary pyridinium
salt, which, although eliminated from most tissues,
is retained in the brain. Retention of the pyridinium
salt in the brain is due to the 'locking in' of the
ionized moiety hy the BBB. Subsequently, cleavage
of the carrier releases the free active drug.^-^i
During the past decade, targeted drug delivery to
the brain through phosphonated derivatization has
been explored and so-called anionic chemical delivery systems have been designed, synthesized and
evaluated for testosterone'^'' and zidovudine^^^l
1,2 Biological Delivery Systems
There are several mechanisms hy which a molecule can cross the BBB (figure 3).'^^' Some of these
C^eDnJgs 2009; 23(1)

40

Patel el al.

have been used to enhance the transport of drug

from the blood to the brain and include adsorptivemedialed transcytosis, carrier-mediated transport,
receptor-mediated transport, active efflux transport
and peptide vector strategies, each of which is discussed in greater detail below.
J.2.1 Adsorptive-Mediated

Transcytosis

The cellular uptake of proteins such as albumin

and antibodies (IgG) can be enhanced by cationic
modification. The cationized proteins mainly cross
the BBB by adsorptive-mediated transcytosis
(AMT). An electrostatic interaction exists between
the cationized albumin and anionic charges on the
BBB. This interaction also occurs further with sialic
acid moieties on the luminal surface and heparin
sulfate groups on the abluminal surface. AMT of
cationized albumin is triggered by this electrostatic
interaction and results in the transport of the moiety
across the BBB. The use of cationized albumin for
the transport of endorphin, a very large molecule
that cannot cross the BBB, has been reported in
-3(5 34.35) After conjugation with cationized albumin, brain uptake of -endorphin was increased.
When the isoeiectric point of antibodies is raised
from neutral to highly alkaline, cationized antibodies are formed. These antibodies are used mainly
as neu rtxl i agnostic and neuroimaging agents in various diseases, including brain tumours, Alzheimer's
disease and stroke.^-^'^i For example, an antibody
that recognizes a specific antigen on tumour cells
can be used to detect a brain tumour.

1.2.2 Carrier-Mediated Transport

Carrier-mediated transport (CMT) involves the

modification of a daig {small molecule) into a compound with a similar structure that mimics a nutrient
and can thus make use of one of the several specialized CMT systems within the BBB that exist for the
transport of essential compounds, such as amino
acids, hexoses, vitamins and neuropeptides, into the
brain. For example, dopamine, a water-soluble catccholamine, cannot cross the BBB, but once dopamine has been transformed to levodopa, a large
neutral amino acid, it can cross the BBB making use
of the large neutral amino acid transporter
(LNAT).f^^l This transformation of dopamine has
been used for approximately four decades to deliver
dopamine into the brain for the trealment of Parkinson's disease.'-^^' Other drugs that cross the BBB
via the LNAT include a-methyldopa, gabapentin
and melphalan.i"'-^' In addition to the LNAT, Na+dependent vitamin C transporters are also involved
in the transport of drugs across the BBB that would
otherwise be unable to reach the brain, such as
nipecotic acid and kynurenic acid.'"*^' Table I lists
the important transporters in the BBB ind the molecules they transport.
The main goal of BBB biology is the molecular
cloning of the specific transporters that function as
CMT for drugs across the BBB. Many members of
the glucose transporter (GLUT) gene family belong
to the solute carrier (SLC) subgroups. SLC2, SLC7
and SLC 16, among others, have been reported to be
localized at the BBB.'''''i Studies investigating the
number of GLUTI sites have reported that GLUTl
constitutes >90% of BBB glucose transporters. By

Table I. Canier-mediated transporter across the bfood-brain barrier

Transporter

Molecules transponed

Glucose transporter, member 1

Glucose and other hexose molecules, including 2-deoxyglucose and

ttuoro-deoxyglucose

Large neutral amino acid transix>ner, member 1

Large and small neutral amino acids, levodopa

Cationic amino acid transporter, member 1

Basic amino acids, such as lysine and arginine

Lactate, ketone bodies, pyruvate and certain monocarboxylic acid drugs,
such as probenecid

Monocartioxylic acid transporter, member 1

Concentrative nucleoside transporter, member 2

Purine nucleosides and certain pyrimidine nudeosides. such as uridina

Choline transporter*

Choline

Nucleobase transporter^
a

Purine bases
These transporters have not yet been cloned or identified at the molecular level tor the BBB.

2009 Adis Data Information BV. All rights reserved.

CNS Drugs 2009; 23 <1)

Getting into the Brain

conjugating galactose and tyrosine chemically with

glucose, Bonina et al.^"''^''^' have designed prodrug
esters of two anticonvulsant drugs, namely nipeeotic
acid and 7-chloronokynurenic acid, tbat can be
transported across the BBB by GLUTl. The major
LNAT is LAT, whereas the major cationic amino
acid transporter is CATl. In rats, CNT2 is the adenosine transporter in the BBB. It has been shown in
vivo that adenosine flux from the blood to the brain
via CNT2 is a sodium-dependent process in the rat
species.f^**"*^! As indicated in table I, the eholine
transporter and the adenine nucleobase transporter
in the BBB have not yet been cloned.
1.2.3 Receptor-Mediated Transport

Receptor-mediated transport (RMT) is how large

endogenous molecules, such as neuropeptides (insulin, transferrin or leptin), cross the BBB. Table II
lists some of the important RMT systems in the
BBB. Insulin uptake into the brain is mediated by
tbe insulin receptor,'''^! transferrin uptake is mediated by the transferrin receptor (TfR), insulin-like
growth factor (IGF) uptake is mediated by the TGF
receptor and leptin uptake is mediated by the leptin
receptor.f^'' After intracerebral injection, IgG molecules are rapidly effluxed out of the brain by reverse
transcytosis mediated by a BBB Fc receptor (FcR),
also called FeRn (the neonatal Fc receptor) or
the Fc fragment of IgG receptor transporter
(FcGRT).t"-'''^ Brain endothelial cells also express
scavenger receptors (scavenger receptor, class B,
member 1 [SR-BI]), commonly known as acetylated
low-density lipoprotein (LDL) receptors.'"^J
Designing genetically engineered fusion proteins
to make use of RMT to transport molecules across
the BBB is another approach for brain targeting.
These proteins are prepared by fusing human transferrin to mouse-human chimeric IgG3 at three positions: at the end of heavy chain constant region 1,
after the hinge, and after constant region 3. The
resulting proteins reached the brain parenchyma
after intravenous injection by IgG RMTJ''*''
Fusion proteins have also been designed to prevent cerebrovascular tbrombosis. Low molecular
weight, single-chain urokinase-type plasminogen
activator has been fused with anti-platelet-endothe 2009 Adis Data Information BV. All rtghis reserved.

