Advertisement

CNS Drugs

, Volume 23, Issue 1, pp 35–58 | Cite as

Getting into the Brain

Approaches to Enhance Brain Drug Delivery
  • Mayur M. Patel
  • Bhoomika R. Goyal
  • Shraddha V. Bhadada
  • Jay S. Bhatt
  • Avani F. Amin
Review Article

Abstract

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 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 field 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 totransport 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 in 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 alternative 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.

Keywords

Solid Lipid Nanoparticles Ommaya Reservoir Nipecotic Acid Prodrug Approach Large Neutral Amino Acid Transporter 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Despite considerable advances in research in the area of brain and CNS disorders, diseases of the CNS remain the 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 circulating blood compartment of the brain from the extracellular fluid (figure 1). The BBB consists of a continuous layer of endothelial cells joined by complex tight junctions. The luminal plasma membrane of the endothelial cells faces the blood compartment, whereas the abluminal membrane is directed towards the brain extracellular fluid.[1, 2, 3]

Fig. 1

Components of the blood-brain barrier.

A common belief is that small molecules readily cross the BBB; however, findings suggest that 98% of small molecules are not able to cross the BBB and that 100% of large molecules cannot cross the BBB.[4] Limited penetration of a drug into the brain is the rule rather than the exception. One study[5] revealed that of 7000 drugs in the Comprehensive Medicinal Chemistry database,[6] only 5% are used for the treatment of CNS diseases (i.e. mainly depression, schizophrenia and insomnia). Another study[7] revealed that 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 heart disease. The incidence of CNS disorders in humans increases with age; this, along with the fact that very few drugs can cross the BBB, exacerbates the problem of drug delivery to the CNS. It is predicted that by 2020, the number of people in the US aged ≥65 years will increase by 50%,[8] which will result in a simultaneous increase in CNS disorders. This would result in an annual expenditure in the US for Alzheimer’s disease alone of $US0.5 trillion. Because one in every three people will experience a CNS disorder during his/her lifetime, the neuropharmaceutical market is predicted to become the largest sector of the pharmaceutical industry.[9] Although the global market for CNS drugs compared with other classes of drugs has 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.[10] Again, the principal reason for this decrease is the difficulty in getting most CNS drugs to cross the BBB. Taking into the consideration the potential size of the global neuropharmaceutical market and the fact that only a few drugs can cross the BBB, one would predict that a priority for both the pharmaceutical industry and researchers would be the development of drug delivery technologies that enable drugs to cross the BBB.

Modern methods of CNS drug discovery consider expected pharmacological effects only after direct injection of the drug into the brain and not after systemic administration, because the transport of drugs across the BBB after systemic administration is negligible. The flow chart in figure 2 shows an approach made some years ago to the development of CNS drugs. There are two pathways by which CNS drugs may be developed: through trial and error or using rational drug design. Rational drug design is based on high-throughput screening of thousands of molecules and has a tendency to identify drugs with negligible ability to cross the BBB. Therefore, in the absence of parallel progress in the 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.

Fig. 2

Flow chart representing the CNS drug development approach. BBB = blood-brain barrier.

The present review deals mainly with the various approaches used to get drug molecules into the brain and will hopefully provide valuable insights for researchers interested in rational drug design of CNS drugs.

1. Approaches to Enhance Brain Drug Delivery

1.1 Chemical Delivery Systems

There have been various attempts to overcome the limited access of drugs to the brain by chemically modifying particular drugs. Chemical delivery systems can be divided into three main groups, namely lipid-mediated transport (lipidization of small molecules), a prodrug approach and a lock-in system (LIS).

1.1.1 Lipid-Mediated Transport (Lipidization of Small 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 lipid-soluble molecules (with a molecular weight <500 Da) may cross the BBB through the small pores that form transiently within the lipid bilayer.[11,12]

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.[13,14] 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.[15] As a general rule, the BBB permeability of a drug decreases one log order in magnitude for each pair of hydrogen bonds added to the molecule as a polar functional group.[9,16]

Fig. 3

Transport mechanisms across the blood-brain barrier. P-gp = P-glycoprotein.

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.[17, 18, 19] 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 rate.[20,21]

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 all biological membranes in the body, 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.[22] 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.[22,23] Second, increased lipophilicity enhances plasma protein binding, which could neutralize any benefits associated with increased BBB permeability following lipidization.[4] Third, lipidization will increase the molecular weight of a drug. Drugs that have a molecular weight >400–500 Da are unable to cross the BBB in a pharmacologically significant amount. Fischer et al.[24] 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 Å (molecular weight, 200 Da) to 105 Å (molecular weight, 450 Da), its BBB permeability decreases 100-fold.[25]

1.1.2 Prodrug Approach

The transport of drugs across the BBB can be increased using the prodrug approach.[26] The design and use of prodrugs helps overcome any pharmaceutical and/or pharmacokinetic problems 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 by 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 brain. Alternative prodrug formation could include the coupling of the active drug with lipid moieties, such as fatty acids, glycerides or phospholipids.

Prodrugs of acid-containing CNS drugs, such as niflumic acid, valproate, levodopa, vigabatrin and GABA, have been prepared by coupling these drugs with diglycerides or modified diglycerides.[27] 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 metabolites.[28]

1.1.3 Lock-In System

In addition to the lipidization or attachment of hydrophobic groups, chemical modification of a drug moiety can also increase its transport across the BBB. The LIS requires multichemical or enzymatic transformations for release of the active drug.[29] In this system, two types of bioremovable moieties are usually introduced to convert the drug into an inactive precursor: a targetor moiety and a modifier function. The targetor moiety is responsible 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 brain, it is converted into lipid-insoluble 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 between the two systems is that although the prodrug contains one or more modifier function moieties, it does not contain targetor moieties.[30] 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 distributed extensively throughout the body, including the brain.[29] 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 by the BBB. Subsequently, cleavage of the carrier releases the free active drug.[29]

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[31] and zidovudine[32].

1.2 Biological Delivery Systems

There are several mechanisms by which a molecule can cross the BBB (figure 3).[33] Some of these have been used to enhance the transport of drug from the blood to the brain and include adsorptive-mediated transcytosis, carrier-mediated transport, receptor-mediated transport, active efflux transport and peptide vector strategies, each of which is discussed in greater detail below.

1.2.1 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 β-endorphin, a very large molecule that cannot cross the BBB, has been reported in rats.[34,35] After conjugation with cationized albumin, brain uptake of β-endorphin was increased.

When the isoelectric point of antibodies is raised from neutral to highly alkaline, cationized antibodies are formed. These antibodies are used mainly as neurodiagnostic and neuroimaging agents in various diseases, including brain tumours, Alzheimer’s disease and stroke.[34, 35, 36] 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 drug (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 catecholamine, 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).[37] This transformation of dopamine has been used for approximately four decades to deliver dopamine into the brain for the treatment of Parkinson’s disease.[38] Other drugs that cross the BBB via the LNAT include α-methyldopa, gabapentin and melphalan.[39, 40, 41] 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.[42] Table I lists the important transporters in the BBB and the molecules they transport.

Table I

Carrier-mediated transporter across the blood-brain barrier (BBB)[9,43,44]

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 SLC16, among others, have been reported to be localized at the BBB.[45] Studies investigating the number of GLUT1 sites have reported that GLUT1 constitutes >90% of BBB glucose transporters. By conjugating galactose and tyrosine chemically with glucose, Bonina et al.[46,47] have designed prodrug esters of two anticonvulsant drugs, namely nipecotic acid and 7-chloronokynurenic acid, that can be transported across the BBB by GLUT1. The major LNAT is LAT1, whereas the major cationic amino acid transporter is CAT1. 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.[48,49] As indicated in table I, the choline 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 the insulin receptor,[50] transferrin uptake is mediated by the transferrin receptor (TfR), insulin-like growth factor (IGF) uptake is mediated by the IGF receptor and leptin uptake is mediated by the leptin receptor.[51] After intracerebral injection, IgG molecules are rapidly effluxed out of the brain by reverse transcytosis mediated by a BBB Fc receptor (FcR), also called FcRn (the neonatal Fc receptor) or the Fc fragment of IgG receptor transporter (FcGRT).[52,53] Brain endothelial cells also express scavenger receptors (scavenger receptor, class B, member 1 [SR-BI]), commonly known as acetylated low-density lipoprotein (LDL) receptors.[54]

Table II

Important receptor-mediated transporter (RMT) systems at the blood-brain barrier

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 RMT.[55]

Fusion proteins have also been designed to prevent cerebrovascular thrombosis. Low molecular weight, single-chain urokinase-type plasminogen activator has been fused with anti-platelet-endothelial cell adhesion molecule single-chain variable fragment and demonstrated to cross the BBB.[56] 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.[57, 58, 59, 60, 61, 62, 63] In another study, translocation into the rat brain was compared for poly(methoxy-polyethyleneglycol cyanoacrylate-co-n-hexadecylcyanoacrylate) [PEG-PHDCA] nanoparticles and polyhexadecylcyanoacrylate (PHDCA) nanoparticles 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, Baltimore, MD, USA) method.[64] 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 determine the mechanism of transport into the endothelial cells in rat brain and it was found that transport was mediated by the LDL receptor and was the result of endocytosis of PEG-PHDCA nanoparticles into the cells.[65,66]

Advances in nanoparticle technology have resulted in the 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.[67] These SLN, coated with 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 with PEG and thiamine ligands bind to thiamine receptors and are transported into the brain via RMT.[68, 69, 70] Highly specific targeting of SLN can be achieved 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.[71]

1.2.4 Active Efflux Transport

P-glycoprotein is the most widely researched active efflux transporter at the BBB. It is a product of adenosine triphosphate-binding cassette (ABC) transporter, subfamily B, member 1, also called P-glycoprotein gene. Recently, it has 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.[72] The energy-dependent transporter is a member of the ABC gene family and is present at the luminal membrane, whereas the energy-independent transporter is present at the abluminal membrane and belongs to the SLC gene family. Members of the SLC gene family include the organic anion transporter (OAT) or OAT polypeptide, acidic amino acid transporters, such as members of the glutamic acid amino acid transporter family, and active efflux transporters, such as the taurine transporter.[73] It is also possible that the energy-independent transporter is located at the luminal membrane and that the energy-dependent transporter is present at the abluminal membrane.[74]

1.2.5 Peptide Vector Strategies

Using small synthetic peptides that can cross cell membranes is another approach for the delivery of neuropharmaceuticals. Pegelin and penetratin (18 and 16 amino acids, respectively) are small synthetic peptides that can cross the BBB efficiently and have been used effectively to deliver biologically active substances to cells.[13,74] Rousselle et al.[75] coupled doxorubicin, an anticancer agent, with the small peptide vectors (SynB1) using a chemical linker (succinate) and investigated the ability of the complex to cross the BBB in an in situ cerebral perfusion model in rats (figure 4). The results of that study showed that 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.

