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Drug Delivery to the Central Nervous System- A Review

Drug Delivery to the Central Nervous System- A Review

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Published by: Pedro Manuel Abreu Martins on Jan 31, 2011
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J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 6(2):252-273, 2003
Corresponding Author:
Ambikanandan Misra, Pharmacy Depart-ment, Faculty of Technology & Engineering, M.S.University of Baroda,Kalabhavan, Vadodara – 390001. Gujarat. misraan@satyam.net.in,misraan@hotmail.com
Drug delivery to the central nervous system: a review.
Ambikanandan Misra, Ganesh S., Aliasgar ShahiwalaPharmacy Department, M.S. University of BarodaShrenik P. ShahSun Pharma Advanced Research Center, Baroda
Received 16 June 2003, Revised 26 June 2003, Accepted 5 August 2003
The brain is a delicate organ, and evolution built very efficient ways to protect it. Unfortunately, the samemechanisms that protect it against intrusive chemicals canalso frustrate therapeutic interventions. Many existing pharmaceuticals are rendered ineffective in the treatmentof cerebral diseases due to our inability to effectively deliver and sustain them within the brain. General meth-ods that can enhance drug delivery to the brain are, there-fore, of great interest. Despite aggressive research, patientssuffering from fatal and/or debilitating central nervoussystem (CNS) diseases, such as brain tumors, HIV enceph-alopathy, epilepsy, cerebrovascular diseases and neurode-generative disorders, far outnumber those dying of alltypes of systemic cancer or heart disease. The clinical fail-ure of much potentially effective therapeutics is often notdue to a lack of drug potency but rather to shortcomingsin the method by which the drug is delivered. Treating CNS diseases is particularly challenging because a variety of formidable obstacles often impede drug delivery to thebrain and spinal cord. By localizing drugs at their desiredsite of action one can reduce toxicity and increase treat-ment efficiency. In response to the insufficiency in con- ventional delivery mechanisms, aggressive research effortshave recently focused on the development of new strate-gies to more effectively deliver drug molecules to the CNS. This review intends to detail the recent advances in thefield of brain-targeting, rational drug design approach anddrug delivery to CNS. To illustrate the complexity of theproblems that have to be overcome for successful braintargeting, a brief intercellular characterization of theblood–brain barrier (BBB) is also included.
Despite enormous advances in brain research, brain andcentral nervous system disorders remain the world's lead-ing cause of disability, and account for more hospitaliza-tions and prolonged care than almost all other diseasescombined. The major problem in drug delivery to brain isthe presence of the BBB. Drugs that are effective againstdiseases in the CNS and reach the brain via the bloodcompartment must pass the BBB. In order to developdrugs which penetrate the BBB well to exhibit theexpected CNS therapeutic effects, it is of great importanceto understand the mechanisms involved in uptake into andefflux from the brain. The function of the BBB is dynami-cally regulated by various cells present at the level of theBBB (1). This realization implies better understanding of the relationship of transport at the BBB to drug structureand physicochemical properties.Despite successful examples of drug delivery to the CNS,but only some have reached the phase where they can pro- vide safe and effective human applications. As pharmaco-logical strategies improve, there will be less need forinvasive procedures for treating CNS diseases. Consider-able strides have been made in intravascular delivery andneurosurgical invasive procedures to deliver therapeuticsubstances into the brain. This review will prove invaluable to researchers interestedin the fundamental function of the BBB and those in thepharmaceutical industry interested in rational drug designdirected at delivering drugs to the brain.
 The failure of systemically delivered drugs to effectively treat many CNS diseases can be rationalized by consider-ing a number of barriers that inhibit drug delivery to theCNS.
