Novel Central Nervous System Drug Delivery Systems
Jocelyn Stockwell1,2,Nabiha Abdi1,2,
Xiaofan Lu1,2,Oshin Maheshwari1,2and
Changiz Taghibiglou2,*
1Department of Physiology,2D01Health Sciences,107 Wiggins Rd.,Saskatoon,SK,S7N5E5,Canada
2Department of Pharmacology,2D01Health Sciences, 107Wiggins Rd.,Saskatoon,SK,S7N5E5,Canada
*Corresponding author:Changiz Taghibiglou,
changiz.taghibiglou@usask.ca
For decades,biomedical and pharmaceutical rearch-ers have worked to devi new and more effective therapeutics to treat dias affecting the central ner-vous system.The blood–brain barrier effectively pro-tects the brain,but pos a profound challenge to drug delivery across this barrier.Man
y traditional drugs cannot cross the blood–brain barrier in appre-ciable concentrations,with less than1%of most drugs reaching the central nervous system,leading to a lack of available treatments for many central nervous sys-tem dias,such as stroke,neurodegenerative dis-orders,and brain tumors.Due to the ineffective nature of most treatments for central nervous system disor-ders,the development of novel drug delivery systems is an area of great interest and active rearch.Multi-ple novel strategies show promi for effective central nervous system drug delivery,giving potential for more effective and safer therapies in the future.This review outlines veral novel drug delivery techniques, including intranasal drug delivery,nanoparticles,drug modifications,convection-enhanced infusion,and ultra-sound-mediated drug delivery.It also asss possible clinical applications,limitations,and examples of cur-rent clinical and preclinical rearch for each of the drug delivery approaches.Improved central nervous system drug delivery is extremely important and will allow for improved treatment of central nervous sys-tem dias,causing improved therapies for tho who are affected by central nervous system dias.
Key words:drug delivery/ADMET,drug design,drug discov-ery,ligands(agonist/antagonist),nanotechnology(drug discov-ery),receptor
Received28August2013,revid18November2013and accepted for publication27November2013
The brain is an extremely complex system,which must be tightly regulated at all times to maintain its function.In a dia state or when there is insult to the tissue,thera-peutic intervention is required to alleviate symptoms and the underlying cau of the insult.Many dias affecting the central nervous system(CNS)require therapeutic inter-vention requiring delivery of pharmacological agents to the tissue being affected.The CNS is a complex and delicate system with a natural protective barrier surrounding it,the blood–brain barrier(BBB),which functions to protect the nsitive CNS tissue.
Currently,there is a vast lack of available therapeutics to treat the CNS dias,and some therapeutics that do exist are unable to reach the CNS in effective therapeutic concentrations(1).This means that there is a profound need for new and effective drugs for the treatment of the and other CNS dias.Not only are effective drugs needed,but also new modalities of drug delivery are imperative for the development of effective treatments for various CNS dias.
A major challenge in the therapeutic treatment of the CNS is the delivery of therapeutic agents to the target site in the CNS,while having minimal effects on other tissues within the body(2).There are many obstacles,such as first-pass metabolism of drugs entering through systemic circulation,uptake of a therapeutic by other tissues within the body,and the blood–brain barrier,which occludes almost a
ll foreign substances from entry into the CNS(3). There have been many strategies ud to approach this problem,leading to multiple methods of overcoming the obstacles,as will be outlined further below.
The blood–brain barrier
The BBB is a major obstacle in drug delivery to the CNS. The brain is extremely well vascularized,allowing each neuron to be in contact with a capillary(4,5).There are only two places in the brain that allow blood contents into the CNS,which are the BBB and the blood–cerebrospinal fluid barrier(BCSFB;3,6).The BCSFB is formed by epithe-lial cells in the choroid plexus,which is the site of cerebro-spinalfluid production.Although it is another barrier to the entrance of substances into the CNS,it is approximately 5000times smaller than the BBB,showing that the BBB is a key barrier to the entrance of substances into the CNS(7,8).
The BBB is a complex functional barrier that limits the transport of substances into and out of the CNS(9).The BBB is extremely lectively permeable,allowing only a
Chem Biol Drug Des2014;83:507–520 Review
small fraction of substances in the blood to enter the CNS (8,10).This lectivity allows for the homeostatic regulation of the environment within the CNS,protecting the delicate nervous tissue from insult due to the entrance of foreign material(3,11).The BBB rves to regulate nutrient deliv-ery and ion concentration in the CNS and has a very important protective function for the CNS(6).