Fig. 4

Structure of conjugated doxorubicin.

In another study, Schwarze et al.[76] conjugated the β-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 chronic neuropathological changes, cerebral vasculopathy and seizures.[77,78] Disruption of the BBB can be achieved by osmotic disruption (e.g. hyperosmotic shock), biochemical disruption (e.g. by the administration of vasoactive substances) or by alkylglycerols, as discussed below.

1.3.1 Osmotic Disruption of the BBB (Hyperosmotic Shock)

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 anatomical basis of the BBB.[79,80] 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.[81] However, the use of mannitol to improve drug uptake into the brain should proceed with caution, because Salahuddin et al.[77,82] reported that when hypertonic mannitol was infused into the carotid artery of rats, structural brain damage was observed within regions showing BBB 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 function.[83]

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.[84] Matsukado et al.[84] 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.[85,86] In addition, RMP-7 was found to be more stable and more potent than bradykinin in mice.[84] RMP-7 has been administered with carboplatin to patients with gliomas in a phase II clinical trial.[85,86] However, the trial was abandoned because of the potential for structural brain damage in areas in which the BBB had been disrupted.[83]

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 polysorbate-80 are commonly used in drug formulations and are administered in doses that, in animals, have been shown to disrupt the BBB.[87, 88, 89, 90]

1.3.3 BBB Disruption by Alkylglycerols

A relatively new approach for the transient disruption of the BBB involves the systemic administration of various alkylglycerols.[91, 92, 93] Erdlenbruch et al.[93] 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.[93] 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 studies[91, 92, 93] examining the effect of alkylglycerols on the permeability of isolated brain capillaries to large macromolecules suggest that the increase in permeability is due to temporary breakdown of tight junctions between cells. Although the exact mechanism responsible 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 microvasculature.

The use of alkylglycerols to increase the permeability of the BBB to anticancer agents has been examined in a rat glioma tumour model.[92,94,95] In one of these studies,[95] several different alkylglycerols were examined for their ability 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 brain. 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 the BBB, but was significantly greater than that observed with the bradykinin analogue RMP-7 (labradimil)[94,95]

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[4] 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 system. When attached to a drug or nonviral plasmid DNA, the receptor-specific mAb 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.[96,97] 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.[98] In mice, the rat 8D3 mAb to the mouse TfR is used to cross the BBB,[99] whereas in rats the murine OX26 mAb to the rat TfR is used;[100] the OX26 mAb 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 (Rt1) on brain 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.

Fig. 5

Receptor-mediated transport of a drug (D) across the blood-brain barrier (BBB) using Trojan horse (TH) technology. Rt1 = specific receptors for the TH located on brain capillaries; Rt2 = specific receptors for D located on brain cells.

A definitive test to determine whether a given BBB delivery system is effective is to examine the CNS pharmacological effects of the drug attached to the delivery system in vivo following intravenous administration of low doses of the drug-delivery system complex. It is assumed that an effective delivery system will mediate drug transport across the BBB without disrupting it.[77,78,101] Large pharmaceutical molecules that can cross the BBB in vivo complexed with a molecular trojan horse to produce in vivo CNS pharmacological effects are listed in table III.

Table III

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

1.5 Drug Delivery Approach

1.5.1 Drug Delivery 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 anticancer agents, such as methotrexate, doxorubicin, bleomycin and cisplatin, and biological agents such as interleukin (IL)-2 and interferon-γ, to brain tumours. The Ommaya reservoir may be used in several ways. Its primary function is to facilitate the 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 the stress and pain associated with repeated spinal injections. The Ommaya reservoir also serves as a sampling site for the 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 the Ommaya reservoir in delivering gene therapy to cancer patients (i.e. treating a disease caused by a malfunctioning gene by the introduction of a normal gene back into the patient).[115, 116, 117, 118, 119, 120]

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 the 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.[121] 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 III brain tumour clinical trials.[122]

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.[123] 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,[124, 125, 126] another two multicentre trials reported no significant improvement[127] or the development of major adverse events[128] when patients were implanted with catheters/pumps or were given intracerebroventricular injections of GDNF, respectively. Thus, the drug was withdrawn. It has been suggested by Salvatore et al.[129] 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 Microspheres

Recent attention has focused on the use of lipid-based 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.[130] Recently, IL-2-loaded microspheres have been developed for the local delivery of the cytokine in the treatment of brain tumours.[131] 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.[132]

Menei et al.[133] developed a new method of drug delivery into the brain using implantable, biodegradable microspheres. A phase I study of the stereotaxic implantation of fluorouracil-releasing microspheres was performed in patients with malignant glioma.[133] 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 method also has potential applications in the treatment of patients with other malignancies.

1.5.3 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.[134] Changing the 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 can 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 mutagenic, cytotoxic or teratogenic.[135]

The Gliadel® (carmustine [BCNU]-PCPP : SA polymer) [MGI Pharma, Bloomington, MN, USA] wafer is the only US FDA-approved polymeric system for the local delivery of drugs to brain tumours. Using this system, an improvement in the survival of patients with glioblastoma multiforme brain tumours has been demonstrated.[136] However, owing to insufficient diffusion of the therapeutic agent, it is likely to only reach adjacent sites.[137]

1.5.4 Drug Delivery from Colloidal Drug Carrier Systems

Liposomes

Liposomes have been used extensively to improve drug delivery across the BBB.[138, 139, 140, 141, 142] Thermosensitive liposomes containing doxorubicin have been used for the treatment of malignant gliomas.[140] Drug release was achieved when the tumour core was heated to 40°C by a brain heating system. Unfortunately, conventional liposomes are eliminated from the circulation by the RES. To overcome this problem, a water-soluble polymer-like 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 the body and reduced clearance by the RES system.[143] Novel, highly stable nanoliposomes containing the anticancer drug irinotecan (CPT-11) were demonstrated to prolong tissue retention of the drug and enhance its antitumour effects in an intracranial U87 glioma xenograft model.[144] In addition, large doses of glucocorticosteroids have been delivered using long-circulating PEG-liposomes for the treatment of multiple sclerosis.[145] These types of liposomes have also been created containing doxorubicin and have been shown in clinical trials to be effective in the treatment of glioblastomas and metastatic tumours.[146, 147, 148] Table IV summarizes the application of liposomes in the treatment of CNS disorders.

Table IV

Liposomes as carriers for the delivery of drugs to the brain in the treatment of various 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 the post-ischaemic cerebral endothelium in rats.[150] PEGylated immunoliposomes conjugated with the mAb OX26 were used to target TfR.[150] When encapsulated into liposomes, many compounds, including doxorubicin, digoxin, β-galactosidase gene, hydroxylase plasmid, biotinylated oligonuleotides, neutrophin peptides and striatal tyrosine hydroxylase, have been delivered successfully into the brain.[142,155, 156, 157, 158, 159] PEGylated (stealth) BBB-targeted immunoliposomes have been prepared by coupling with thiolated monoclonal anti-gliofibrillary acidic protein (GFAP) antibodies and used against human GFAP.[141] Because of the problems these liposomes have penetrating an intact BBB, it has been suggested that they could be used to deliver drugs to glial brain tumours (which continue to express GFAP) or to other areas in the brain with a partially disrupted BBB (i.e. pathological loci in the brain).[141]

Genetic material, when encapsulated into cationic liposomes, is protected from the extracellular environment and is thus transferred to target cells. There are many mono- or multivalent cationic lipids currently available for gene transfer, including 1,2-dioleoyl-3-trimethylammonium-propane or N-[1-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride.[160] Matsuo et al.[161] 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 that 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 attach to a receptor expressed on the BBB and to trigger RMT across the BBB. Thus, targeted mAbs can act as molecular trojan horses to transport liposomes across the biological barriers in the brain using endogenous transport systems.[162]

Nanoparticles

The term nanoparticles refers to well defined particles ranging in size from approximately 10 to 1000 nm (1 µm) with a core shell structure (nanocapsules) or a continuous matrix structure (nanospheres). Similar to liposomes, the surface of nanoparticles can be modified by PEGylation to reduce their clearance by the RES system.[163,164] When administered intravenously, doxorubicin-loaded polysorbate 80-coated nanoparticles cured 40% of intracranially transplanted glioblastomas in rats.[63] In another study,[165] 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.[166] Another chelator, namely penicillamine, has been formulated as a nanoparticle and investigated as a therapy for Alzheimer’s and other CNS diseases.[167]

Costantino et al.[168] synthesized nanoparticles by conjugating the biodegradable copolymer poly(D,L-lactide-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 brain perfusion technique and, in one case, after systemic administration (injection into the rat femoral vein). Fluorescent and confocal microscopy studies[168] showed that although PLGA nanoparticles were unable to cross the BBB, for the first time these solid nanoparticles, surface modified with peptides, were shown to cross the BBB.

Similarly, Aktas et al.,[169] 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 OX26 mAb, thus finally giving a chitosan-PEG-OX26 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 et al.[170] prepared nanoparticles of the polyester PLGA conjugated with the glycosylated heptapeptide H2N-Gly-L-Phe-D-Thr-Gly-L-Phe-L-Leu-L-Ser(O-β-D-Glucose)-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 by means of PBCA nanoparticles coated with poloxamer-188 and polysorbate-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 nanoparticle surface and drug delivery across the BBB.[171]

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.[172, 173, 174] When camptothecin and doxorubicin were loaded into SLN, drug accumulation was observed in the brain after both oral and intravenous administration.[175,176] However, when the surface characteristics of SLN were modified by means of PEG derivatives or PEG-containing surfactants, better results were achieved in terms of brain targeting.[175,177, 178, 179] Two new SLN formulations made with biocompatible materials, namely emulsifying wax and Brij® 72, stabilized by polysorbate-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.[180, 181, 182] SLN loaded with superparamagnetic iron oxide is a new type of nuclear magnetic resonance contrast agent,[183] which is able to cross the BBB and accumulate in the brain parenchyma after intravenous injection in rats.[177]

Yang et al.[184] studied the in vivo transport of carboxylated 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 tight junctions.[63]

Yumi et al.[185] developed bionanocapsules 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 glioblastoma. In their study, Yumi et al.[185] replaced the pre-S1 peptide with the antibody affinity motif of protein A and made hybrid bionanocapsules conjugated with anti-human EGFR antibody recognizing EGFRvIII. 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 model[185] suggests that this approach using bionanocapsules has considerable promise in brain tumour-targeted drug delivery.