41

TaWe 1). Important receptor-mediated transporter {RMT) systems

at the blood-brain barrier
RMT systems

Molecules transported

INSR

Insulin

TtR

Transferrin

1GF-1R, GF-2R

IGF

LEPR

Leptin

FcGRT

Immunoglobuiln

SR-BI or acetylated LDL

LDL particiGs, nanoparticles and

sofid iipid nanoparticles
FcGRT = Fo fragment of IgG receptor transporter: IGF = insuiin-iike
growth factor; IGF-1R = iGF-1 receptor; IGF-2R = IGF-2
receptor; INSR = insulin receptor; LDL = low-density lipoprotein;
LEPR = leptin receptor; SR-BI = scavenger receptor, class B,
member 1; TfR = transferrin receptor.

liai cell adhesion molecule single-chain variable

fragment and demonstrated to cross the BBB.'^^^
When studied in mice, it was found that this fusion
protein accumulated in the brain after intravascular
injection and, without causing haemorrhagic complications, it lysed clots lodged in the cerebral arterial vasculature, resulting in rapid and stable cerebral
reperfusion.
Recently, the use of nanoparticles to transport
molecules via RMT has gained interest. Drugs in the
nanoparticulate form that have been transported successfully to the brain via RMT include the hexapeptide dalargin, the dipeptide kytorphin, loperamide,
tubocurarine, the NMDA receptor antagonist MRZ
2/576 and doxorubicin. It is believed that the
nanoparticles mimic LDL particles and are subsequently transported by the LDL receptor.^^''"^^1 In
another study, translocation into the rat brain was
compared for poly(methoxy-polyethyleneglycol
cyanoacrylate-co-n-hexadecylcyanoacrylate) [PEGPHDCA] nanoparticles and polyhexadecylcyanoacrylate (PHDCA) nanopartieles after intravenous injection using two-dimensional polyacrylamide gel electrophoresis, capillary electrophoresis
and the Protein Lab-on-chip (Johns Hopkins Whiting School of Engineering and the School of Medicine. BaUimore, MD, USA) method.i'^J In that
study, it was demonstrated that PEG-PHDCA
nanoparticles were able to translocate into the brain,
whereas non-PEGylated PHDCA nanoparticles
were not. Further studies were undertaken to deter-

CNS Drugs 2009; 23 CD

Patcl ct ai

42

mine tbe mecbanism of transport into the endotbeiial

cells in rat brain and it was found tbat transport was
mediated by tbe LDL receptor and was the result of
endocytosis of PEG-PHDCA nanoparticles into tbe
Advances in nanoparticle technology have resulted in tbe development of solid lipid nanoparticles
(SLN), which consist of spherical solid lipid particles in the nanometre range, dispersed in water or
in aqueous surfactant solution.'*^J Tbese SLN, coated witb hydrophilic polymer and specific ligands,
are detected to a lesser degree in the reticuloendothelial system (RES) and gain access to the brain
by RMT. For example, SLN coated witb PEG and
tbiamine ligands bind to tbiamine receptors and are
transported into the brain via RMT.f*^^ Highly
specific targeting of SLN can be acbieved by using
peptidomimetic antibodies to coat the SLN; these
targeted PEGylated immunonanoparticles bind to a
transcytotic receptor and cross the BBB without
changing its permeability.'^''
1.2.4 Active Etttux Transport

P-glycoprotein is tbe most widely researcbed aclive efflux transporter at tbe BBB. It is a product of
adenosine triphospbate-binding cassette (ABC)
transporter, subfamily B, member I, also called Pglycoprotein gene. Recently, it bas been reported
that the active efflux transport of drug from the brain
to the blood is mediated by two types of transporters: energy-dependent and energy-independent
transporters J^^l The energy-dependent transporter is

a member of tbe ABC gene family and is present at

tbe luminal membrane, wbereas tbe energy-independent transporter is present at tbe abluminal membrane and belongs to the SLC gene family. Members
of tbe SLC gene family include the organic anion
transporter (OAT) or OAT polypeptide, acidic
amino acid transporters, sucb as members of tbe
giutamic acid amino acid transporter family, and
active efflux transporters, such as tbe taurine transporter.f^'^ It is also possible tbat tbe energy-independent transporter is locaied at ibe luminal membrane
and tbat tbe energy-dependent transporter is present
at tbe abluminal membrane.'^"*'
1.2.5 Peptide Vector Strategies

Using small syntbetic peptides tbat can cross cell

membranes is another approach for the delivery of
neuropbarmaceuticals. Pegelin and peneiratin (18
and 16 amino acids, respectively) are small syntbetic peptides that can cross tbe BBB efficiently and
have been used effectively to deliver biologically
active substances to cells.f''-^"*! Rousselle et al.'''^i
coupled doxorubicin, an anticancer agent, witb the
small peptide vectors (SynBI) using a chemical
linker (succinate) and investigated tbe ability of the
complex to cross tbe BBB in an in situ cerebral
perfusion model in rats (figure 4). Tbe results oftbat
study sbowed tbat the brain uptake of doxorubicin
alone is very low because of efficient efflux by the
P-glycoprotein pump within the BBB. However,
when doxorubicin was coupled with the peptide
vectors, its uptake was increased significantly.

ONH

Doxorubucin

Peptide

Linker

Fig. 4. Structure of conjugated doxorubicin.