The BBB is a layered structure,forming a complex barrier. It is compod of endothelial cells,the capillary bament membrane,pericytes,which are embedded in the ba-ment membrane,and astrocyte endfeet,which tightly sur-round the capillaries,forming a sheath(12).Between each of the endothelial cells in the BBB capillaries,tight junc-tions prevent diffusion of particles between the cells(3). Only small lipophilic compounds,such as O2,CO2,and H2O,are able to freely diffu across the BBB along their concentration gradient(13).
Multiple endogenous transport mechanisms exist in the BBB to tightly regulate the entrance of substances,such as nutrients,into the CNS.Figure1outlines important transport mechanisms prent at the BBB.Only small, lipophilic compounds are able to easily diffu through the BBB.Larger molecules require additional active transport mechanisms,such as receptor-mediated transport and carrier-mediated transport(6).The transport mecha-nisms must be considered when designing a drug for entry into the CNS through systemic circulation.
The BBB is extremely effective at lectively regulating the environment within the CNS,but the same physiological characteristic also prevents delivery of therapeutic com-pounds into the CNS.Due to the extreme lectivity at the BBB,often less than1%of a drug administered through systemic IV injection will reach the CNS,if any at all(11). To overcome challenges to delivery therapeutics to the CNS,multiple strategies have been developed with the aim to increa active and effective drug delivery to the CNS(14).
Strategies for Central Nervous System
Drug Delivery
Due to many features of the BBB mentioned previously, drug delivery to the CNS is highly limited at prent.How-ever,novel targeted drug delivery increas patient compli-ance,prolongs product/drug life,reduces healthcare costs,and improves the pharmacokinetics of degradable proteins and peptides(15).Multiple strategies have been developed to overcome the obstacles to delivery therapeu-tic agents to the CNS.Figure2outlines divisions of CNS drug delivery strategies under the two broad categories of invasive and non-invasive drug delivery.Two broad cate-gories of the various strategies ud are invasive and non-invasive methods,bad on the method of drug entry into the C
NS.Invasive methods aim to deliver the therapeutic agent into the brain parenchyma by either directly entering the CNS or disrupting the BBB(16),whereas non-invasive approaches take advantage of endogenous mechanisms to enhance drug delivery into the CNS(11).This review will focus on novel developments in both invasive and non-invasive drug delivery techniques and will discuss the
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Figure1:Multiple transport mechanisms exist at the BBB to tightly regulate the passage of lect molecules through the BBB.(A)Efflux pumps such as P-glycoprotein(P-gp)remove unwanted material from the CNS.(B)Endocytosis mechanisms,such as GLUT1-mediated endocytosis,mediate transport
of large molecules such as gluco.(C)Paracellular transport is passive diffusion of small molecules that are permeable through the tight junctions between capillary endothelial cells.(D)Transcellular passive diffusion also exists for small lipophilic molecules.(E)Receptor-mediated transport,for example insulin receptor-mediated transport,are a major mechanism of the transport of molecules across the BBB.
Stockwell et al.
applications and limitations of the novel drug delivery techniques.
Invasive Drug Delivery Approaches
Invasive drug delivery approaches involve physically enter-ing the CNS using surgical methods,disruption of the BBB,or injecting a therapeutic agent directly into the tar-get site within the CNS.Invasive strategies can be aggres-sive and aim to maximize the amount of a therapeutic that reaches the target tissue with minimal exposure to surrounding healthy tissue (17).This is important when considering the treatment of brain tumors,for example,as many chemotherapeutic agents are toxic substances (18).Invasive strategies can also exclude drugs from entering systemic circulation,thus reducing or eliminating periph-eral adver effects (19).Transcranial injections,either
intracerebrally or intracerebroventricularly,are a gold stan-dard for invasive drug delivery techniques,which include injection of a cannula or probe into the brain target site and direct injection of the drug (20).Direct injection of a drug into the CNS has the advantage of infusing the ther-apeutic agent directly into the target site,but it is largely diffusion dependent,meaning that treatment area may remain small,often within a few millimeters of the injection site (21).