Nanogels

Vinogradov et al.[186, 187, 188, 189] have developed nanogels as a new class of carrier systems for the delivery of drugs and biomacromolecules to the CNS. Nanogels are prepared from a network of cross-linked ionic polyethyleneimine and non-ionic PEG chains (PEG-cl-polyethyleneimine). The effect of nanogels on the receptor-mediated delivery of 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.[190] Kabanov and Batrakova[191] reported a further increase in oligonucleotide transport following modification of nanogel carriers by insulin or transferrin ligands.

1.5.5 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.[192] Owing to the lack of neurovascular innervation, the chances of the transplanted tissue surviving are limited. In attempting to overcome this problem, Leigh et al.[193] demonstrated enhanced vascularization and microvascular permeability in cell suspension embryonic 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, cells are genetically modified prior to implantation to release the desired therapeutic agent.[194]

Recently, the therapeutic delivery of proteins has been reviewed using non-neural cells.[195] 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.[196]

1.5.6 Drug Delivery from Microchips

Microchips are a promising and novel method to deliver either 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.[197]

1.6 Other Alternative Routes/Methods

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 therapeutic proteins, such as the delivery of BDNF to the olfactory bulb for the treatment of Alzheimer’s disease.[198] After intranasal administration, it is believed that drug delivery to the CNS is either through intra- or extraneuronal routes.[199,200] Thorne et al.[201] 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 the BBB via olfactory and trigeminal-associated extracellular pathways to rapidly elicit biological effects at multiple sites within the brain and spinal cord.

Recent studies in animal models,[202] as well as in humans,[203, 204, 205, 206, 207] 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 the right nostril of mice, [3H]-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;[208] the concentration of [3H]-dopamine reached in the right olfactory bulb was higher than that following its intravenous administration and subsequent uptake into the brain. A similar study[209] was performed using radiolabelled morphine, which found that morphine was transferred along the olfactory pathway to the CNS. Some of the latest studies[204,205,210] performed in humans have revealed that insulin, apomorphine and melatonin/hydroxocobalamin are delivered to the brain after intranasal administration.

Fig. 6

Route by which an intranasally administered drug reaches the CSF and brain tissues.

Xiaomei et al.[211] investigated whether direct nose-to-brain transport of estradiol exists by measuring the uptake of estradiol into the CSF after its 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.[212] The results of that study were promising. Gao et al.[213, 214, 215] demonstrated enhanced intrabrain delivery after the intranasal administration of vasoactive intestinal peptide in PEG-poly (lactic acid) nanoparticles 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 pathology (e.g. the common cold). However, despite these inherent difficulties, direct nose-to-brain transport of three neuropeptides and direct access of these neuropeptides to the CSF, bypassing the bloodstream, has recently been observed in human trials.[216] One obvious advantage of this technique is that it is non-invasive.

1.6.2 Convection-Enhanced 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.[217] This type of delivery system is being investigated in clinical trials of high-grade gliomas.[218, 219, 220, 221] One of the trials[219] uses IL-13 PE38QQR, a recombinant toxin composed of the enzymatically active portion of Pseudomonas Exotoxin A (Neopharm Ltd, Petach-Tiqva, Israel) conjugated with human IL-13. IL-13 PE38QQR binds to the IL-13 receptor, which 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.[218, 219, 220, 221] Another phase I/II study[222] investigated IL-13 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.[222] Another phase III clinical trial[223,224] investigated the convection-enhanced 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 CRM107 portion acts intracellularly to exert its cytotoxic effects.[223,224]

1.6.3 Intrathecal/Intraventricular Drug Delivery to 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 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.[225] Following intra-CSF administration, the concentration of macromolecules (e.g. proteins) in the brain parenchyma was found to be negligible.[137,226] For this reason, treatment of intraparenchymal CNS tumours with chemotherapy administered into the CSF has not been proven effective. However, using the intrathecal route of administration for drug delivery to the brain has proven successful. For example, intrathecal injection of baclofen has been used to treat spasticity,[227] opioids have been infused intrathecally for the treatment of severe chronic pain[228] and glycopeptide and aminoglycoside antibacterials have been administered intracerebroventricularly for the treatment of meningitis and the intraventricular treatment of meningeal metastasis.[229] In all cases, the intrathecal/intraventricular approach has delivered the drugs near to ventricular surfaces.[230,231]

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 this 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 with more effective mechanisms for delivering these drugs to their CNS targets.

Notes

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.