2009 Aclis Dato Information BV. All rights reserved.

CNSDiugs2009:23Cl)

Getting into the Brain

In another study. Schwarze et al.'^^' conjugated

the -galactosidase protein with a peptide derived
from transactivating regulatory proteins. Intraperitoneal injection of the peptide-fused proteins in mice
resulted in their transport to all biological tissues,
including the brain, whereas there was no transport
of unfused proteins into the brain.
1.3 Disruption of the Blood Brain-Barrier (BBB)

The presence of endothelial tight junctions prevents the passage of drugs across the BBB. Disruption of these tight junctions can lead to increased
drug delivery to the brain. The disruption of the
BBB must be transient and reversible to facilitate
the delivery of therapeutic molecules. Disruption of
the BBB leads to opening of either a paracellular
route through the endothelium by opening the tight
junctions or a transcellular route through the endothelium. The extent of the disruption of the BBB is
important because this intrusion may be highly toxic
and may lead to chronie ncuropathological changes,
cerebral vaseulopathy and seizures.''"'^^l Disruption
of the BBB can be achieved by osmotic disruption
(e.g. hyperosmotic shoek), biochemical disruption
(e.g. by the administration of vasoactive substances)
or by alkylglycerols, as discussed below.
1.3.1 Osmotic Disruption otthe BBB
(Hyperosmotic Stiock)

Osmotic disruption of the BBB increases the

brain delivery of water-soluble drugs. It occurs as a
result of shrinkage of endothelial cells because of
the hypertonic environment and the opening of the
endothelial tight junctions that constitute the analomical basis of tbe BBB.'^^-^^' Mannitol, a hyperosmolar agent that has been approved for use in patients, has been investigated in both preclinical and
clinical trials. Mannitol is used mainly for the administration of anticancer agents, such as cyclophosphamide, procarbazine and methotrexate, in the
treatment of brain tumours.'^'^ However, the use of
mannitol to improve drug uptake into the brain
should proceed with caution, because Salahuddin et
y| 177.82] cepxirted that when hypertonic mannitol was
infused into the carotid artery of rats, structural brain
damage was observed within regions showing BBB

2009 Adte Data Irrtormotion BV. All rights reserved.

43

disruption. Other risk factors associated with the use

of mannitol include the passage of plasma proteins
across the BBB, altered glucose uptake, expression
of heat shock proteins and microembolism or abnormal neuronal
1.3.2 Biochemical Disruption of the BBB
(Administration of Vasoactive Substances)

It has been reported that infusion of vasoactive

amines such as histamine, bradykinin and the bradykinin analogue receptor-mediated permeabilizer
(RMP)-7 selectively opens the blood-tumour barrier
in experimental animals. Bradykinin increases tight
junction permeability by activating bradykinin B2
receptors on endothelial cells.'^'*^ Matsukado et al.'^"^'
reported that RMP-7 increases drug delivery to
tumours and the survival of glioma-bearing rats.
Based on these findings, clinical trials were initiated
using RMP-7 to enhance the brain delivery of antitumour agents.f'*^'^''' In addition, RMP-7 was found to
be more stable and more potent tban bradykinin
in mice.^^''^ RMP-7 has been administered with
carboplatin to patients with gliomas in a phase II
clinical trial.t^^-^^l However, the trial was abandoned
because of the potential for structural brain damage
in areas in which the BBB had been disrupted.l*^^'
It has been observed that the solvents, stabilizers
or adjuvants present in some drug formulations can
inadvertently disrupt the BBB. Solvents such as
sodium laurilsulfate (sodium dodecyl sulfate), ethanol, dimethyl-sulfoxide, glycerol and polysorbate80 are commonly used in drug formulations and are
administered in doses that, in animals, have been
shown to disrupt the BBB.t^'^-^'^l
1.3.3 BBB Disruption by Alicyiglycrols

A relatively new approach lor ihe transient disruption of the BBB involves the systemic administration of various alkylglycerols. 1^'"^-^' Erdlenbruch
et al.t^^' reported reversible and concentration-dependent increases in BBB permeability to several
anticancer and antibacterial agents. In addition, the
permeability of the BBB to methotrexate has been
reported to increase from 2- to 200-fold using this
approach.'''^1 The degree of disruption of the BBB
depends on the length of the alkyl group and the
number of glycerols present in the structure. Recent

CNS Drugs 2009; 23 CD

44

Patel el al.

^ examining the effect of alkylglycerols

on the permeahility of isolated brain capillaries to
large macroniolecules suggest that the increase in
permeahility is due to temporary breakdown of tight
junctions hetween cells. Although the exact mechanism responsihle for the transient disruption in the
BBB observed with alkylglycerols remains unknown, the fact that the response is concentration
and structure dependent suggests an interaction with
receptor sites within the brain micro vasculature.
The use of alkylglycerols to increase the permeability of the BBB to anticancer agents has heen
examined in a rat glioma tumour model.^^-^''^^^ In
one of these studies,^^''' several different alkylglycerols were examined for their ahility to increase the
CNS delivery of methotrexate in C6 glioma-bearing
rats. The results indicate a significant increase in
methotrexate accumulation at both tumour and nontumour sites within the hrain. The effects of the
alkylglycerols were concentration dependent. However, the magnitude of the increase in methotrexate
delivery to the tumour site detected with the highest
doses of alkylglycerols examined was comparable
to that observed following osmotic disruption of
tbe BBB, hut was significantly greater than that
observed with the bradykinin analogue RMP-7

1,4 Molecular Trojan Horses for Brain

Drug Delivery
Drugs that cannot be modified by lipidization or
are too large to diffuse across the BBB require other
approaches to gain entry to the brain. When a vector
that can access a specific catalysed transport mechanism is attached to an active moiety, it can ferry the
drug, like a 'Trojan horse', across the BBB.
Pardridge'"*! reported that certain peptidomimetic
monoclonal antibodies (mAbs), along with endogenous ligands, undergo RMT across the BBB via
endogenous peptide receptor transporters. The receptor-specific mAb binds to an exofacial epitope
on the receptor that is spatially removed from the
binding site of the endogenous ligand, and this receptor binding allows the mAb to be "piggy backed'
across the BBB through the endogenous RMT sysS) 2009 Adb Ddfa Information BV. Allrightsreserved.