 Blood-Brain Barrier 
It is now well established that the BBB is a unique mem-branous barrier that tightly segregates the brain from the
J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 6(2):252-273, 2003
circulating blood (2, 3). The CNS consist blood capillaries which are structurally different from the blood capillariesin other tissues; these structural differences result in a per-meability barrier between the blood within brain capillariesand the extracellular fluid in brain tissue. Capillaries of the vertebrate brain and spinal cord lack the small pores thatallow rapid movement of solutes from circulation intoother organs; these capillaries are lined with a layer of spe-cial endothelial cells that lack fenestrations and are sealed with tight junctions. Tight epithelium, similar in nature tothis barrier, is also found in other organs (skin, bladder,colon, and lung) (4).This permeability barrier, comprising,the brain capillary endothelium, is known as the BBB.Ependymal cells lining the cerebral ventricles and glial cellsare of three types. Astrocytes form the structural frame work for the neurons and control their biochemical envi-ronment. Astrocytes foot processes or limbs that spreadout and abutting one other, encapsulate the capillaries areclosely associated with the blood vessels to form the BBB.Oligodendrocytes are responsible for the formation andmaintenance of the myelin sheath, which surrounds axonsand is essential for the fast transmission of action poten-tials by salutatory conduction. Microglias are blood derivedmononuclear macrophages. The tight junctions betweenendothelial cells results in a very high trans-endothelialelectrical resistance of 1500-2000
compared to 3-33
of other tissues which reduces the aqueous basedpara-cellular diffusion that is observed in other organs (5,6).Micro-vessels make up an estimated 95% of the total sur-face area of the BBB, and represent the principal route by  which chemicals enter the brain. Vessels in brain werefound to have somewhat smaller diameter and thinner wallthan vessels in other organs. Also, the mitochondrial den-sity in brain micro-vessels was found to be higher than inother capillaries not because of more numerous or largermitochondria, but because of the small dimensions of thebrain micro-vessels and consequently, smaller cytoplasmicarea. In brain capillaries, intercellular cleft, pinocytosis, andfenestrae are virtually nonexistent; exchange must passtrans-cellularly. Therefore, only lipid-soluble solutes thatcan freely diffuse through the capillary endothelial mem-brane may passively cross the BBB. In capillaries of otherparts of the body, such exchange is overshadowed by othernonspecific exchanges. Despite the estimated total lengthof 650km and total surface area of 12 m2 of capillaries inhuman brain, this barrier is very efficient and makes thebrain practically inaccessible for lipid- insoluble com-pounds such as polar molecules and small ions. As a con-sequence, the therapeutic value of many promising drugsis diminished, and cerebral diseases have proved to bemost refractory to therapeutic interventions. Given theprevalence of brain diseases alone, this is a considerableproblem. Practically all drugs currently used for disordersof the brain are lipid-soluble and can readily cross the BBBfollowing oral administration. Although antimicrobial b-lactam antibiotics, when administered intracerebroventric-ularly, cause severe convulsion, fortunately these antibiot-ics, when administered intravenously or orally, do notcause such central nervous system (CNS) side effectbecause their limited transport across the blood–brain bar-rier (BBB). Further, in spite of being well distributed into various tissues, a lipophilic new quinolone antimicrobialagent, grepafloxacin, cannot enter the brain, resulting inthe avoidance of CNS side effects such as headache anddizziness due to the displacement of g-aminobutyric acid(GABA) from the GABA receptor binding sites. On theother hand, benzodiazepines such as diazepam have beenused as sedative-hypnotic agents, because these lipophilicdrugs readily cross the BBB. However, the BBB transportof an immunosuppressive agent, cyclosporin A, which ismore lipophilic than diazepam, is highly restricted. Simi-larly, almost all of the lipophilic anticancer agents such asdoxorubicin, epipodophylotoxin and Vinca alkaloids (e.g., vincristine and vinblastine) hardly enter the brain, causing difficulty in the treatment of brain tumors. Althoughlevodopa, which is useful for treatment of Parkinson’s dis-ease, is very hydrophilic, it can readily penetrate the BBB. What mechanisms underlie these diverse BBB transportcharacteristics of drugs which are apparently structurally and pharmacologically unrelated? In order to avoid over-lap with this section, the drug transport across the BBB of small-molecular drugs by carrier-mediated transport andof peptide drugs by the adsorptive-mediated transcytosisare discussed in section 7.1.4 and 7.1.5 respectively.Some regions of the CNS do not express the classical BBBcapillary endothelial cells, but have micro-vessels similar tothose of the periphery. These areas are adjacent to the ven-tricles of the brain and are termed the circumventricularorgans (CVOs). The CVOs include the choroid plexus, themedian eminence, neurohypophysis, pineal gland,organum vasculosum of the lamina terminalis, subfornicalorgan, subcommisaral organ and the area postrema. Though in the CVO brain regions the capillaries are morepermeable to solutes, the epithelial cells of the choroidplexus and the tanycytes of other regions form tight junc-