Convection-enhanced drug delivery
Convection-enhanced drug delivery (CED)is an invasive drug delivery mechanism,which bypass the BBB using direct intracerebral injection of the drug and positive hydrostatic pressure during drug infusion (22,94).This pressure delivers a therapeutic agent to a specifically tar-geted region of the brain,establishing a fluid pressure gra-dient that caus the drug to penetrate farther into the target tissue (22).Unlike other currently available invasive techniques for CNS drug delivery,such as direct diffusion-dependent drug injections,CED us bulk flow for a uni-form distribution of the drug throughout the target region (19,20).Drugs,peptides,siRNA,and other molecules can potentially be delivered to brain tissue using CED (23).The mechanism of convection-enhanced delivery involves imaging-guided inrtion of a small catheter into the target site within the brain.Imaging techniques such as ultra-sound are ud to guide the placement of the catheter.Through the catheter,the drug is
actively pumped into the brain using continuous positive pressure generated by an infusion pump,which caus the drug to penetrate into the interstitial space (24).Experimental data have shown that the amount of drugs delivered to the target site matches the amount that was infud,implying that with CED,relative control of drug distribution can be obtained,which increas delivery efficiency (19).
In addition,CED caus minimal structural damage to the brain,with the exception of the catheter track,which is why a small catheter should be ud.Convection-enhanced drug delivery has many possible clinical applica-tions and can be ud in the clinical treatment of neurological dias such as malignant brain tumors (25–31),neurodegenerative disorders (32–34),epilepsy (19),and stroke (24,35).CED has recently been shown as a feasible method of intracerebral drug delivery,which appears to be safe,and has been ud in both preclinical and clinical studies (36–38).
In a preclinical study carried out by Murad et al.(17),CED techniques were ud to deliver tumor-targeted cytotoxin interleukin 13bound to Pudomonas exotoxin (IL13-PE),which is a drug of choice in treating certain malignant brain tumors.The study ud both rat and primate animal models and ud the surrogate magnetic resonance imaging tracer gadolinium-bound albumin (Gd-albumin),which aided in monitoring the distribution of the drug in real time.Results indicated that neit
her the rats nor primates showed signs of toxicity and the drugs were uni-formly distributed throughout the target brain region (17).This result shows that CED has the ability to distribute the therapeutic agent to the target site with minimal side-effects due to actions on surrounding tissue.In another preclinical study carried out by Gasior et al.(39),rats with kindled epilepsy were given botulinum neurotoxins A and B,which are anticonvulsants,into the amygdala using CED.Rats that were given neurotoxins showed
attenuated
Figure 2:Different central nervous system (CNS)drug delivery
strategies divided into the broad categories of invasive and non-invasive drug delivery.The
categories encompass a wide array of techniques which are,or have the potential to be ud to target CNS tissue.Invasive methods aim to physically penetrate the blood-brain barrier (BBB),whereas non-invasive techniques aim to enter or bypass the BBB with no physical breach of the BBB.
Novel CNS Drug Delivery Systems
izure activity,gained weight,and behaved normally when compared to kindled rats that did not receive botulinum toxin via CED(39).
Clinically,CED has been ud in the delivery of chemotherapeutic agents to tumors in the treatment for gli-omas,which are aggressive brain tumors with currently few effective treatments.In thefirst trial of its type,Kunwar et al.
(40)compared the effects using CED of cintredekin besudo-tox(CB)versus the u of Gliadel wafers in the treatment for glioblastoma multiforme(GBM)in a pha3clinical trial. Patients were parated into two groups,one receiving CB by CED and the other having Gliadel wafers implanted at the targe
t site.Both treatments were given immediately after tumor rection surgery,and the CED group received infu-sions of CB over96h.Both treatments had the same sur-vival rate with similar adver effects(40).This trial shows the potential for CED as an effective and relatively safe drug infusion method to enhance drug delivery across the BBB. Modulation of BBB permeability
The application of minimally invasive drug delivery techniques is ideal when effective therapeutic concentra-tions of a drug can be delivered to the target site in the CNS.Modulation of vascular permeability involves transient disruption of the cells in the BBB,thus allowing macromo-lecular drugs to leak into the CNS(41).The techniques can allow for specific spatial delivery,reducing side-effects on surrounding tissue.Temporal specificity can also be achieved due to the fact that BBB permeability will recover after treatment,allowing for control over transient opening of the BBB(20).Osmotic BBB disruption has been a mainstay for increasing permeability of the BBB,usually using high concentrations of mannitol introduced into the carotid artery.A major problem with osmotic BBB disrup-tion stems from the lack of spatial specificity as well as temporal specificity in this technique(42).Novel tech-niques have been developed to disrupt the BBB with the aim of providing spatially specific BBB disruption which is transient,and wherein the tissue recovers quickly with no permanent damage to the BBB and surrounding cells. Ultrasound-mediated blood–brain barrier
disruption
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Ultrasound-mediated drug delivery(USMD)is a transient drug delivery technique that delivers therapeutic agents into the CNS by disrupting the BBB(41).USMD us microbubbles activated by ultrasound waves to exert mechanical force on a targeted area of the BBB,causing temporary disruption to allow a therapeutic compound to leak into the target tissue(18,41,43).The microbubbles are small air-filled,lipid-or protein-shelled bubbles that facili-tate reversible disruption of the blood–brain barrier(43).