tem. When attached to a drug or nonviral plasmid

DNA, the receptor-specific mAh assists the moiety
to cross the BBB, thus acting as a molecular trojan
horse. The human insulin receptor (HIR), the most
potent molecular trojan horse in the BBB, is active
in humans and rhesus monkeys. Brain drug delivery
in the rhesus monkey was achieved by attaching a
murine 83-14 mAb to the HIR.t^^'''" A genetically
engineered fusion protein for HIRs was prepared by
fusing human brain-derived neurotrophic factor
(BDNF) to the chimeric mAb and, after intravenous
administration to a rhesus monkey, it was found that
this fusion protein was transported into the brain.''''^'
In mice, the rat 8D3 mAb to the mouse TfR is used
to cross the BBB,'^**l whereas in rats the murine
0X26 mAb to the rat TfR is used;"' the 0X26
mAh is not active in mice or other species.
The complex formed by a trojan horse and a
nontransportable drug is called a chimeric peptide
because the molecule is bifunctional. When administered systemically, the trojan horse part of the
chimeric complex binds to specific receptors (Rtl)
on hrain capillaries, which are part of the BBB, thus
enabling transport of the drug across the BBB. Once
the chimeric peptide has penetrated the brain, the
drug part of the chimeric complex can bind to its
receptor (Rt2) on brain cells to initiate its pharmacological effect {figure 5). However, when the drug is
administered alone, it is not pharmacologically active because it cannot cross the BBB.
A defmitive test to determine whether a given
BBB delivery system is effective is to examine the
CNS pharmacological effects of the drug attached to

Blood

Fig. 5. Receptor-mediatBd transport of a drug (D) across the bloodbrain barrier (BBB) using Trojan tiorse {TH) technology. Hti - specific receptors for the TH located on brain capillaries; Rt2 = specific
receptors tor D located on brain cells.

CNS Drugs 2009. 23(1)

Getting into the Brain

Table II
horses

45

In vivo CNS effects of antisense radiopharmaoeutioals, enzymes, peptides and nonviral genes attached to molecular Trojan

Class

Agent

Species

Pharmacological indications

References

Antisense
rad iopharmaceutica 1

PNA-GFAP

Mouse, rat

Brain ischaemia imaging

102

PNA-CAV

Mouse, rat

Brain cancer imaging

Enzymes

'Galactosidase

Mouse

Lysosoma! enzyme

Peptides

A (1-40)

Mouse

Imaging brain amyloid

103
104
105

BDNF

Rat

Focal brain ischaemia

106,107

BDNF

Rat

Global brain ischaemia

108

EGF

Rat

Imaging brain cancer

loe
110
111
112
113

Gene therapy

FGF-2

Rat

Focal brain ischaemia

VIP

Rat

Cerebral blood flow

Tyrosine hydroxylase

Rat

Parkinson's disease

Anti-EGFR RNAi

Mouse

Brain cancer

Anti-EGFR antisense RNA

Mouse
Brain cancer
114
A[i (1-40) = amyloid -peptide (1-40); BDNF = brain-den'ved neurotrophic factor; CAV = caveolin; EGF = epidermal growth factor; EGFR =
EGF receptor; FGF = tibroblast growth factor; GFAP ^ glial fibrillary acidic protein; PNA = peptide nucleic acid; BNA = ribonucleic acid;
RNAi = RNA interference; VIP = vasoactive intestinal peptide.

the delivery system in vivo following intravenous

administration of low doses of the drug-delivery
system complex. It is assumed that an effective
deiivery system will mediate drug transport across
the BBB without disrupting t.t^-'^.'oi] Large pharmaceutical molecules that can cross the BBB in vivo
complexed vi'ith a molecular trojan horse to produce
in vivo CNS pharmacological effects are listed in
table III.
1.5 Drug Delivery Approach
J.S. 1 Drug DeUvery via Catheters and Pumps

The simplest method to overcome the BBB is to

deliver drugs by direct infusion into the brain interstitium via a catheter. The Ommaya reservoir or
implantable pump was developed for this purpose
and has been used for many years to deliver various
antieancer agents, such as methotrexate, doxorubicin, bieomycin and cisplatin, and biological
agents such as interleukin (IL)-2 and interferon-y, to
brain tumours. The Ommaya reservoir may be used
in several ways. Its primary function is to facilitate
(he uniform delivery of intrathecal chemotherapy.
By implanting the Ommaya reservoir, multiple
rounds of chemotherapy may be given through a
single access site, thereby increasing patient comfort
and reducing ibe stress and pain associated with

2009 Adis Dolo Information BV. All rights reserved.

repeated spinal injections. The Ommaya reservoir

also serves as a sampling site for tbe removal of
CSF. Samples are withdrawn and analysed for the
presence of abnormal cells. Some physicians use the
reservoir to deliver pain medication and, more recently, trials have been conducted to test the efficacy
of tbe Ommaya reservoir in delivering gene tberapy
to cancer patients (i.e. treating a disease caused by a
malfunctioning gene by tbe introduction of a normal
gene back into the patieni).'"^"'-"l
Recently, newer types of implantable pumps,
such as the MiniMed PIMS pumps (MiniMed,
Sylmor, CA, USA), Medtronic SynchroMed system
(Medtronic, Minneapolis, MN, USA) and Infusaid
pump (Infusaid, Norwood, MA, USA), have been
developed to overcome the drawbacks associated
with tbe Ommaya reservoir, i.e. slow rate of drug
distribution within the CSF and increase in intracranial pressure associated with fluid injection or
infusion into small ventricular volumes, resulting in
high clinical incidence of haemorrhage, CSF leaks,
neurotoxicity and CNS infections.''-'' These newer
systems deliver drugs at a constant rate and for an
extended period of time. These pumps have been
demonstrated to be of use in experimental brain
tumour models and are currently being used in many
phase HI brain tumour clinical

CNS Dtugs 2009:23(1)

