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challenging research areas in pharmaceutical sciences. The blood-brain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics,antineoplastic agents, and a variety of central nervous system (CNS)-active drugs, especially neuropeptides. Therefore, various strategies have been proposed to improve the delivery of different drugs to this tissue which includes liposomes, colloidal drug carriers, micelles,chimeric peptide technology, intranasal and olfactory route of administration and nano technology. This review deals in brief about the status of the BBB, different pathologies of brain like neurodegenerative, cerebrovascular and inflammatory diseases. The first part of this article aims to review the strategies developed to circumvent the BBB and deliver drugs into the brain. The use of nano technology and liposomes are discussed which are crucial part of this article as mainly used to target various CNS disorders. The later part of this article contains future aspects of brain drug targeting. Keywords: Brain targeting technology, Colloidal drug carriers, Micelles, Liposomes, Nano Technology Introduction:The global market for drugs for the central nervous system (CNS) is greatly under penetrated and would have to grow by over 500% just to be comparable to the global market for cardiovascular drugs. The principle reason for this under-development of the global brain drug market is that the great majority of drugs do not cross the brain capillary wall, which forms the blood brain barrier (BBB) in vivo. The bloodbrain barrier (BBB) represents an insurmountable obstacle for a large number of drugs, including antibiotics, antineoplastic agents and a variety of central nervous system drugs (CNS)-active drugs, especially neuropeptides. It is located at the level of brain capillaries, where there is a convergence of different cell types; endothelial cells, pericytes, astrocytes and microglias (perivascular macrophages). The brain micro vessel endothelial cell (BMEC) that form the BBB, display important morphological characteristics such as the presence of tight junctions between the cells, the absence of fenestrations and a diminished pinocytics activity, that together help to restrict the passage of compounds from the blood into the extra cellular environment of the brain. [8, 9]This barrier permits the exchange of essential gases and nutrients between the bloodstream and the brain, while blocking larger entities such as microbes, immune cells and most drugs from entering. This barrier system is a perfectly logical arrangement, since the brain is the most sensitive and complex organ in the human body and it would not make sense for it to become the battleground of infection and immune response. This biological demilitarization zone is enforced by an elaborate and dense network of capillary vessels that feeds the brain and removes waste products. [7, 9]Each capillary vessel is bound by a single layer of endothelial cells, connected by tight junction , thereby making it very difficult for most molecules to exit the capillaries and permeate into the brain. Tight junctions provide significant transendothelial electrical resistance (TEER) to BMEC and impede the penetration of potential therapeutic agents such as oligonucleosides, antibodies, peptides and proteins. Furthermore, BMEC express a variety of enzymes, both cytosolic and on the extra cellular membrane which also contribute to the restrictive nature of the BBB. P-glycoprotein (P-gp) is also present in the luminal plasma membrane of BMEC.
The water -soluble parts of the drugs restricts BBB transport conversion of water-soluble drug into lipidsoluble pro drug is the traditional chemistry driven solution to the BBB problem. Nevertheless. a detergent that can disrupt the BBB.  Brain Targeting Technology:The usual noninvasive approach to solving the brain drug delivery problem is to lipidize the drug. Whereas 98% of all small-molecule drugs do not cross the BBB. In other studies.  The major neurological diseases affecting the brain may be categorized asneurodegerative. the large size of the liposomes that were used produced micro embolisms that gave a false impression of brain uptake.cerebrovascular. and nearly 100% of large-molecule drugs do not cross the BBB. Under normal conditions the BBB acts as a barrier to toxic agents and safeguards the integrity of the brain. and incorrectly attributing the detergent effects to their own nanoparticles. several disorders and diseases can affect the brain leading to some loss of BBB integrity.This is an ATP-dependant efflux pump and a member of a family of intrinsic membrane proteins. Figure 1:. inflammatory (infections or autoimmune) and cancer. [4. .Outline of a program for developing BBB drug targeting strategies derived from either chemistry based or biology-based disciplines. with the drug as a stabilizing agent. Rate-limiting role of the BBB in brain drug development:Present-day incongruities in brain drug development are illustrated by a consideration of some of the characteristics of the CNS drug industry. 6]P-gp is known to prevent the intracellular accumulation of an extensive variety of chemotherapeutic agents and hydrophobic compounds. with some studies having co injected Polysorbate 80.