In the prence of an ultrasound wave,the microbubbles increa the permeability of the BBB by mechanical dis-ruption,which subquently allows site-specific delivery of the therapeutic agent(18).Experimental data have shown that an increa in the amount microbubbles ud is also associated with tissue damage(44).Due to the disruption of the BBB,the drug does not need to be chemically modified,thus maintaining the drug’s therapeutic activity. The therapeutic agents,along with a measured volume of microbubbles,are injected intravenously into systemic cir-culation of the patient(43).The microbubbles and the drug will distribute throughout the systemic circulation of the subject.An ultrasound beam is then focud on the tar-geted location of the BBB,which is the area of the BBB that will be disrupted(44).The ultrasound beam caus the microbubbles to oscillate,exertin
g mechanical forces on the target ction of the BBB capillary.This mechanical force disrupts the tight junctions of the BBB,allowing the pharmacological agent to leak into the target tissue (18,43).Additionally,due to the fact that the ultrasound wave can be targeted within an area of a few millimeters, the drug delivery can be localized,reducing possible drug toxicity in surrounding healthy tissue.In most situations, the capillaries will not rupture and will recover their normal lective permeability within a few hours of treatment(43). This makes USMD an ideal candidate for the treatment of brain tumors requiring aggressive chemotherapy,such as glioblastoma(18).
Although USMD has not been ud clinically,much pre-clinical rearch has been performed using animal models. There is a potential in the future to u this technique in the treatment of chemotherapeutic cancer treatments, which require the u of drugs that are toxic to non-tumor neurons.In a preclinical study,Treat et al.(44)aimed to asss the effectiveness of USMD in a ries of experiments that were performed using rat models.The experiment ud three parts to asss the ultrasound power required to cau BBB disruption,the concentra-tions of an anticancer drug(doxorubicin),which reaches the target region of the brain,andfinally the effect of alter-ing the do of microbubbles ud.The results showed that with the u of USMD,optimal concentrations of the drug can reach the target tissue within the CNS when administered through IV injection with micr
obubbles. Another important result showed that if the microbubble concentration becomes too high in the circulation,capillar-ies can be disrupted for extended periods,or even perma-nently,causing toxicities due to influx of blood proteins and other substances from the blood into the CNS(44).In another study carried out to asss the integrity of BBB tight junction after USMD was performed,the data showed that shortly after the sonication with ultrasound waves,the tight junctions regained their protein complexes and thus regained their structural integrity(43).
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Although USMD has the ability to deliver high concentra-tions of unmodified drugs into the tissues within the brain, it may cau toxic substances such as bacteria and
Stockwell et al.
antibodies to leak into the CNS while the BBB is disrupted.This also pos a problem if the microbubble concentration is too high,causing permanent capillary damage.Due to the concerns,USMD is still in preclinical stages and at this point still needs improved procedures to increa safety and optimize procedures before clinical treatments should be considered.
垃圾分类宣传画
Optical modulation of vascular permeability Permeability of the BBB can be achieved by optical modulation,namely lar irradiation to induce leakage of the blood plasma out of the BBB.Using a fe
mtocond near-infrared puld lar,deep tissue penetration can be achieved with minimal scattering and localized nonlinear absorption(20).The short-puld lars have been suc-cessfully ud for in vivo imaging,cell permeabilization, and subcellular organelle disruption(45,46).This enables minimally invasive optical modulation of cells in vivo,and once the lar irradiation is discontinued,the targeted blood vesls recover fully with no damage to the integrity of the BBB.The reversible nature of this method makes it promising for u in targeted macromolecular drug delivery to the CNS.Other potential molecules that could be deliv-ered by this method are monoclonal antibodies,recombi-nant proteins,transactivator of transcription(TAT) peptides,and gene therapies(45–47).When paired with i.v.drug injection,the near-infrared lar puls can be ud to deliver the drug into the target site by permeabiliz-ing the BBB at the specific target.As the drug is prent in systemic circulation,the leaky BBB allows the unmodi-fied molecules to pass through and enter into the CNS (20).