Patel et ai

46

Although these catheters and pumps appear to be

a promising strategy for brain delivery, clinical studies of the delivery of glial cell line-derived neurotrophic factor (GDNF) using these catheters and pumps
have not been successful. In an initial study in
rhesus monkeys. Grondin et al.''-^^^ reported that the
prolonged and controlled delivery of GDNF into the
brain had beneficial effects in long-term neurodegenerative disease processes, such as Parkinson's
disease. However, the results of subsequent clinical
trials were mixed because although two phase I
trials suggested a beneficial effect of GDNF infused
intraputaminally through implanted programmable
catheters and pumps in patients with Parkinson's
disease,''-'*'-*^ another two multicentre trials reported no significant improvement^'-^i or the development of major adverse events''"^' when patients
were implanted with catheters/pumps or were given
intracerebroventricular injections of GDNF, respectively. Thus, tbe drug was withdrawn. It has been
suggested by Salvatore et alJ'-^' that the failure of
GDNF in these studies was due to inadequate bioavailability and brain targeting (i.e. GDNF was unable to reach the putamen and substantia nigra to
exert its effects).
1.5.2 Drug Delivery from Microsptieres

Recent attention has focused on the use of lipidbased polymeric devices, such as microspheres, for
the delivery of anticancer agents. When a polymeric-based chemotherapeutic agent is conjugated with
a water-soluble macromolecule, drug penetration
into the brain is improved as a result of longer
retention of the drug in brain tissue.l''*^' Recently,
IL-2-loaded microspheres have been developed for
the local delivery of the cytokine in the treatment of
brain tumours.f'-"' The major advantage of the
microparticulate system is that it can be implanted
easily by stereotaxy in discrete, precise and functional areas of the brain without damaging surrounding tissue. This type of implantation is more convenient than the insertion of catheters and pumps via
open surgery, and can be repeated if required.'"^'
Menei et al.''^^' developed a new method of drug
delivery into the brain using implantable, biodegradable microspheres. A phase I study of the stereotaxic
2009 Adis Doia Infonnaiion BV. All rights reserved.

implantation of fluorouracil-releasing microspheres

was performed in patients with malignant glioma.f'"' In this study, the authors demonstrated that
the biodegradable microspheres could be implanted
by stereotaxy and were efficient systems for drug
delivery into brain tumours. This methtxi also has
potential applications in the treatment of patients
with other malignancies.
.5.3 Drug Delivery from Biodegradable Wafers

The development of biodegradable polymers is

a major step in polymer technology and its clinical application. The polyanhydride poly[bis(p-carboxyphenoxy) propane : sebacic acid] (PCPP : SA)
polymer is one example of a biodegradable polymer
that releases drugs following polymer diffusion and
degradation.I'-'"'' Changing tbe ratio of carboxyphenoxy propane to sebacic acid changes the degradation properties of the polymer from days to years.
PCPP-SA polymers can be fabricated into different
shapes (e.g. rods, wafers or microspheres) and ean
be used to deliver various compounds, including
hormones, neurotransmitters, enzymes and antineoplastics. Because of the biodegradable nature of the
polymer, no foreign residue is left behind and the
biodegradable products are not mutagenie, eytotoxie
or teratogenic.'''''J
The Gliadel (carmustine [BCNUl-PCPP : SA
polymer) [MGI Phiuina, Bloomington, MN, USA]
wafer is the only US FDA-approved polymeric system for the loeal delivery of drugs to brain tumours.
Using this system, an improvement in the survival
of patients with glioblastoma multiforme brain
tumours has been demonstrated.f'^^' However, owing to insufficient diffusion of the therapeutic agent,
it is likely to only reach adjacent sites.^'^^i
1.5.4 Drug Delivery from Colloidal Drug
Carrier Systems
Liposomes

Liposomes have been used extensively to improve drug delivery across the BBB.'''**"'*-' Thermosensitive liposomes containing doxorubicin have
been used for the treatment of malignant
gliomas.i'"**"! Drug release was achieved when the
tumour core was heated to 40C by a brain heating
CNS DiuQs 2009; 23(1)

Getting into the Brain

47

system. Unfortunately, conventional liposotnes are

eliminated frotn tbe circulation by tbe RES. To
overcome this problem, a water-soluble polymeriike PEG is attached to the surface of the liposomes
and they are converted to stealth liposomes, which
have been reported to have longer circulation in tbe
body and reduced clearance by the RES system.''"'^^
Novel, highly stable nanoliposomes containing the
anticancer drug irinotecan (CPT-ll) were demonstrated to prolong tissue retention of the drug and
enhance its antitumour effects in an intracranial U87
glioma xenograft model.''^^ In addition, large doses
of glucocorticosteroids have been delivered using
long-circulating PEG-liposomes for the treatment of
multiple sclerosis.''"^''l These types of liposomes
bave also been created containing doxorubicin and
have been shown in clinical trials to be effective in
tbe treatment of glioblastomas and metastatic
tumours.''"'^'''^' Table IV summarizes tbe application of liposomes in the treatment of CNS disorders.
Immunoreactive moieties can also be targeted to
the BBB by attaching them to PEGylated liposomes. PEGylated liposomes conjugated with transferrin have been delivered successfully to tbe postischaemic cerebral endothelium in rats.''^ PEGylated immunoliposomes conjugated with the mAb
0X26 were used to target TfR.^'^' When encapsulated into liposomes, many compounds, including doxorubicin, digoxin, -galactosidase gene, hydroxylase plasmid, biotinylated oligonuleotides,
ncutrophin peptides and striatal tyrosine hydroxy-

lase, have been delivered successfully into the

j,rain.li'"-t59] pEGylated (stealth) BBB-targeted
immunoliposomes have been prepared by coupling
witb tbiolated monoclonal anti-gliofibrillary acidic
protein (GEAP) antibodies and used against human
GEAP.''""' Because of tbe problems ibese liposomes
have penetrating an intact BBB, it has been suggested tbat tbey could be used to deliver drugs to glial
brain tumours (which continue to express GEAP) or
to otber areas in the brain with a partially disrupted
BBB (i.e. pathological loci in tbe brain).''"*'^
Genetic material, wben encapsulated into cationie liposomes, is protected from the extracellular
environment and is thus transferred to target cells.
Tbere are many mono- or multivalent cationic
lipids currently available for gene transfer, including
l,2-dioleoyl-3-trimetbylammonium-propane or N[ I -(23-dioIeyloxy)propyl]-A',A',A'-trimethylammonium chloride.''*^! Matsuo et al.''^'^ used haemagglutatinin virus of Japan liposomes with fusogenic
activity to introduce oligodeoxynucleotides into
mouse brain capillary endothelial C4 cells. Unfortunately, gene transfer into the brain via cationic liposomes requires an invasive route of administration.
By complexing liposomes with an antibody or a
ligand tbat will be recognized by cell surface receptors in the targeted tissue, active targeting can be
achieved. PEGylated liposomes can be targeted to
the brain using mAbs, because they are able to
attacb to a receptor expressed on the BBB and lo
trigger RMT across tbe BBB. Tbus, targeted mAbs