malignantglioma and disseminated CNS germ cell tumors.Strategies for drug delivery to the brain:Several drugs do not have adequate physiochemical characteristics such as high lipid solubility. vesicle and liquid crystal dispersions. This method permitted the delivery of chemotherapeutic agents in patients with cerebral lymphoma. Drug injection into the CSF is a suitable strategy for sites close to the ventricles only. Possible systems for drug delivery:Colloidal drug carriers:Colloidal drug carrier systems such as micellar solutions. carrier-mediated transport. and may even influence it due to molecular interactions. The effect lasts for 20-30 minute. the olfactory mucosa may be reached and drug transport into the brain and/or CSF via the olfactory receptor neurons may occur. The incorporated drug participates in the microstructure of the system. and absorption through trancytosis. The goal is to obtain systems with optimized drug loading and release properties. Physiological stress. as well as nanoparticle dispersions consisting of small particles of 10 400 nm diameter show great promise as drug delivery systems. transient increase in intracranial pressure. during which time drugs diffuse freely. Disruption of the BBB: The thought behind this approach was to break down the barrier momentarily by injecting mannitol solution into arteries in the neck. long shelf-life and low toxicity. especially if the drug possesses amphiphilic and/ormesogenic properties. Intraventricular / Intrathecal delivery : Here using a plastic reservoir which implanted subcutaneously in the scalp and connected to the ventricles within the brain by an outlet catheter.  . and unwanted delivery of anticancer agents to normal brain tissues are the undesired side-effects of this approach in humans. low molecular size and positive charge which are essential to succeed in traversing BBB. Intra nasal drug delivery: After nasal delivery drugs first reach the respiratory epithelium. that would not normally cross the BBB. The resulting high sugar concentration in brain capillaries takes up water out of the endothelial cells. where compounds can be absorbed into the systemic circulation by Tran cellular and Para cellular passive absorption. shrinking them thus opening tight junction. When a nasal drug formulation is delivered deep and high enough into the nasal cavity.
Figure 2:-Pharmaceutical carriers Micelles:Micelles formed by self-assembly of amphiphilic block copolymers (5-50 nm) in aqueous solutions are of great interest for drug delivery applications.  In addition. As a result.solubility. The drugs can be physically entrapped in the core of block copolymer micelles and transported at concentrations that can exceed their intrinsic water. the corona may prevent recognition by the reticuloendothelial system and therefore preliminary elimination of the micelles from the bloodstream. total molecular weight and block length ratios can be easily changed. Moreover.Functionalization of block copolymers with cross linkable groups can increase the stability of the corresponding micelles and improve their temporal control. which allows control of the size and morphology of the micelles. the contents of the hydrophobic core are effectively protected against hydrolysis and enzymatic degradation. Figure3:-Block copolymer micelles . the hydrophilic blocks can form hydrogen bonds with the aqueous surroundings and form a tight shell around the micellar core. The fact that their chemical composition.
Bangham. releasing their or drugs into the cell. Nanoparticles and nanoformulations have already been applied as drug delivery systems with great success. 56-58] Figure 4:.Gly. the liposomes are taken up. Water-soluble medications added to the water were trapped inside the aggregation of the hydrophobic ends.Phe-Leu-Arg). with their additional potential to combine diagnosis and therapy. emerge as one of the major tools in nanomedicine. the phospholipid walls are acted upon by organelles called lysosomes. in the delivery of proteins.Liposomes. The first drug that was de-livered to the brain using nanoparticles was the hexapeptidedalargin (Tyr-D-Ala. including anti-tumors therapy. 17-20. Micelles.Bilayer sheet Nano technology:Nanoparticulate systems for brain delivery of drugs:One of the possibilities to deliver drugs to the brain is the employment of nanoparticles. Poly (butylcyanoacrylate) nanoparticles represent the only nanoparticles that were so far successfully used for the in vivo delivery of drugs to the brain. antibiotics. and AIDS therapy. gene therapy. to mediate the bio- . fat-soluble medications were incorporated into the phospholipid layer. as are ways in which to target them to specific diseased tissues.brain barrier.Liposomes :Liposomes were first produced in England in 1961 by Alec D. One end of each molecule is water soluble. [8.Nanopartiacles are polymeric particles made of natural or artificial polymers ranging in size between about 10 and 1000 nm (1 mm) . Liposomal delivery systems are still largely experimental. [6.virostatics. delivery and release and.  The main goals are to improve their stability in the biological environment. 9] Nanoparticles provide massive advantages regarding drug targeting. while the opposite end is water insoluble.  In some cases liposomes attach to cellular membranes and appear to fuse with them. and nanoparticulate drug delivery systems have still greater potential for many applications.Drugs may be bound inform of a solid solution or dispersion or be adsorbed to the surface or chemically attached. and the medication is released. 22-27.  In the case of phagocytic cells. aLeuenkephalin analogue with opioid activity. the precise mechanisms of their action in the body are under study. radiotherapy. and vaccines and as vesicles to pass the blood .