References

  1. 1.
    Brightman MW. Morphology of blood-brain interfaces. Exp Eye Res 1977; 25 Suppl.: 1–25PubMedCrossRefGoogle Scholar
  2. 2.
    Schlosshauer B. The blood-brain barrier: morphology, molecules, and neurothelin. Bioassays 1993 May; 15: 341–6CrossRefGoogle Scholar
  3. 3.
    Ricci M, Blasi P, Giovagnoli S, et al. Delivering drugs to the central nervous system: a medicinal chemistry or a pharmaceutical technology issue? Curr Med Chem 2006; 13: 1757–75PubMedCrossRefGoogle Scholar
  4. 4.
    Pardridge WM. Brain drug targeting: the future of brain drug development. Cambridge: Cambridge University Press, 2001CrossRefGoogle Scholar
  5. 5.
    Ghose AK, Viswanadhan VN, Wendoloski JJ. A knowledgebased approach in designing combinatorial or medicinal chemistry libraries for drug discovery: I. A qualitative and quantitative characterization of known drug databases. J Comb Chem 1999 Jan; 1: 55–68Google Scholar
  6. 6.
    MDL® comprehensive medicinal chemistry [online]. Available from URL: http://www.mdl.com/products/knowledge/medicinal_chem/index.jsp [Accessed 2008 Nov 26]
  7. 7.
    Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. J Pharmacol Toxicol Methods 2000 Jul–Aug; 44: 235–49PubMedCrossRefGoogle Scholar
  8. 8.
    Regier DA, Boyd JH, Burke JD Jr, et al. One-month prevalence of mental disorders in the United States: based on five epidemiologic catchment area sites. Arch Gen Psychiatry 1988; 45: 977–86PubMedCrossRefGoogle Scholar
  9. 9.
    Pardridge WM. Blood-brain barrier delivery. Drug Discov Today 2007 Jan; 12: 54–61PubMedCrossRefGoogle Scholar
  10. 10.
    Pardridge WM. Why is the global CNS pharmaceutical market so underpenetrated? Drug Discov Today 2002 Jan; 7: 5–7PubMedCrossRefGoogle Scholar
  11. 11.
    Misra A, Ganesh S, Aliasgar S, et al. Drug delivery to the central nervous system: a review. J Pharm Pharmaceut Sci 2003 May–Aug; 6: 252–73Google Scholar
  12. 12.
    Pardridge WM. Recent advances in blood brain-barrier transport. Annu Rev Pharmacol Toxicol 1988 Apr; 28: 25–39PubMedCrossRefGoogle Scholar
  13. 13.
    Jamal T, Scherrmann JM, Rees AR, et al. Brain drug delivery technologies: novel approaches for transporting therapeutics. Pharm Sci Technol Today 2000 May; 3: 155–62CrossRefGoogle Scholar
  14. 14.
    Greig NH. Drug delivery to the brain by blood-barrier: circumvention and drug modification. In: Neuwelt EA, editor. Implications of the blood-brain barrier and its manipulation. New York: Plenum Press, 1989: 311–67CrossRefGoogle Scholar
  15. 15.
    Sawynok J. The therapeutic use of heroin: a review of the pharmacological literature. Can J Physiol Pharmacol 1986 Jan; 64: 1–6PubMedCrossRefGoogle Scholar
  16. 16.
    Pardridge WM, Mietus LJ. Transport of steroid hormones through the rat blood-brain barrier: primary role of albumin-bound hormone. J Clin Invest 1979 Jul; 64: 145–54PubMedCrossRefGoogle Scholar
  17. 17.
    Lesniak MS. Novel advances in drug delivery to brain cancer. Technol Cancer Res Treat 2005 Aug; 4: 417–28PubMedGoogle Scholar
  18. 18.
    Albrecht KW, de Witt PC, Leenstra S, et al. High concentration of daunorubicin and daunorubicinol in human malignant astrocytomas after systemic administration of liposomal daunorubicin. J Neurooncol 2001 Jul; 53: 267–71PubMedCrossRefGoogle Scholar
  19. 19.
    Koukourakis MI, Koukouraki S, Fezoulidis I, et al. High intratumoural accumulation of stealth liposomal doxorubicin (caelyx) in glioblastomas and in metastatic brain tumours. Br J Cancer 2000 Nov; 83: 1281–6PubMedCrossRefGoogle Scholar
  20. 20.
    Fabel K, Dietrich J, Hau P, et al. Long-term stabilization in patients with malignant glioma after treatment with liposomal doxorubicin. Cancer 2001 Oct; 92: 1936–42PubMedCrossRefGoogle Scholar
  21. 21.
    Lippens RJ. Liposomal daunorubicin (Daunoxome) in children with recurrent or progressive brain tumors. Pediatr Hematol Oncol 1999 Mar–Apr; 16: 131–9PubMedCrossRefGoogle Scholar
  22. 22.
    Greig NH, Daly EM, Sweeney DJ, et al. Pharmacokinetics of chlorambucil-tertiary butyl ester, a lipophilic chlorambucil derivative that achieves and maintains high concentrations in brain. Cancer Chemother Pharmacol 1990; 25: 320–5PubMedCrossRefGoogle Scholar
  23. 23.
    Pardridge WM. Drug targeting to the brain. Pharm Res 2007 Sep; 24: 1733–44PubMedCrossRefGoogle Scholar
  24. 24.
    Fischer H, Gottschlich R, Seelig A. Blood-brain barrier permeation: molecular parameters governing passive diffusion. J Membrane Biol 1998 Oct; 165: 201–11CrossRefGoogle Scholar
  25. 25.
    Pardridge WM. Blood-brain barrier drug targeting: the future of brain drug development. Mol Interv 2003 Mar; 3: 90–105PubMedCrossRefGoogle Scholar
  26. 26.
    Bodor N, Kaminski JJ. Prodrugs and site-specific chemical delivery systems. Annu Rep Med Chem 1987; 22: 303–13CrossRefGoogle Scholar
  27. 27.
    Lambert DM. Rationale and applications of lipids as prodrug carriers. Eur J Pharm Sci 2000; 11Suppl. 2: S15–27PubMedCrossRefGoogle Scholar
  28. 28.
    Han HK, Amidon GL. Targeted prodrug design to optimize drug delivery. AAPS PharmSci 2000; 2: E6PubMedGoogle Scholar
  29. 29.
    Bodor N. Drug targeting and retrometabolic drug design approaches. Adv Drug Deliv Rev 1994 Jun–Jul; 14: 157–66CrossRefGoogle Scholar
  30. 30.
    Bodor N, Buchwald P. Drug targeting via retrometabolic approaches. Pharmacol Ther 1997 Oct–Dec; 76: 1–27PubMedCrossRefGoogle Scholar
  31. 31.
    Somogyi G, Nishitani S, Nomi D, et al. Targeted drug delivery to the brain via phosphonate derivatives: I. Design, synthesis, and evaluation of an anionic chemical delivery system for testosterone. Int J Pharm 1998 May; 166: 15–26Google Scholar
  32. 32.
    Somogyi G, Buchwald P, Nomi D, et al. Targeted drug delivery to the brain via phosphonate derivatives: II. Anionic chemical delivery system for zidovudine (AZT). Int J Pharm 1998; 166: 27–35Google Scholar
  33. 33.
    Terasaki T, Tsuji A. Drug delivery to the brain utilizing bloodbrain barrier transport systems. J Control Release 1994 Feb; 29: 163–9CrossRefGoogle Scholar
  34. 34.
    Pardridge WM. New approaches to drug delivery through the blood-brain barrier. Trends Biotechnol 1994 Jun; 12: 239–45PubMedCrossRefGoogle Scholar
  35. 35.
    Kang YS, Pardridge WM. Brain delivery of biotin bound to a conjugate of neutral avidin and cationized human albumin. Pharm Res 1994 Sep; 11: 1257–64PubMedCrossRefGoogle Scholar
  36. 36.
    Pardridge WM, Triguero D, Buciak JL, et al. Beta-endorphin chimeric peptides: transport through the blood-brain barrier in vivo and cleavage of disulfide linkage by brain. Endocrinology 1990 Feb; 126: 977–84PubMedCrossRefGoogle Scholar
  37. 37.
    Oldendorf WH. Brain uptake of radiolabeled amino acids, amines and hexoses after arterial injection. Am J Physiol 1971 Dec; 221: 1629–39PubMedGoogle Scholar
  38. 38.
    Mena I, Cotzias GC. Protein intake and treatment of Parkinson’s disease with levodopa. N Engl J Med 1975 Jan; 292: 181–4PubMedCrossRefGoogle Scholar
  39. 39.
    Cornford EM, Young D, Paxton JW, et al. Melphalan penetration of the blood-brain barrier via the neurtral amino acid transporter in tumor-bearing brain. Cancer Res 1992 Jan; 52: 138–43PubMedGoogle Scholar
  40. 40.
    Markovitz DC, Fernstrom JD. Diet and uptake of aldomet by the brain: competition with natural large neutral amino acids. Science 1977 Sep; 197: 1014–5PubMedCrossRefGoogle Scholar
  41. 41.
    Uchino H, Kanai Y, Kim DK, et al. Transport of amino acidrelated compounds mediated by L-type amino acid transporterl (LAT1): insights into the mechanisms of substrate recognition. Mol Pharmacol 2002 Apr; 61: 729–37PubMedCrossRefGoogle Scholar
  42. 42.
    Dalpiaz A, Pavan B, Vertuani S, et al. Ascorbic and 6-Brascorbic acid conjugates as a tool to increase the therapeutic effects of potentially central active drugs. Eur J Pharm Sci 2005 Mar; 24: 259–69PubMedCrossRefGoogle Scholar
  43. 43.
    Cornford EM, Oldendorf WH. Independent blood-brain barrier transport systems for nucleic acid precursors. Biochim Biophys Acta 1975 Jun; 394: 211–9PubMedCrossRefGoogle Scholar
  44. 44.
    Cornford EM, Braun LD, Oldendorf WH. Carrier mediated blood-brain barrier transport of choline and certain choline analogs. J Neurochem 1978 Feb; 30: 299–308PubMedCrossRefGoogle Scholar
  45. 45.
    Pardridge WM, Boado RJ, Farrell CR. Brain-type glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier: studies with quantitative western blotting and in situ hybridization. J Biol Chem 1990 Oct; 265: 18035–40PubMedGoogle Scholar
  46. 46.
    Bonina FP, Arenare L, Palagiano F, et al. Synthesis, stability, and pharmacological evaluation of nipecotic acid prodrugs. J Pharm Sci 1999 May; 88: 561–7PubMedCrossRefGoogle Scholar
  47. 47.
    Bonina FP, Arenare L, Ippolito R, et al. Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs. Int J Pharm 2000 Jul; 202: 79–88PubMedCrossRefGoogle Scholar
  48. 48.
    Li JY, Boado RJ, Pardridge WM. Cloned blood-brain barrier adenosine transporter is identical to the rat concentrative Na+ nucleoside cotransporter CNT2. J Cereb Blood Flow Metab 2001 Aug; 21: 929–36PubMedCrossRefGoogle Scholar
  49. 49.
    Pardridge WM, Yoshikawa T, Kang YS, et al. Blood-brain barrier transport and brain metabolism of adenosine and adenosine analogs. J Pharmacol Exp Ther 1994 Jan; 268: 14–8PubMedGoogle Scholar
  50. 50.
    Duffy KR, Pardridge WM. Blood-brain barrier transcytosis of insulin in developing rabbits. Brain Res 1987 Sep; 420: 32–8PubMedCrossRefGoogle Scholar
  51. 51.
    Holly J, Perks C. The role of insulin-like growth factor binding proteins. Neuroendocrinology 2006; 83: 154–60PubMedCrossRefGoogle Scholar