Table iV. Liposomes as carriers for the deiivery ol drugs to the brain in the Irealment of various CNS disorders
Type of liposomes

Compounds tested

Disease/condition

References

Cafiortic liposomes

Antisense epidermal growth factor

CM-Dif

Brain tumour
Ischaemia

149
150

Doxorubicin

Brain tumour

147,148

[3H]-Prednisolone

Exprimentai autoimmune
encephaiitis

151

Cationic Iiposomes

IFN- gene plasmJd

Brain tumour

152

Liposomes (AmBisoma; Fujisawa, Deerfieid,

iL, USA)

Ampholericin B

Infection

153

Cationic iiposomes

Recombinant adenovirai vector:

herpes simplex vinjs ihymidine kinase

Brain tumour

154

PEGyiated iiposomes coupied witfi fransferrin

PEGyiated Iiposomes (Caeiyx*; ScheringPiougli Corporation, Keniiwoftfi, NJ, iJSA)
PEGyiated Iiposomes

Chioromethyl-benzamidodialkylcarbocyanine {a red fluorescent tracer dye).

IFN = Interferon.

2009 Adis Dato Information BV. Allrightsreserved.

CNS Drugs 2009; 23 CD

48

Patel ct al.

can act as molecular trojan horses to transport liposomes across the biological barriers in the brain
using endogenous transport s y s t J ^ '
Nanoparticles

The term nanoparticles refers to well defined

particles ranging in size from approximately 10 to
1000 nm (I |j.m) with a core shell structure (nanocapsuies) or a continuous matrix structure (nanospheres). Similar to liposomes, the surface of
nanoparticles can be modified hy PEGylation to
reduce their clearance hy the RES system.''^^'^^
When administered intravenously, doxorubicinloaded polysorbate 80-coated nanoparticles cured
40% of in traern i ally transplanted glioblastomas in
rats.'''-'' In another study,''^-^1 valproic acid-loaded
nanoparticles were demonstrated to reduce the toxicity normally associated with this therapy, not only
because of a reduction in the dose necessary, but
also because of the inhibition of the formation of
toxic metabolites.
Antineoplastic agents (doxorubicin), the NMDA
receptor antagonist MRZ 2/576, peptides (dalargin
and kytorphin) and analgesics (dalargin and loperamide) have all been delivered to the CNS following
either their incorporation into or absorption onto
the surface of poly(butyl)cyanoacrylate (PBCA)
nanoparticles.''^'^' Another chelator. namely penicillamine, has been formulated as a nanoparticle und
investigated as a therapy for Alzheimer's and other
CNS diseases.!'^^1
Costantino et al.''^^' synthesized nanoparticles by
conjugating the biodegradable copolymer poly(D,Llactide-co-glycolide) [PLGA] with five short peptides by means of an amidic linkage. These peptides,
which are similar to synthetic opioid peptides, were
synthesized in turn by means of 9-fluorenylmethoxycarbonyl solid-phase peptide synthesis. The
ability of these nanoparticles to cross the BBB was
assessed in vivo using the rat hrain perfusion technique and. in one case, after systemic administration
(injection into the rat femoral vein). Fluorescent and
confocal microscopy studies''^^' showed that although PLGA nanoparticles were unable to cross the
BBB, for the first time these solid nanoparticles,
2009 Adis Data Informatton BV. All rights resetved.

surface modified with peptides, were shown to cross

the BBB.
Similarly, Aktas et al.,''^^' designed nanoparticles
of the peptide Z-DEVD-FMK, which is a specific
caspase inhibitor that reduces vulnerability to neuronal cell death after cerebral ischaemia. Nanoparticles were prepared by conjugating poliglusam
(chitosan) with PEG. This PEG was conjugated with
the 0X26 mAb, thus finally giving a chitosan-PEG0X26 nanoparticle loaded with the Z-DEVD-FMK
peptide. After fluorescent labelling, these nanoparticles were administered intravenously to mice.
Electron microscopy revealed that the nanoparticles
were able to reach brain areas outside the intravascular compartment. Consequently, these novel
nanoparticles appear to be promising carriers for the
transport of the anticaspase peptide Z-DEVD-FMK
into the brain. In another study. Tosi ei al.''' prepared nanoparticles of the polyester PLGA conjugated with the glycosylated heptapeptide H2N-GlyL-Phe-D-Thr-GIy-L-Phe-L-Leu-L-Ser(O--D^GIucose)-CONH2 loaded with loperamide. Following
intravenous administration, it was found that the
nanoparticles were able to cross the BBB and deliver loperamide into the brain.
A recent investigation has indicated that the delivery of doxorubicin to the brain hy means of
PBCA nanoparticles coated with poIoxamer-188
and polysorbatc-80 may be augmented by an interaction between apolipoprotein A-I adsorbed on the
surface of nanoparticles in plasma and the scavenger
receptor SR-BI located at the BBB. This is the first
study showing a significant correlation between the
adsorption of apolipoprotein A-I on the nanopartiele
surface and drug delivery across the BBB.''^''
As mentioned in section 1.2.3, SLN are a potential drug delivery system for brain targeting, and
modification of the surface properties of these SLN
can decrease their uptake by the RES."^-"*' When
camptothecin and doxorubicin were loaded into
SLN. drug accumulation was observed in the brain
after both oral and intravenous administrationJ"''"^' However, when the surface characteristics of SLN were modified by means of PEG derivatives or PEG-con tain ing surfactants, better results
CNS Drugs 2009:23(1)