Currently,a major limitation of this technique is the limited tissue penetration of the lar,which currently is only able to penetrate approximately1mm into the tissue(48).This makes deep brain drug delivery unattainable at this point. It has also been shown that u of a near-infrared lar can evoke the generation of reactive oxygen species within the cell,leading to membrane dysfunction,DNA fragmen-tation,and ultimately apoptosis(49).
骆驼祥子道理
Choi et al.(20)ud optical BBB disruption to test the ability of the lar to improve drug delivery across the BBB,using chemical probes to test the concentration of molecules entering the brain through the leaky BBB.They were able to show that the lar was able to make the BBB transiently permeable to blood plasma and macro-molecules and that after the lar was turned off,the BBB recovered and was no longer leaky.The experiment showed that drug delivery can be achieved using this technique with minimal adver effects and that it should be developed further(20).Due to the current limitations, optical BBB disruption is not likely to be ud in a clinical tting in the near future,but with improvements in lar manufacturing and optical resolution,this is a promising drug delivery technique for the future.Non-invasive Drug Delivery Approaches
A major drawback to invasive treatments is that the can be unrealistic in the treatment for chronic disorders requiring long-term intervention,such as neurodegenera-tive disorders(50).Invasive techniques also require hospitalization and are inherently risky,as they often require surgery(19).Non-invasive drug delivery strategies, on the other hand,aim to enter or bypass the BBB, utilizing endogenous transport mechanisms(11).Three non-invasive strategies of drug delivery to the CNS include biological drug delivery,which us carriers such as custom lipid or peptide designs to transport a thera-peutic into the CNS(51),chemical modification,which us structural mo
dification or prodrug synthesis to enhance transport into the CNS(52),and intranasal drug delivery,which bypass the BBB,taking advantage of the direct pathway to the CNS through the olfactory epi-thelium(50).
Chemical approaches
Small molecular weight drugs(MW<400Da)can easily cross the BBB through diffusion(11);however,the majority of drugs lack this chemical property.In the cas,a prodrug strategy can be ud to enable CNS drug delivery.Molecular weight,solubility,and permeability are some characteristics that can be modified to improve the physiochemical deficiency of drugs,impeding CNS delivery.Other factors,including affinity of the drug for efflux proteins,and metabolism by other tissues,also need thorough understanding when designing a prodrug(3). The concept of a prodrug wasfirst introduced by Albert in 1958(53),and he defined a prodrug as an inactive drug form that must undergo bioconversion to the active parent form,by either chemical or enzymatic reaction in vivo(54). An ideal prodrug should be converted into the parent compound to exert its therapeutic effect only when it pen-etrates the BBB.The active drug form cannot diffu back into circulation,which builds a‘locked-in’system(55).This is a major feature of the prodrug approach in CNS drug delivery.
Prodrug lipidization
The most common chemical approach to delivering CNS drugs across the BBB is to‘lipidize’the drug by con-verting non-polar functional groups into polar groups to make a lipophilic prodrug(55).By increasing lipophilicity, one would predict that the prodrug should have improved permeability across the BBB.A good example of the prodrug lipidization approach is the deacetylated product of morphine,which is heroin.Morphine,which is the parent compound,has a low brain uptake rate.The O-acetylation of morphine produces heroin,which is able to cross the BBB approximately100-fold better than morphine(56).
Novel CNS Drug Delivery Systems
One of the biggest challenges with prodrugs is whether they can achieve a site-specific effect.To achieve site-specific prodrug delivery,the prodrug must be able to access the appropriate tissue within the CNS,convert into the active drug form within the CNS,and exhibit prolonged parent drug retention within the target tissue(57). Unfortunately,some prodrugs experience unfavorable bioconversion lectivity.This caus veral problems associated with lipidized prodrugs.
Many prodrug molecules can easily penetrate plasma membranes and convert into the active parent
drug before they reach the CNS,resulting in the poor tissue lectivity. Lipid-soluble prodrugs diffu into tissues,causing incread tissue burden(58).The rate of oxidative metab-olism by cytochrome P-450and other metabolic enzymes increas when there is an increa in drug lipophilicity(3). This highly one-dimensional approach may not guarantee the therapeutic results(56,59).In fact,there are only a small number of CNS prodrugs currently designed and synthesized,which are successfully using a simple lipidiza-tion of the molecule’s polar groups.