  52. 52.
    Zhang Y, Pardridge WM. Mediated efflux of IgG molecules from brain to blood across the blood-brain barrier. J Neuroimmunol 2001 Mar; 114: 168–72PubMedCrossRefGoogle Scholar
  53. 53.
    Schlachetzki F, Zhu C, Pardridge WM. Expression of the neonatal Fc receptor (FcRn) at the blood-brain barrier. J Neurochem 2002 Apr; 81: 203–6PubMedCrossRefGoogle Scholar
  54. 54.
    Triguero D, Buciak J, Pardridge WM. Capillary depletion method for quantification of blood—brain barrier transport of circulating peptides and plasma proteins. J Neurochem 1990 Jun; 54: 1882–8PubMedCrossRefGoogle Scholar
  55. 55.
    Shin SU, Friden P, Moran M, et al. Transferrin-antibody fusion proteins are effective in brain targeting. Proc Natl Acad Sci 1995 Mar; 92: 2820–4PubMedCrossRefGoogle Scholar
  56. 56.
    Danielyan K, Ding BS, Gottstein C, et al. Delivery of antiplatelet-endothelial cell adhesion molecule single-chain variable fragment-urokinase fusion protein to the cerebral vasculature lyses arterial clots and attenuates postischemic brain edema. J Pharmacol Exp Ther 2007 Jun; 321: 947–52PubMedCrossRefGoogle Scholar
  57. 57.
    Kreuter J, et al. Passage of peptides through the blood-brain barrier with colloidal polymer particles (nanoparticles). Brain Res 1995 Mar; 674: 171–4PubMedCrossRefGoogle Scholar
  58. 58.
    Schroeder U, Sommerfeld P, Ulrich S, et al. Nanoparticle technology for delivery of drugs across the blood-brain barrier. J Pharm Sci 1998 Nov; 87: 1305–7PubMedCrossRefGoogle Scholar
  59. 59.
    Alyautdin RN, Petrov VE, Langer K, et al. Delivery of loperamide across the bloodbrain barrier with polysorbate 80-coated polybutylcyanoacrylate nanoparticles. Pharm Res 1997 Mar; 14: 325–8PubMedCrossRefGoogle Scholar
  60. 60.
    Alyautdin RN, Tezikov EB, Ramge P, et al. Significant entry of tubocurarine into the brain of rats by adsorption to polysorbate 80-coated polybutylcyanoacrylate nanoparticles: an in situ brain perfusion study. J Microencapsul 1998 Jan–Feb; 15: 67–74PubMedCrossRefGoogle Scholar
  61. 61.
    Friese A, Seiller E, Quack G, et al. Increase of the duration of the anticonvulsive activity of a novel NMDA receptor antagonist using poly(butylcyanoacrylate) nanoparticles as a parenteral controlled release system. Eur J Pharm Biopharm 2000 Mar; 49: 103–9PubMedCrossRefGoogle Scholar
  62. 62.
    Gulyaev AE, Gelperina SE, Skidan IN, et al. Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles. Pharm Res 1999 Oct; 16: 1564–9PubMedCrossRefGoogle Scholar
  63. 63.
    Kreuter J. Nanoparticlate systems for brain delivery of drugs. Adv Drug Deliv Rev 2001 Mar; 47: 65–81PubMedCrossRefGoogle Scholar
  64. 64.
    Kim HR, Andrieux K, Delomenie C, et al. Analysis of plasma protein adsorption onto PEGylated nanoparticles by complementary methods: 2-DE, CE and Protein Lab-on-chip® system. Electrophoresis 2007 Jul; 28: 2252–61PubMedCrossRefGoogle Scholar
  65. 65.
    Kim HR, Andrieux K, Gil S, et al. Translocation of poly(ethylene glycol-co-hexadecyl)cyanoacrylate nanoparticles into rat brain endothelial cells: role of apolipoproteins in receptormediated endocytosis. Biomacromolecules 2007 Mar; 8: 793–9PubMedCrossRefGoogle Scholar
  66. 66.
    Kim HR, Gill S, Andrieux K, et al. Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells. Cell Mol Life Sci 2007 Feb; 64: 356–64PubMedCrossRefGoogle Scholar
  67. 67.
    Kaur IP, Bhandari R, Bhandari S, et al. Potential of solid lipid nanoparticles in brain targeting. J Control Release 2008 Apr; 127: 97–109PubMedCrossRefGoogle Scholar
  68. 68.
    Oyewumi MO, Yokel RA, Jay M, et al. Comparison of cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice. J Control Release 2004 Mar; 95: 613–26PubMedCrossRefGoogle Scholar
  69. 69.
    Weitman SD, Lark RH, Coney LR, et al. Distribution of the folate receptor GP38 in normal and malignant cell lines and tissues. Cancer Res 1992 Jun; 52: 3396–401PubMedGoogle Scholar
  70. 70.
    Lee RJ, Low PS. Folate-mediated tumor cell targeting of liposome-entrapped doxorubicin in vitro. Biochim Biophys Acta 1995 Feb; 1233: 134–44PubMedCrossRefGoogle Scholar
  71. 71.
    Harris JM, Chess RB. Effect of pegylation on pharmaceuticals. Nat Rev Drug Discov 2003 Mar; 2: 214–21PubMedCrossRefGoogle Scholar
  72. 72.
    Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. NeuroRx 2005 Jan; 2: 3–14PubMedCrossRefGoogle Scholar
  73. 73.
    Cornford EM, Hyman S, Swartz BE. The human brain GLUT1 glucose transporter: ultrastructural localization to the bloodbrain barrier endothelia. J Cereb Blood Flow Metab 1994 Jan; 14: 106–12PubMedCrossRefGoogle Scholar
  74. 74.
    Derossi D, Chassaing G, Prochiantz A. Trojan peptides: the penetratin system for intracellular delivery. Trends Cell Biol 1998 Feb; 8: 84–7PubMedGoogle Scholar
  75. 75.
    Rousselle C, Clair P, Lefauconnier JM, et al. New advances in the transport of doxorubicin through the blood-brain barrier by a peptide vector-mediated strategy. Mol Pharmacol 2000 April; 57: 679–86PubMedGoogle Scholar
  76. 76.
    Schwarze SR, Ho A, Vocero-Akbani A, et al. In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 1999 Sep; 285: 1569–72PubMedCrossRefGoogle Scholar
  77. 77.
    Salahuddin TS, Johansson BB, Kalimo H, et al. Structural changes in the rat brain after carotid infusions of hyperosmolar solutions: an electron microscopic study. Acta Neuropathol 1988; 77: 5–13PubMedCrossRefGoogle Scholar
  78. 78.
    Lossinsky AS, Vorbrodt AW, Wisniewski HM. Scanning and transmission electron microscopic studies of microvascular pathology in the osmotically impaired blood-brain barrier. J Neurocytol 1995 Oct; 24: 795–806PubMedCrossRefGoogle Scholar
  79. 79.
    Kroll RA, Neuwelt EA. Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means. Neurosurgery 1998 May; 42: 1083–100PubMedCrossRefGoogle Scholar
  80. 80.
    Greenwood J, Luthert PJ, Pratt OE, et al. Hyperosmolar opening of the blood-brain barrier in the energy-depleted rat brain: part 1. Permeability studies. J Cereb Blood Flow Metab 1988 Feb; 8: 9–15CrossRefGoogle Scholar
  81. 81.
    Doolittle ND, Petrillo A, Bell S, et al. Blood-brain barrier disruption for the treatment of malignant brain tumors: the National Program. J Neurosci Nurs 1998 Apr; 30: 81–90PubMedCrossRefGoogle Scholar
  82. 82.
    Salahuddin TS, Johansson BB, Kalimo H, et al. Structural changes in the rat brain after carotid infusions of hyperosmolar solutions: a light microscopic and immunohistochemical study. Neuropathol Appl Neurobiol Neuropeptides 1988 Nov–Dec; 14: 467–82CrossRefGoogle Scholar
  83. 83.
    Miller G. Drug targeting: breaking down barriers. Science 2002 Aug; 297: 1116–8PubMedCrossRefGoogle Scholar
  84. 84.
    Matsukado K, Inamura T, Nakano S, et al. Enhanced tumor uptake of carboplatin and survival in glioma-bearing rats by intracarotid infusion of the bradykinin analog, RMP-7. Neurosurgery 1996 Jul; 39: 125–33PubMedCrossRefGoogle Scholar
  85. 85.
    Abbott NJ, Romero IA. Transporting therapeutics across the blood-brain barrier. Mol Med Today 1996 Mar; 2: 106–13PubMedCrossRefGoogle Scholar
  86. 86.
    Emerich DF, Dean RL, Osborn C, et al. The development of the bradykinin agonist labradimil as a means to increase the permeability of the blood-brain barrier: from concept to clinical evaluation. Clin Pharmacokinet 2001; 40: 105–23PubMedCrossRefGoogle Scholar
  87. 87.
    Saija A, Princi P, Trombetta D, et al. Changes in the permeability of the blood-brain barrier following sodium dodecyl sulphate administration in the rat. Exp Brain Res 1997; 115: 546–51PubMedCrossRefGoogle Scholar
  88. 88.
    Hanig JP, Morrison JM Jr, Krop S, et al. Ethanol enhancement of blood-brain barrier permeability to catecholamines in chicks. Eur J Pharmacol 1972 Apr; 18: 79–82PubMedCrossRefGoogle Scholar
  89. 89.
    Kobiler D, Lustig S, Gozes Y, et al. Sodium dodecylsulphate induces a breach in the blood-brain barrier and enables a West Nile virus variant to penetrate into mouse brain. Brain Res 1989 Sep; 496: 314–6PubMedCrossRefGoogle Scholar
  90. 90.
    Azmin MN, Stuart JF, Florence AT, et al. The distribution and elimination of methotrexate in mouse blood and brain after concurrent administration of polysorbate 80. Cancer Chemother Pharmacol 1985; 14: 238–42PubMedCrossRefGoogle Scholar
  91. 91.
    Zhang Y, Miller DW. Pathways for drug delivery to the central nervous system. In: Wang B, Siahaan T, Soltero RA, editors. Drug delivery: principles and applications. New Jersey (NJ): Wiley Interscience, 2005: 29–56CrossRefGoogle Scholar
  92. 92.
    Erdlenbruch B, Alipour M, Fricker G, et al. Alkylglycerol opening of the blood-brain barrier to small and large fluorescence markers in normal and C6 glioma-bearing rats and isolated rat brain capillaries. Br J Pharm 2003 Dec; 140: 1201–10CrossRefGoogle Scholar
  93. 93.
    Erdlenbruch B, Jendrossek V, Eibl H, et al. Transient and controllable opening of the blood-brain barrier to cytostatic and antibiotic agents by alkylglycerols in rats. Exp Brain Res 2000 Dec; 135: 417–22PubMedCrossRefGoogle Scholar
  94. 94.
    Erdlenbruch B, Jendrossek V, Kugler W, et al. Increased delivery of erucylphosphocholine to C6 gliomas by chemical opening of the blood-brain barrier using intracarotid pentylglycerol in rats. Cancer Chemother Pharmacol 2002 Oct; 50: 299–304PubMedCrossRefGoogle Scholar
  95. 95.
    Erdlenbruch B, Schinkhof C, Kugler W, et al. Intracarotid administration of short-chain alkylglycerols for increased delivery of methotrexate to the rat brain. Br J Pharm 2003 Jun; 139: 685–94CrossRefGoogle Scholar
  96. 96.