Getting into the Brain

were achieved in terms of hrain

Two new SLN formulations made with biocompatihle materials, namely emulsifying wax and BHj
72, stahilized by polysorhate-80 and Brij 78 (Sigma-Aldrich Corporation, St Louis, MO, USA),
showed significant brain uptake, as measured during
a short-term in situ rat brain perfusion experiment.t'^^'^^l SLN loaded with superparamagnetic
iron oxide is a new type of nuclear magnetic
resonance contrast agent,''^^^ which is able to cross
the BBB and accumulate in the brain parenchyma
after intravenous injection in rats.''^^^
Yang et al.''^"^' studied the m vivo transport of
carhoxylated polystyrene nanospheres (20 nm)
across the BBB following cerebral ischaemia and
reperfusion. A transient increase in fluorescence
intensity induced by cerebral ischaemia and reperfusion was observed, indicating accumulation of the
nanospheres in the brain as a result of the opening of
Yumi et al.''^^ developed hionanocapsules selectively targeted to brain tumours. Epidermal growth
factor receptor (EGFR), specifically a constitutively
active genomic sequence deletion variant of the
EGFR (EGFRvIII), is overexpressed in human
gliobiastoma. In their study, Yumi et al.''^^^ replaced
the pre-SI peptide with the antihody affinity motif
of protein A and made hybrid bionanocapsules conjugated with anti-human EGFR antibody recognizing EGFRvill. The hybrid bionanocapsules were
efficiently delivered to glioma cells, but not normal
glial cells. Moreover, delivery of the hybrid bionanocapsules to brain tumours in an in vivo brain
tumour niodeli'^^l suggests that this approach using
bionanocapsules has considerable promise in brain
tumour-targeted drug delivery.
Nanogels

Vinogradov et al.''^^'^^^ have developed nanogels as a new class of carrier systems for the
delivery of drugs and hiomacromolecules to the
CNS. Nanogels are prepared from a network of
cross-linked ionic polyethyleneimine and non-ionic
PEG chains (PEG-cl-poIyethyleneimine). The effect
of nanogels on the receptor-mediated delivery of
' 2009 Adis Data Informotion 8V. All rights reserved.

49

oligonucleotides across polarized monolayers of bovine brain microvessel endothelial cells has been
investigated. Following the incorporation of the oligonucleotides into nanogels, there was an increase
in their transport across the cell monolayers.''^^
Kabanov and Batrakova''^'^ reported a further increase in oligonucleotide transport following modification of nanogel carriers by insulin or transferrin
ligands.
1.5.S Drug Delivery from Biological Tissues

Drug delivery from biological tissues involves

implantation of a tissue into the brain that secretes
the desired therapeutic substance. This approach has
been used extensively for the treatment of Parkinson's disease.''^^1 Owing to the lack of neurovascular innervation, the chances of the transplanted tissue surviving are limited. In attempting to overcome
this prohlem, Leigh et al.^'^*' demonstrated enhanced vascularization and microvascular permeahility in cell suspension emhryonic neural grafts
compared with solid grafts. Gene therapy has been
used as an alternative method to develop an optimized biological tissue for interstitial drug delivery.
In this technique, ceils are genetically modified prior to implantation to release the desired therapeutic
Recently, the therapeutic delivery of proteins has
been reviewed using non-neural cells.'''''' The duration of survival of the biological tissue can be improved by co-grafting the cells engineered to release
neurotropic factors with cells engineered to release
therapeutic proteins.'''^'
1.5.6 Drug Delivery from Microchips

Microchips are a promising and novel method to

deliver cither single or multiple chemical substances
into the brain. This type of drug delivery uses a
solid-state silicon microchip from which controlled
drug release can be obtained. The mechanism of
drug release depends on the electrochemical dissolution of a thin anode membrane covering multiple
microreservoirs filled with solids, liquids or gels. By
selecting a biocompatible device, a microchip can
be used to deliver up to 1000 different drugs.'''"^

CNS Drugs 2009; 23 CD

Patel et al.

50

1.6 Other Alternative Routes/Methods

Nasal
cavity

1.6.1 intranasal Drug Delivery to the Brain

When administered intranasally, a significant

amount of drug can reach the CSF and olfactory
bulb via olfactory sensory neurons. Theoretically,
this approach could be useful for the delivery
of tberapeutic proteins, such as tbe delivery of
BDNF to the olfactory bulb for the treatment of
Alzheimer's disease.''^^^ After intranasal administration, it is believed tbat drug delivery to the CNS is
either through intra- or extraneuronal routes.^'^^'"^1
Thome et al.'^'"^ investigated the CNS drug delivery
of IGF-I, a 7.65 kDa neurotrophic factor, following
its intranasal administration and the possible pathways and mechanisms underlying its transport from
the nasal passage to the CNS. The results of that
study suggested that intranasally delivered IGF-I
bypasses tbe BBB via olfactory and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within tbe brain and
spinal cord.
Recent studies in animal models.'-^^^^ as well as in
humans,'^'^^"-^^^ revealed that drug uptake in the CSF
and brain depends on the molecular weight and
lipophilicity of the drug molecule. Figure 6 shows
the route by which intranasally administered drugs
reach the CSF and brain tissues. In a recent study,
after nasal administration into tbe right nostril of
mice. [^H]-dopamine was found in the right olfactory bulb and, after 4 hours, its concentration in the
right olfactory bulb was 27-fold greater than that in
the left bulb;ii the concentration of [''H]-dopamine reacbed in the right olfactory bulb was higher
than Ihat following its intravenous administration
and subsequent uptake into the brain. A similar
study'-*^! was performed using radiolabelled morphine, which found that morphine was transferred
along the olfactory pathway to the CNS. Some of the
latest studies'^'^-'*^''*'' performed in humans have
revealed that insulin, apomorphine and melatonin/
hydroxocobalamin are delivered to the brain after
intranasal administration.
Xiaomei et alJ^"^ investigated wbether direct
nose-to-brain transport of estradiol exists by measuring tbe uptake of estradiol into the CSF after its
2039 Adis Dala Intormatlon BV. All rights reserved.