Prodrug action through carrier-mediated transport Targeting of prodrugs to endogenous transporters can facilitate site-specific transport and reprents a novel strategy for CNS drug delivery(60).Receptor-mediated transport(RMT)and carrier-mediated transport(CMT)are two major endogenous transport mechanisms utilized for CNS drug delivery.Certain large peptides and proteins uti-lize RMT across the BBB via the endocytic process. Examples of well-known endogenous peptide receptors located at the BBB are insulin receptor(INSR),transferrin receptor(TFR),and insulin-like growth factor receptors (IGF1R,IGF2R).Carrier-mediated transport is well suited for the transport of smaller molecules(MW<600Da). Several CNS prodrugs have been designed and synthesized by utilizing CMT systems for CNS drug delivery(55).The CMT system is designed to transport nutrients,vitamins,and hormones into the CNS.Six types of nutrients being tran
sported through the CMT system have been identified at the BBB(Table1).The CMT pro-drug approach is mainly bad on two strategies,which are to modify a drug into a pudo-nutrient prodrug structure,which can be carried by the CMT system,and to conjugate a drug into a nutrient substrate of a CMT system(51).Of the CMT systems expresd in the BBB, the carriers for neutral amino acid(LAT1)and gluco (GLUT1)have been found to have a high transport capac-ity compared with other CMT systems(61,62).
曹操的主要事迹Prodrugs and the LAT1system.The L-amino acid transporter(LAT)is expresd at the BBB and is a type of membrane transport protein,which is responsible for carrying large neutral amino acids(L-phenylalanine, L-tyrosine,L-leucine,etc.)in a Na+-independent manner. Of the amino acid transporters prented at the BBB, LAT1has been shown to have a prime role in transporting neutral amino acids into the brain(52).Not only can the naturally occurring amino acids be transported by LAT1, but some amino acid-related products such as L-DOPA and gabapentin(anticonvulsant)are also able to utilize the LAT1(63).
A classic example of a prodrug designed to target the LAT1system is the u of L-DOPA,which is a precursor of dopamine,ud to treat Parkinson’s dia.Carboxyl-ation of dopamine yields L-DOPA,which acts as a pudo-nutrient substrate for LAT1.Once L-DOPA enters the brain,a decarbox
yla enzyme induces the decarbox-ylation of L-DOPA,delivering dopamine into the brain.A possible risk of L-DOPA treatment is that the prodrug can be converted into dopamine through peripheral metabo-lism,providing adver effects due to premature conver-sion.To inhibit the premature bioconversion of L-DOPA, patients with Parkinson’s dia are given Sinemetâ,a combination of carbidopa and L-dopa.Carbidopa acts as a decarboxyla inhibitor.There is also current rearch focusing on developing a new hybrid glutathione–methio-nine peptidomimetic prodrug to resist oxidative degrada-tion of L-DOPA in gastricfluid(64).
Another attractive strategy is to conjugate an endogenous transporter substrate to an active drug molecule.Peura et al.(52)have designed four phenylalanine derivatives of valproic acid using drug conjugation.They have shown that meta-substituted phenylalanine prodrugs bind to LAT1with a higher affinity compared with the affinity of the para-substituted derivative and the plain valproic acid in a rat model(52).In another study,Gynther et al.(65)conju-gated ketoprofen to L-lysine,so that the prodrug could uti-lize LAT1.The LAT1-mediated brain uptake of the prodrug was demonstrated with in situ rat brain perfusion tech-niques,and a rapid brain uptake was obrved with both in situ and in vivo experiments(65).Therefore,LAT1could be an efficient prodrug delivery carrier.
Prodrugs and the GLUT1system.Gluco is an esntial nutrient for the brain,which is able to cross t
he BBB using GLUT transporters.Among the GLUT family expresd at the BBB,GLUT1constitutes more than90 percent of all GLUT transporters(59).GLUT1can carry
Table1:Examples of endogenous transporters that can be exploited by the carrier-mediated transport(CMT)system
Carrier Type Carrier Reprentative Substrate
LAT1Neutral amino acid L-phenylalanine GLUT1Hexo Gluco
MCT1Monocarboxylic acid Lactic acid CAT1Cationic amino acid Arginine
CNT2Nucleoside Adenosine SVCT2Ascorbic acid Vitamin C Stockwell et al.