    Pardridge WM, Kang YS, Buciak JL, et al. Human insulin receptor monoclonal antibody undergoes high affinity binding to human brain capillaries in vitro and rapid transcytosis through the blood-brain barrier in vivo in the primate. Pharm Res 1995 Jun; 12: 807–16PubMedCrossRefGoogle Scholar
  97. 97.
    Wu D, Yang J, Pardridge WM. Drug targeting of a peptide radiopharmaceutical through the primate blood-brain barrier in vivo with a monoclonal antibody to the human insulin receptor. J Clin Invest 1997 Oct; 100: 1804–12PubMedCrossRefGoogle Scholar
  98. 98.
    Boado RJ, Zhang Y, Zhang Y, et al. Genetic engineering, expression, and activity of a fusion protein of a human neurotrophin and a molecular Trojan horse for delivery across the human blood-brain barrier. Biotechnol Bioeng 2007 Aug; 97: 1376–86PubMedCrossRefGoogle Scholar
  99. 99.
    Lee HJ, Engelhardt B, Lesley J, et al. Targeting rat anti-mouse transferrin receptor monoclonal antibodies through blood-brain barrier in mouse. J Pharmacol Exp Ther 2000 Mar; 292: 1048–52PubMedGoogle Scholar
  100. 100.
    Pardridge WM, Buciak JL, Friden PM. Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. J Pharmacol Exp Ther 1991 Oct; 259: 66–70PubMedGoogle Scholar
  101. 101.
    Neuwelt EA, Rapoport SI. Modification of the blood-brain barrier in the chemotherapy of malignant brain tumors. Fed Proc 1984 Feb; 43: 214–9PubMedGoogle Scholar
  102. 102.
    Suzuki T, Zhang Y, Zhang YF, et al. Imaging gene expression in regional brain ischemia in vivo with a targeted [111in]-antisense radiopharmaceutical. Mol Imaging 2004 Oct; 3: 356–63PubMedCrossRefGoogle Scholar
  103. 103.
    Suzuki T, Wu D, Schlachetzki F, et al. Imaging endogenous gene expression in brain cancer in vivo with 111In-peptide nucleic acid antisense radiopharmaceuticals and brain drug-targeting technology. J Nucl Med 2004 Oct; 45: 1766–75PubMedGoogle Scholar
  104. 104.
    Zhang Y, Pardridge WM. Delivery of beta-galactosidase to mouse brain via the blood-brain barrier transferrin receptor. J Pharmacol Exp Ther 2005 Jun; 313: 1075–81PubMedCrossRefGoogle Scholar
  105. 105.
    Lee HJ, Zhang Y, Zhu C, et al. Imaging brain amyloid of Alzheimer disease in vivo in transgenic mice with an Abeta peptide radiopharmaceutical. J Cereb Blood Flow Metab 2002 Feb; 22: 223–31PubMedCrossRefGoogle Scholar
  106. 106.
    Zhang Y, Pardridge WM. Conjugation of brain-derived neurotrophic factor to a blood-brain barrier drug targeting system enables neuroprotection in regional brain ischemia following intravenous injection of the neurotrophin. Brain Res 2001 Jan; 889: 49–56PubMedCrossRefGoogle Scholar
  107. 107.
    Zhang Y, Pardridge WM. Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood-brain barrier drug targeting system. Stroke 2001 Jun; 32: 1378–84PubMedCrossRefGoogle Scholar
  108. 108.
    Wu D, Pardridge WM. Neuroprotection with noninvasive neurotrophin delivery to the brain. Proc Natl Acad Sci U S A 1999 Jan; 96: 254–9PubMedCrossRefGoogle Scholar
  109. 109.
    Kurihara A, Pardridge WM. Imaging brain tumors by targeting peptide radiopharmaceuticals through the blood-brain barrier. Cancer Res 1999 Dec; 59: 6159–63PubMedGoogle Scholar
  110. 110.
    Song BW, Vinters HV, Wu D, et al. Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood-brain barrier delivery vector. J Pharmacol Exp Ther 2002 May; 301: 605–10PubMedCrossRefGoogle Scholar
  111. 111.
    Wu D, Pardridge WM. Central nervous system pharmacologic effect in conscious rats after intravenous injection of a biotinylated vasoactive intestinal peptide analog coupled to a blood-brain barrier drug delivery system. J Pharmacol Exp Ther 1996 Oct; 279: 770–83Google Scholar
  112. 112.
    Zhang Y, Schlachetzki F, Zhang YF, et al. Normalization of striatal tyrosine hydroxylase and reversal of motor impairment in experimental parkinsonism with intravenous nonviral gene therapy and a brain-specific promoter. Hum Gene Ther 2004 Apr; 15: 339–50PubMedCrossRefGoogle Scholar
  113. 113.
    Zhang Y, Zhang YF, Bryant J, et al. Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin Cancer Res 2004 Jun; 10: 3667–77PubMedCrossRefGoogle Scholar
  114. 114.
    Zhang Y, Zhu C, Pardridge WM. Antisense gene therapy of brain cancer with an artificial virus gene delivery system. Mol Ther 2002 Jul; 6: 67–72PubMedCrossRefGoogle Scholar
  115. 115.
    Boiardi A, Eoli M, Pozzi A, et al. Locally delivered chemotherapy and repeated surgery can improve survival in glioblastoma patients. Ital J Neurol Sci 1999 Feb; 20: 43–8PubMedCrossRefGoogle Scholar
  116. 116.
    Morantz RA, Kimler BF, Vats TS, et al. Bleomycin and brain tumors: a review. J Neurooncol 1983; 1: 249–55PubMedCrossRefGoogle Scholar
  117. 117.
    Patchell RA, Regine WF, Ashton P, et al. A phase I trial of continuously infused intratumoral bleomycin for the treatment of recurrent glioblastoma multiforme. J Neurooncol 2002 Oct; 60: 37–42PubMedCrossRefGoogle Scholar
  118. 118.
    Voulgaris S, Partheni M, Karamouzis M, et al. Intratumoral doxorubicin in patients with malignant brain gliomas. Am J Clin Oncol 2002 Feb; 25: 60–4PubMedCrossRefGoogle Scholar
  119. 119.
    Huang Y, Hayes RL, Wertheim S, et al. Treatment of refractory recurrent malignant glioma with adoptive cellular immunotherapy: a case report. Crit Rev Oncol Hematol 2001 Jul–Aug; 39: 17–23PubMedCrossRefGoogle Scholar
  120. 120.
    Boiardi A, Silvani A, Milanesi I, et al. Local immunotherapy (beta-ifn) and systemic chemotherapy in primary glial tumors. Ital J Neurol Sci 1991 Apr; 12: 163–8PubMedCrossRefGoogle Scholar
  121. 121.
    Scheid WM. Drug delivery to the central nervous system: general principles and relevance to therapy for infections of the central nervous system. Rev Infect Dis 1989; 11Suppl. 7: S1669–90Google Scholar
  122. 122.
    Giussani C, Carrabba G, Pluderi M, et al. Local intracerebral delivery of endogenous inhibitors by osmotic minipumps effectively suppresses glioma growth in vivo. Cancer Res 2003 May; 63: 2499–505PubMedGoogle Scholar
  123. 123.
    Grondin R, Zhang Z, Yi A, et al. Chronic, controlled GDNF infusion promotes structural and functional recovery in advanced parkinsonian monkeys. Brain 2002 Oct; 125: 2191–201PubMedCrossRefGoogle Scholar
  124. 124.
    Gill SS, Patel NK, Hotton GR, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med 2003 May; 9: 589–95PubMedCrossRefGoogle Scholar
  125. 125.
    Patel NK, Bunnage M, Plaha P, et al. Intraputamenal infusion of glial cell line-derived neurotrophic factor in PD: a two-year outcome study. Ann Neurol 2005 Feb; 57: 298–302PubMedCrossRefGoogle Scholar
  126. 126.
    Slevin JT, Gerhardt GA, Smith CD, et al. Improvement of bilateral motor functions in patients with Parkinson disease through the unilateral intraputaminal infusion of glial cell linederived neurotrophic factor. J Neurosurg 2005 Feb; 102: 216–22PubMedCrossRefGoogle Scholar
  127. 127.
    Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol 2006 Mar; 59: 459–66PubMedCrossRefGoogle Scholar
  128. 128.
    Nutt JG, Burchiel KJ, Cornelia CL. Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD. Neurology 2003 Jan 14; 60: 69–73PubMedCrossRefGoogle Scholar
  129. 129.
    Salvatore MF, Ai Y, Fischer B, et al. Point source concentration of GDNF may explain failure of phase II clinical trial. Exp Neurol 2006 Dec; 202: 497–505PubMedCrossRefGoogle Scholar
  130. 130.
    Dang W, Colvin OM, Brem H, et al. Covalent coupling of methotrexate dextran enhances the penetration of cytotoxicity into a tissue like matrix. Cancer Res 1994 Apr; 54: 1729–35PubMedGoogle Scholar
  131. 131.
    Batycky RP, Hanes J, Langer R, et al. A theoretical model of erosion and macromolecular drug release from biodegrading microspheres. J Pharm Sci 1997 Dec; 86: 1464–77PubMedCrossRefGoogle Scholar
  132. 132.
    Benoit JP, Faisant N, Venier-Julienne MC, et al. Development of microspheres for neurological disorders: from basics to clinical applications. J Control Release 2000 Mar; 65: 285–96PubMedCrossRefGoogle Scholar
  133. 133.
    Menei P, Jadaud E, Faisant N, et al. Stereotaxic implantation of 5-fluorouracil-releasing microspheres in malignant glioma. Cancer 2004 Jan; 100: 405–10PubMedCrossRefGoogle Scholar
  134. 134.
    Leong KW, Brott BC, Langer R. Bioerodible polyanhydrides as drug-carrier matrices: I. Characterization, degradation, and release characteristics. J Biomed Mater Res 1985 Oct; 19: 941–55Google Scholar
  135. 135.
    Leong KW, D’Amore PD, Marietta M, et al. Bioerodible polyanhydrides as drug-carrier matrices: II. Biocompatibility and chemical reactivity. J Biomed Mater Res 1986 Jan; 20: 51–64CrossRefGoogle Scholar
  136. 136.
    Brem H, Gabikian P. Biodegradable polymer implants to treat brain tumors. J Control Release 2001 Jul; 74: 63–7PubMedCrossRefGoogle Scholar
  137. 137.
    Newcomb R, Abbruscato TJ, Singh T, et al. Bioavailability of ziconotide in brain: influx from blood, stability and diffusion. Peptides 2000 Apr; 21: 491–501PubMedCrossRefGoogle Scholar
  138. 138.
    Elena B, Alexander VK. Polymers for CNS drug delivery. Pharm Tech. Epub 2007 May 1Google Scholar
  139. 139.
    Umezawa F, Eto Y. Liposome targeting to mouse brain: mannose as a recognition marker. Biochem Biophys Res Comm 1988 Jun; 153: 1038–44PubMedCrossRefGoogle Scholar
  140. 140.
    Aoki H, Kakinuma K, Morita K, et al. Therapeutic efficacy of targeting chemotherapy using local hyperthermia and thermosensitive liposome: evaluation of drug distribution in a rat glioma model. Int J Hyperther 2004 Sep; 20: 595–605CrossRefGoogle Scholar
  141. 141.