J Pharm Pharmaceut Sci (www.ualberta.ca/~csps) 6(2):252-273, 2003
tions to prevent transport from the abluminal extracellularfluid (ECF) to the brain ECF. The choroid plexus may beof importance when considering the transport of peptidedrugs, because it is the major site of cerebrospinal-fluid(CSF) production, and both the CSF and brain ECF freely exchange (7). The BBB also has an additional enzymatic aspect. Solutescrossing the cell membrane are subsequently exposed todegrading enzymes present in large numbers inside theendothelial cells that contain large densities of mitochon-dria, metabolically highly active organelles. BBB enzymesalso recognize and rapidly degrade most peptides, includ-ing naturally occurring neuropeptides (8, 9).Finally, the BBB is further reinforced by a high concentra-tion of P-glycoprotein (Pgp), active –drug-efflux-trans-porter protein in the luminal membranes of the cerebralcapillary endothelium. This efflux transporter actively removes a broad range of drug molecules from the endot-helial cell cytoplasm before they cross into the brain paren-chyma. Figure-1 gives a schematic representation of allthese BBB properties using a comparison between brainand general capillaries.
Figure 1: Schematic comparison between general (left)and brain (right) capillaries.
 Blood-Cerebrospinal Fluid Barrier 
 The second barrier that a systemically administered drug encounters before entering the CNS is known as theblood-cerebrospinal fluid barrier (BCB). Since the CSFcan exchange molecules with the interstitial fluid of thebrain parenchyma, the passage of blood-borne moleculesinto the CSF is also carefully regulated by the BCB. Physio-logically, the BCB is found in the epithelium of the chor-oids plexus, which are arranged in a manner that limits thepassage of molecules and cells into the CSF. The choroidplexus and the arachnoid membrane act together at thebarriers between the blood and CSF. On the external sur-face of the brain the ependymal cells fold over onto them-selves to form a double layered structure, which liesbetween the dura and pia, this is called the arachnoidmembrane. Within the double layer is the subarachnoidspace, which participates in CSF drainage. Passage of sub-stances from the blood through the arachnoid membraneis prevented by tight junctions (10). The arachnoid mem-brane is generally impermeable to hydrophilic substances,and its role is forming the Blood-CSF barrier is largely pas-sive. The choroid plexus forms the CSF and actively regu-lates the concentration of molecules in the CSF. Thechoroid plexus consist of highly vascularized, "cauliflower-like" masses of pia mater tissue that dip into pocketsformed by ependymal cells. The preponderance of choroidplexus is distributed throughout the fourth ventricle nearthe base of the brain and in the lateral ventricles inside theright and left cerebral hemispheres. The cells of the chor-oidal epithelium are modified and have epithelial charac-teristics. These ependymal cells have microvilli on the CSFside, basolateral interdigitations, and abundant mitochon-dria. The ependymal cells, which line the ventricles, form acontinuous sheet around the choroid plexus. While thecapillaries of the choroid plexus are fenestrated, non-con-tinuous and have gaps between the capillary endothelialcells allowing the free-movement of small molecules, theadjacent choroidal epithelial cells form tight junctions pre- venting most macromolecules from effectively passing into the CSF from the blood (11). However, these epithe-lial-like cells have shown a low resistance as compared thecerebral endothelial cells, approximately 200
between blood and CSF (12).In addition, the BCB is fortified by an active organic acidtransporter system in the choroids plexus capable of driv-ing CSF-borne organic acids into the blood. As a result a variety of therapeutic organic acids such as the antibioticpenicillin, the anti-neoplastic agent methotrexate, and theantiviral agent zidovudine are actively removed from theCSF and therefore inhibited from diffusing into the brainparenchyma. Furthermore, substantial inconsistenciesoften exist between the composition of the CSF and inter-stitial fluid of the brain parenchyma, suggesting the pres-ence of what is sometimes called the CSF-brain barrier(13). This barrier is attributed to the insurmountable diffu-sion distances required for equilibration between the CSFand the brain interstitial fluid. Therefore, entry into theCSF does not guarantee a drug’s penetration into the brain.

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