Olfactory
region

Blood

CSF
L

Brain
tissues

Elimination

Tissue or
organs
Fig. 6. Route by which an intranasally administered drug reaches
the CSF and brain tissues.

intranasal and intravenous administration to rats.

These authors found that estradiol is transported into
the CSF via olfactory neurons. Similarly, the effectiveness of the intranasal administration of ergoloid
mesylate, which is subject to first-pass metabolism
after oral administration, for intrabrain delivery was
investigated.'-'-' The resuhs of that study were
promising. Gao et al.'-'^'^'^l demonstrated enhanced
intrabrain delivery after the intranasal administration of vasoactive intestinal peptide in PEG-poly
(lactic acid) nanopartides modified with wheat
germ agglutinin and Ulex europaeus agglutinin-I.
There are still some difficulties that need to be
overcome with this technique, such as the possibility
of mucosal irritation, the enzymatically active and
low-pH nasal epithelium and the possibility of considerable variability in results because of nasal patbology (e.g. tbe common cold). However, despite
tbese inberent difficulties, direct nose-to-brain transport of three neuropeptides and direct access of
these neuropeptides to the CSF. bypassing the
bloodstream, bas recently been observed in human
CNS Daigs 2009: 23(1)

Getting into the Brain

trials.f^'^' One obvious advantage of this technique is

that it is non-invasive.
1.6.2 Convection-Er^hanced Diffusion

In convection-enhanced diffusion, drug distribution takes place via bulk flow. A catheter is implanted in the brain and is connected to a pump that
drives fluid flow to the brain at a prescribed rate of
infusion.'-'^^ This type of delivery system is being
investigated in clinical trials of high-grade
gliomas.'^'8-22i] One of the trials^^"'] uses IL-13
PE38QQR, a recombinant toxin composed of the
enzymatically active portion o Pseudomonas Exotoxin A (Neopharm Ltd, Petach-Tiqva. Israel) conjugated with human IL-13. IL-13 PE38QQR binds
to the IL-13 receptor, wbich is overexpressed in
malignant gliomas. By binding to the IL-13 receptor, the recombinant toxin is able to gain entry to the
glioma cells; however, at nanomolar concentrations,
selective and potent cytotoxicity may develop.f^'^-'' Another phase I/II study''-^^ investigated IL-L3 PE38QQR as an antitumour agent for the
treatment of patients with recurrent malignant
gliomas. These trials reported safe local delivery of
IL-13 PE38QQR with an increased survival rate of
patients (70.3 weeks) compared with those patients
treated using an optimal catheter (41.4 weeks). The
median survival for this same patient population on
the basis of a report of clinical trials with other
treatments is only 20-26 weeks.'--^^ Another phase
III clinical trialf--^-^"*! investigated the convectionenhanced diffusion of the targeted toxin TransMID (Xenova Group Ltd, Berkshire, United
Kingdom). TransMID^" is a conjugate of human
transferrin and a diphtheria toxin containing a point
mutation (CRM107). To achieve tumour specificity,
the transferrin portion of the conjugate binds to TfR
present on metabolically active cells and, after binding, the CRM 107 portion acts intracellularly to exert
its eytotoxie effects.f-^'-^^-*!
1.6.3 Infrathecai/lntraventricuiar Drug Delivery fo
the Brain

An intrathecal/intraventricular approach delivers

a drug into the CSF, bypassing the brain-CSF barrier. Because molecules can be exchanged freely between the CSF and extracellular fluids of the brain
2009 Adis Dota Information BV. All rights reserved.

51

parenchyma, delivering drugs to CSF could theoretically result in increased therapeutic drug concentrations. Drug diffusion through the brain parenchyma
is very slow and inversely proportional to the molecular weight of the drug.'"'*'' Following intra-CSF
administration, the concentration of macromoleeules (e.g. proteins) in the brain parenchyma was
found to be negligible.''"-"^*' For this reason, treatment of intraparenchymal CNS tumours with
chemotherapy administered into the CSF has not
been proven effective. However, using the intratbecal route of administration for drug delivery to the
brain has proven successful. For example, intratbecal injection of baclofen has been used to treat
spasticity,'-^^! opioids have been infused intrathecally for the treatment of severe chronic pain'^-*' and
glycopeptide and aminoglycoside antibacterials
have been administered i ntracerebro ventricular I y
for the treatment of meningitis and the intraventricuiar treatment of meningeal metastasis.'^^^' In all
cases, the intrathecal/intraventricular approach has
delivered the drugs near to ventricular sur-

2. Conclusion
The delivery of drugs to the CNS has been a
challenging area of research for several decades.
Considerable efforts have been made to develop
various CNS drug delivery systems, revealing the
unlimited potential of these methods. The investigation of a variety of strategies reflects the inherent
difficulty in transporting therapeutic and imaging
agents across the BBB. The lipidization of molecules has shown considerable potential for the transfer of drugs across the BBB; however, more studies
are required before the advantages of tbis approach
are fully defined. The use of endogenous transporters also has considerable potential in transporting of
a variety of molecules across the BBB. Various drug
delivery strategies using particulate carriers have
been explored, with some currently under clinical
trial and others already available on the market.
Substantial progress will be achieved only if continuous vigorous research efforts to develop less toxic
and more therapeutic drug molecules are paralleled

CNS Dnjgs 2009; 23(1)

52

Patel et al.

witb more effective mecbanisms for delivering these

drugs to tbeir CNS targets.

19.

Acknowledgements
No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest
that are directly relevant to the content of this review.

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Correspondence: Dr Avani F. Amin, Department of Pharmaceutics and Pharmaceutical Technology, Institute of

Pharmacy, Nirma University of Science and Technology,
Sarkhej Gandhinagar Highway, Ahmedabad 382 481, Gujarat, India.
E-mail: avanifamin@yahoo.com

CNSDnjos2009;23Cl)