    Chekhonin VP, Zhirkov YA, Gurina OI, et al. PEGylated immunoliposomes directed against brain astrocytes. Drug Deliv 2005 Jan–Feb; 12: 1–6PubMedCrossRefGoogle Scholar
  142. 142.
    Pardridge WM. Tyrosine hydroxylase replacement in experimental parkinson’s disease with transvascular gene therapy. NeuroRx 2005 Jan; 2: 129–38PubMedCrossRefGoogle Scholar
  143. 143.
    Voinea M, Simionescu M. Designing of ‘intelligent’ liposomes for efficient delivery of drugs. J Cell Mol Med 2002 Oct–Dec; 6: 465–74PubMedCrossRefGoogle Scholar
  144. 144.
    Noble CO, Krauze MT, Drummond DC, et al. Novel nanoliposomal CPT-11 infused by convection-enhanced delivery in intracranial tumors: pharmacology and efficacy. Cancer Res 2006 Mar; 66: 2801–6PubMedCrossRefGoogle Scholar
  145. 145.
    Schmidt J, Metselaar JM, Wauben MH, et al. Drug targeting by long-circulating liposomal glucocorticosteroids increases therapeutic efficacy in a model of multiple sclerosis. Brain 2003; 126: 1895–904PubMedCrossRefGoogle Scholar
  146. 146.
    Garcia-Garcia E, Andrieux K, Gil S, et al. Colloidal carriers and blood-brain barrier (BBB) translocation: a way to deliver drugs to the brain? Int J Pharm 2005 May; 298: 274–92PubMedCrossRefGoogle Scholar
  147. 147.
    Koukourakis MI, Koukouraki S, Giatromanolaki A, et al. High intratumoral accumulation of stealth liposomal doxorubicin in sarcomas: rationale for combination with radiotherapy. Acta Oncol 2000; 39: 207–11PubMedCrossRefGoogle Scholar
  148. 148.
    Hau P, Fabel K, Baumgart U, et al. PEGylated liposomal doxorubicin-efficacy in patients with recurrent high-grade glioma. Cancer 2004 Mar; 100: 1199–207PubMedCrossRefGoogle Scholar
  149. 149.
    Sugawa N, Ueda S, Nakagawa Y, et al. An antisense EGFR oligonucleotide enveloped in Lipofectin induces growth inhibition in human malignant gliomas in vitro. J Neuro-Oncol 1998 Sep; 39: 237–44CrossRefGoogle Scholar
  150. 150.
    Omori N, Maruyama K, Jin G, et al. Targeting of post-ischemic cerebral endothelium in rat by liposomes bearing polyethylene glycol-coupled transferrin. Neurol Res 2003 Apr; 25: 275–9PubMedCrossRefGoogle Scholar
  151. 151.
    Schmidt J, Metselaar JM, Gold R. Intravenous liposomal prednisolone downregulates in situ TNF-alpha production by Tcells in experimental autoimmune encephalomyelitis. J Histochem Cytochem 2003 Sep; 51: 1241–4PubMedCrossRefGoogle Scholar
  152. 152.
    Yoshida J, Mizuno M, Fujii M, et al. Human gene therapy for malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma) by in vivo transduction with human interferon beta gene using cationic liposomes. Hum Gene Ther 2004 Jan; 15: 77–86PubMedCrossRefGoogle Scholar
  153. 153.
    Groll AH, Giri N, Petraitis V, et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis 2000 Jul; 182: 274–82PubMedCrossRefGoogle Scholar
  154. 154.
    Mizuno M, Ryuke Y, Yoshida J. Cationic liposomes conjugation to recombinant adenoviral vectors containing herpes simplex virus thymidine kinase gene followed by ganciclovir treatment reduces viral antigenicity and maintains antitumor activity in mouse experimental glioma models. Cancer Gene Ther 2002 Oct; 9: 825–9PubMedCrossRefGoogle Scholar
  155. 155.
    Shi N, Zhang Y, Zhu C, et al. Brain-specific expression of an exogenous gene after i.v. administration. Proc Natl Acad Sci U S A 2001 Oct; 98: 12754–9CrossRefGoogle Scholar
  156. 156.
    Huwyler J, Cerletti A, Fricker G, et al. By-passing of P-glycoprotein using immunoliposomes. J Drug Target 2002 Feb; 10: 73–9PubMedCrossRefGoogle Scholar
  157. 157.
    Wu D, Song BW, Vinters HV, et al. Pharmacokinetics and brain uptake of biotinylated basic fibroblast growth factor conjugated to a blood-brain barrier drug delivery system. J Drug Target 2002 May; 10: 239–45PubMedCrossRefGoogle Scholar
  158. 158.
    Wu D, Boado RJ, Pardridge WM. Pharmacokinetics and blood-brain barrier transport of [3H]-biotinylated phosphorothioate oligodeoxynucleotide conjugated to a vector-mediated drug delivery system. J Pharmacol Exp Ther 1996 Jan; 276: 206–11PubMedGoogle Scholar
  159. 159.
    Gosk S, Vermehren C, Storm G, et al. Targeting anti-transferrin receptor antibody (OX26) and OX26-conjugated liposomes to brain capillary endothelial cells using in situ perfusion. J Cereb Blood Flow Metab 2004 Nov; 24: 1193–204PubMedCrossRefGoogle Scholar
  160. 160.
    da Cruz MT, Simoes S, de Lima MC. Improving lipoplexmediated gene transfer into C6 glioma cells and primary neurons. Exp Neurol 2004 May; 187: 65–75PubMedCrossRefGoogle Scholar
  161. 161.
    Matsuo H, Okamura T, Chen J, et al. Efficient introduction of macromolecules and oligonucleotides into brain capillary endothelial cells using HVJ-liposomes. J Drug Target 2000; 8: 207–16PubMedCrossRefGoogle Scholar
  162. 162.
    Zhang Y, Zhang YF, Bryant J, et al. Intravenous RNA interference gene therapy targeting the human epidermal growth factor receptor prolongs survival in intracranial brain cancer. Clin Cancer Res 2004 Jun; 10: 3667–77PubMedCrossRefGoogle Scholar
  163. 163.
    Tosi G, Costantino L, Ruozi B, et al. Polymeric nanoparticles for the drug delivery to the central nervous system. Expert Opin Drug Deliv 2008 Feb; 5: 155–74PubMedCrossRefGoogle Scholar
  164. 164.
    Calvo P, Gouritin B, Villarroya H, et al. Quantification and localization of PEGylated polycyanoacrylate nanoparticles in brain and spinal cord during experimental allergic encephalomyelitis in the rat. Eur J Neurosci 2002 Apr; 15: 1317–26PubMedCrossRefGoogle Scholar
  165. 165.
    Darius J, Meyer FP, Sabel BA, et al. Influence of nanoparticles on the brain-to-serum distribution and the metabolism of valproic acid in mice. J Pharm Pharmacol 2000; 562: 1043–7CrossRefGoogle Scholar
  166. 166.
    Steiniger SC, Kreuter J, Khalansky AS, et al. Chemotherapy of glioblastoma in rats using doxorubicin-loaded nanoparticles. Int J Cancer 2004 May; 109: 759–67PubMedCrossRefGoogle Scholar
  167. 167.
    Cui Z, Lockman PR, Atwood CS, et al. Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer’s and other CNS diseases. Eur J Pharm Biopharm 2005 Feb; 59: 263–72PubMedCrossRefGoogle Scholar
  168. 168.
    Costantino L, Gandolfi F, Tosi G, et al. Peptide-derivatized biodegradable nanoparticles able to cross the blood-brain barrier. J Control Release 2005 Nov; 108: 84–96PubMedCrossRefGoogle Scholar
  169. 169.
    Aktas Y, Yemisci M, Andrieux K, et al. Development and brain delivery of chitosan-PEG nanoparticles functionalized with the monoclonal antibody OX26. Bioconjugate Chem 2005 Nov–Dec; 16: 1503–11CrossRefGoogle Scholar
  170. 170.
    Tosi G, Costantino L, Rivasi F, et al. Targeting the central nervous system: in vivo experiments with peptide-derivatized nanoparticles loaded with loperamide and rhodamine-123. J Control Release 2007 Sep; 122: 1–9PubMedCrossRefGoogle Scholar
  171. 171.
    Petri B, Bootz A, Khalansky A, et al. Chemotherapy of brain tumour using doxorubicin bound to surfactant-coated poly(butyl cyanoacrylate) nanoparticles: revisiting the role of surfactants. J Control Release 2007 Jan; 117: 51–8PubMedCrossRefGoogle Scholar
  172. 172.
    Blasi P, Giovagnoli S, Schoubben A, et al. Solid lipid nanoparticles for targeted brain drug delivery. Adv Drug Delivery Rev 2007 Jul; 59: 454–77CrossRefGoogle Scholar
  173. 173.
    Gabizon A, Martin F. Polyethylene glycol-coated (pegylated) liposomal doxorubicin rationale for use in solid tumours. Drugs 1997; 54Suppl. 4: 15–21PubMedCrossRefGoogle Scholar
  174. 174.
    Owens DE III, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int J Pharm 2006 Jan; 307: 93–102PubMedCrossRefGoogle Scholar
  175. 175.
    Yang S, Zhu J, Lu Y, et al. Body distribution of camptothecin solid lipid nanoparticles after oral administration. Pharm Res 1999 May; 16: 751–7PubMedCrossRefGoogle Scholar
  176. 176.
    Zara GP, Cavalli R, Fundarò A, et al. Pharmacokinetics of doxorubicin incorporated in solid lipid nanospheres (SLN). Pharmacol Res 1999 Sep; 40: 281–6PubMedCrossRefGoogle Scholar
  177. 177.
    Podio V, Zara GP, Carazzonet M, et al. Biodistribution of stealth and non-stealth solid lipid nanospheres after intravenous administration to rats. J Pharm Pharmacol 2000 Sep; 52: 1057–63PubMedCrossRefGoogle Scholar
  178. 178.
    Yang SC, Lu LF, Cai Y, et al. Body distribution in mice of intravenously injected camptothecin solid lipid nanoparticles and targeting effect on brain. J Control Release 1999 Jun; 59: 299–307PubMedCrossRefGoogle Scholar
  179. 179.
    Fundarò A, Cavalli R, Bargoni A, et al. Non-stealth and stealth solid lipid nanoparticles (SLN) carrying doxorubicin: pharmacokinetics and tissue distribution after i.v. administration to rats. Pharmacol Res 2000 Oct; 42: 337–43Google Scholar
  180. 180.
    Koziara JM, Lockman PR, Allen DD, et al. In situ blood-brain barrier transport of nanoparticles. Pharm Res 2003 Nov; 20: 1772–8PubMedCrossRefGoogle Scholar
  181. 181.
    Koziara JM, Lockman PR, Allen DD, et al. Paclitaxel nanoparticles for the potential treatment of brain tumors. J Control Release 2004 Sep; 99: 259–69PubMedCrossRefGoogle Scholar
  182. 182.
    Lockman PR, Koziara J, Roder KE, et al. In vivo and in vitro assessment of baseline blood brain barrier parameters in the presence of novel nanoparticles. Pharm Res 2003 May; 20: 705–13PubMedCrossRefGoogle Scholar
  183. 183.
    Peira E, Marzola P, Podio V, et al. In vitro and in vivo study of solid lipid nanoparticles loaded with superparamagnetic iron oxide. J Drug Target 2003 Jan; 11: 19–24PubMedCrossRefGoogle Scholar
  184. 184.
    Yang C, Chang CH, Tsai PJ, et al. Nanoparticle-based in vivo investigation on blood-brain barrier permeability following ischemia and reperfusion. Anal Chem 2004 Aug; 76: 4465–71PubMedCrossRefGoogle Scholar
  185. 185.
    Yumi T, Kazuhito T, Mana N, et al. Development of bionanocapsules targeting brain tumors. J Control Release 2007 Sep; 122: 159–64CrossRefGoogle Scholar
  186. 186.
    Vinogradov SV, Batrakova EV, Kabanov AV. Poly(ethylene glycol)-polyethyleneimine nanogel particles: novel drug delivery systems for antisense oligonucleotides. Colloids Surf B: Biointerfaces 1999 Nov; 16: 291–304CrossRefGoogle Scholar
  187. 187.
    Vinogradov SV, Bronich TK, Kabanov AV. Nanosized cationic hydrogels for drug delivery: preparation, properties and interactions with cells. Adv Drug Deliv Rev 2002 Jan; 54: 135–47PubMedCrossRefGoogle Scholar
  188. 188.
    Vinogradov SV, Kohli E, Zeman AD. Cross-linked polymeric nanogel formulations of 5′-triphosphates of nucleoside analogues: role of the cellular membrane in drug release. Mol Pharm 2005 Nov–Dec; 2: 449–61PubMedCrossRefGoogle Scholar
  189. 189.
    Vinogradov SV, Zeman AD, Batrakova EV. Polyplex nanogel formulations for drug delivery of cytotoxic nucleoside analogs. J Control Release 2005 Sep; 107: 143–57PubMedCrossRefGoogle Scholar
  190. 190.
    Vinogradov SV, Batrakova EV, Kabanov AV. Nanogels for oligonucleotide delivery to the brain. Bioconjug Chem 2004 Jan–Feb; 15: 50–60PubMedCrossRefGoogle Scholar
  191. 191.
    Kabanov AV, Batrakova EV. New technologies for drug delivery across the blood brain barrier. Curr Pharm Design 2004; 10: 1355–63CrossRefGoogle Scholar
  192. 192.
    Madrid Y, Langer LF, Brem H, et al. New directions in the delivery of drugs and other substances to the central nervous system. Adv Pharmacol 1991; 22: 299–324PubMedCrossRefGoogle Scholar
  193. 193.
    Leigh K, Elisevich K, Rogers KA. Vascularization and microvascular permeability in solid versus cell-suspension embryonic neural grafts. J Neurosurg 1994 Aug; 81: 272–83PubMedCrossRefGoogle Scholar
  194. 194.
    Lal B, Indurti RR, Couraud PO, et al. Endothelial cell implantation and survival within experimental gliomas. Proc Natl Acad Sci US A 1994 Oct; 91: 9695–9CrossRefGoogle Scholar
  195. 195.
    Snyder EY, Senut MC. The use of non neuronal cells for gene delivery. Neurobiol Dis 1997; 4: 69–102PubMedCrossRefGoogle Scholar
  196. 196.
    Yurek DM, Sladek JR Jr. Dopamine cell replacement: Parkinson’s disease. Annu Rev Neurosci 1990; 13: 415–40PubMedCrossRefGoogle Scholar
  197. 197.
    Santini JT Jr, Cima MJ, Langer R. A controlled-release microchip. Nature 1999 Jan; 397: 335–8PubMedCrossRefGoogle Scholar
  198. 198.
    Thorne RG, Emory CR, Ala TA, et al. Quantitative analysis of the olfactory pathway for drug delivery to the brain. Brain Res 1995 Sep; 692: 278–82PubMedCrossRefGoogle Scholar
  199. 199.
    Thorne RG, Frey II WH. Delivery of neurotropic factore to the central nervous system: pharmacokinetic consideration. Clin Pharmacokinet 2001; 40: 907–46PubMedCrossRefGoogle Scholar
  200. 200.
    Born J, Lange T, Kern W. Sniffing neuropeptides: a transnasal approach to the human brain. Nat Neurosci 2002 Jun; 5: 514–6PubMedCrossRefGoogle Scholar
  201. 201.
    Thorne RG, Pronk GJ, Padmanabhan V, et al. Delivery of insulin like growth factor-I to the rat brain and spinal cord along olfactory and trigeminal pathways following intranasal administration. Neuroscience 2004; 127: 481–96PubMedCrossRefGoogle Scholar
  202. 202.
    Ilium L. Nasal drug delivery: possibilities, problems and solutions. J Control Release 2003 Feb; 87: 187–98CrossRefGoogle Scholar
  203. 203.
    Ilium L. Transport of drugs from the nasal cavity to the central nervous system. Eur J Pharm Sci 2000 Jul; 11: 1–18CrossRefGoogle Scholar
  204. 204.
    Quay SC. Successful delivery of apomorphine to the brain following intranasal administration demonstrated in clinical study [online]. Available from URL: http://www.riskworld.com/PressRel/2001/01q3/PR01a006.htm [Accessed 2008 Nov 26]
  205. 205.
    Fehm HL, Perras B, Smolnik R, et al. Manipulating neuropeptidergic pathways in humans: a novel approach to neuropharmacology. Eur J Pharmacol 2000 Sep; 405: 43–54PubMedCrossRefGoogle Scholar
  206. 206.
    Perras B, Pannenborg H, Marshall L, et al. Beneficial treatment of age-related sleep disturbances with prolonged intranasal vasopressin. J Clin Psychopharmacol 1999 Feb; 19: 28–36PubMedCrossRefGoogle Scholar
  207. 207.
    Perras B, Marshall L, Kohler G, et al. Sleep and endocrine changes after intranasal administration of growth hormonereleasing hormone in young and aged humans. Psychoneuroendocrinology 1999 Oct; 24: 743–57PubMedCrossRefGoogle Scholar
  208. 208.
    Dahlin M, Bergman U, Jansson B, et al. Transfer of dopamine in the olfactory pathway following nasal administration in mice. Pharm Res 2000 Jun; 17: 737–42PubMedCrossRefGoogle Scholar
  209. 209.
    Ulrika W, Elena P, Björn J, et al. Transfer of morphine along the olfactory pathway to the central nervous system after nasal administration to rodents. Eur J Pharm Sci 2005 Apr; 24: 565–73CrossRefGoogle Scholar
  210. 210.
    Merkus P. Nose to brain: management forum nasal drug delivery symposium. 2001 Mar 26–27; LondonGoogle Scholar
  211. 211.
    Xiaomei W, Haibing H, Wei L, et al. Evaluation of braintargeting for the nasal delivery of estradiol by the microdialysis method. Int J Pharm 2006 Jul; 317: 40–6CrossRefGoogle Scholar
  212. 212.
    Jian C, Xiaomei W, Juan W. Evaluation of brain targeting for the nasal delivery of ergoloid mesylate by the micro dialysis methods in the rats. Eur J Pharm Biopharm 2008 Mar; 68: 694–700CrossRefGoogle Scholar
  213. 213.
    Gao X, Tao W, Lu W, et al. Lectin-conjugated PEG-PLA nanoparticles: preparation and brain delivery after intra nasal administration. Biomaterials 2006 Jun; 27: 3482–90PubMedCrossRefGoogle Scholar
  214. 214.
    Gao X, Wu B, Zhang Q, et al. Brain delivery of vasoactive intestinal peptide enhanced with the nanoparticles conjugated with the wheat germ agglutinin following intranasal administration. J Control Release 2007 Aug; 121: 156–67PubMedCrossRefGoogle Scholar
  215. 215.
    Gao X, Chen J, Tao W, et al. UEA I-bearing nanoparticles for brain delivery following intranasal administration. Int J Pharm 2007 Aug; 340: 207–15PubMedCrossRefGoogle Scholar
  216. 216.
    Illum L. Nasal drug delivery: new development strategies. Drug Discov Today 2002; 7: 1184–9PubMedCrossRefGoogle Scholar
  217. 217.
    Krauze MT, Saito R, Noble C, et al. Effects of the perivascular space on convection-enhanced delivery of liposomes in primate putamen. Exp Neurol 2005; 196: 104–11PubMedCrossRefGoogle Scholar
  218. 218.
    Debinski W, Gibo DM, Puri RK. Novel way to increase targeting specificity to a human glioblastoma-associated receptor for interleukin 13. Int J Cancer 1998; 76: 547–51PubMedCrossRefGoogle Scholar
  219. 219.
    Debinski W, Obiri NI, Powers SK, et al. Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin. Clin Cancer Res 1995 Nov; 1: 1253–8PubMedGoogle Scholar
  220. 220.
    Debinski W, Gibo DM, Hulet SW, et al. Receptor for interleukin 13 is a marker and therapeutic target for human high-grade gliomas. Clin Cancer Res 1999 May; 5: 985–90PubMedGoogle Scholar
  221. 221.
    Debinski W, Slagle B, Gibo DM, et al. Expression of a restrictive receptor for Interleukin 13 is associated with glial transformation. J Neurooncol 2000 Jun; 48: 103–11PubMedCrossRefGoogle Scholar
  222. 222.
    Kunwar S. Convection enhanced delivery of I13-PE38QQR for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies. Acta Neurochir 2003; 88 Suppl.: 105–11Google Scholar
  223. 223.
    Hall WA, Godai A, Juell S, et al. In vitro efficacy of transferrintoxinconjugates against glioblastoma multiforme. J Neurosurg 1992 May; 76: 838–44PubMedCrossRefGoogle Scholar
  224. 224.
    Martell LA, Agrawal A, Ross DA. Efficacy of transferrin receptor-targeted immunotoxins in brain tumor cell lines and pediatric brain tumors. Cancer Res 1993 Mar; 53: 1348–53PubMedGoogle Scholar
  225. 225.
    Buchwald P, Bodor N. A simple, predictive, structure-based skin permeability model. J Pharm Pharmacol 2001 Aug; 53: 1087–98PubMedCrossRefGoogle Scholar
  226. 226.
    Krewson CE, Klarman ML, Saltzman WM. Distribution of nerve growth factor following direct delivery to brain interstitium. Brain Res 1995 May; 680: 196–206PubMedCrossRefGoogle Scholar
  227. 227.
    Rietman JS, Geertzen JH. Efficacy of intrathecal baclofen delivery in the management of severe spasticity in upper motor neuron syndrome. Acta Neurotic Suppl 2007; 97 (Pt 1): 205–11CrossRefGoogle Scholar
  228. 228.
    Winkelmüller M, Winkelmüller W. Long-term effects of continuous intrathecal opioid treatment in chronic pain of nonmalignant etiology. J Neurosurg 1996 Sep; 85: 458–67PubMedCrossRefGoogle Scholar
  229. 229.
    Varelas PN, Rehman M, Pierce W, et al. Vancomycin-resistant enterococcal meningitis treated with intrathecal streptomycin. Clin Neurol Neurosurg 2008 Apr; 110(4): 376–80PubMedCrossRefGoogle Scholar
  230. 230.
    Blasberg RG, Patlak C, Fenstermacher JD. Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion. J Pharmacol Exp Ther 1975 Oct; 195: 73–83PubMedGoogle Scholar
  231. 231.
    Huang TY, Arita N, Hayakawa T, et al. ACNU, MTX and 5-FU penetration of rat brain tissue and tumors. J Neurooncol 1999; 45: 9–17PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • Mayur M. Patel
    • 1
  • Bhoomika R. Goyal
    • 1
  • Shraddha V. Bhadada
    • 1
  • Jay S. Bhatt
    • 1
  • Avani F. Amin
    • 1
  1. 1.Institute of PharmacyNirma University of Science and TechnologyAhmedabadIndia

Personalised recommendations