but it is thought to depend on the particles size. The nanoparticles are the drug carrier system which is made from a broad number of materials such as poly (alkylcyanoacrylates) (pacas).  Nowadays nanotechnology is proved to be more efficient for enhancing drug delivery to brain. Recent advances in nanotechnology:The research team of University of Michigan has developed a tool to diagnose and treat the most virulent forms of brain cancer. When injected into thethe bloodstream. the pebbles accumulate in the brain tumor enabling a clear MRI image within just a few hours. 1992. transport. For example. The cytotoxicity of nanoparticles or their degradation products remains a major problem. They designed the pebbles to carry a variety of agents on their surface.  2) The use of biodegradable materials fornanoparticle preparation.polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL). The major potential advantage of using thesenanoparticles to treat cancer is of multifunctional. thenanoparticles travel their way through the bloodstream. 2001. their characterization and medical application have been reviewed in details earlier (Kreuter. allowing an efficient drug accumulation at the targeted sites in the body.Fattal andVauthier 2002). while a third agent attached to the PEBBLE could deliver a destructive dose of drug or toxin to nearby cancer cells. [8. and interaction with biological barriers. 10] The nanotechnology includes. And because they can transverse they have a targeting agent attached.Kopelman introduced the common MRI contrast element gadolinium to the pebbles. targeting. In some cases it is reported to mimic molecules that would normally be transported to brain. One target molecule immobilized on the surface could be used to help visualize the target using magnetic resonance imaging (MRI). each with a unique function. allows sustained drug release at the targeted site after injection over a period of days or even weeks (Vinogradov et al. 2002). [8. That is 20 to 200 nanometer diameternanoparticles. All three functions can be combined in a single tiny polymerspere to make a potent weapon againstcancer. 2002). improve drug loading. material composition.  .1) Coated nanoparticles 2)Pegylated nanoparticles 3)Solid Lipidnanoparticles (SLN) 4)Nanogels Advantages of nanotechnology :1) Due to their small sizenanoparticles penetrate into even small capillaries and are taken up within cells. allowing them to be transported across the capillary wall and into the brain by hitchingaride on the LDL receptor (Kreuter et al. polysaccharides. and copolymers..distribution of active compounds. and improvements in biocompatibility obviously are a main concern of future research. release. and structure. 10]The exact mechanism of nanoparticle transport into brain is not understood. The methods of preparation of nanoparticles. polyacetates. they dubbed Probes Encapsulated by Biologically Localized Embedding (pebbles).Barrattetal.
32] ProteinNeurotherapeutic agent andneuroprotection in stroke:Virtually all small-moleculeneuroprotective agents have failed in clinical stroke trials because either (a) these molecules have unfavorable safety profiles or (b) the drugs do not cross the BBB. Monoclonal antibody/avid in andmab/SA fusion genes and fusion proteins are produced with genetic engineering. In this . brainderivedneurotrophic factor (BDNF). Whereas there are less than a dozenmonoaminergic or aminoacidergic neurotransmitter systems. in which the drug is drawn through the blood stream to tumors cells. a special type of laser light activates the drug to attack the tumor. [35. The brain uptake of the HIRmab in the rhesus monkey is 2% to 4% of the injected dose which is a level of brain uptake that is 1 to 2 log orders greater than the brain uptake of aneuroactive small molecule such as morphine. there are hundreds ofpeptidergic neurotransmission systems. A model neurotrophin. Many malignantgliomas over express the EGF receptor (EGF-R) and EGF are a potential peptide radiopharmaceutical for the imaging of brain tumors. 36.Peptidomimeticmabs bind toexofacialepitopes on the BBB receptor that are removed from the endogenousligand binding site and piggyback across the BBB on the endogenous RMT system within the BBB. there is instantaneous capture of thebiotinylatedneurotherapeutic agent by the vector/avid in or vector/SA fusion protein. chances forneuroprotection have been lost. 40. and during this time. The activity of the genetically engineeredchimeric HIRmab is identical to that of the originalmurine HIRmab and thechimeric antibody is avidly taken up by the primate brain. The therapeutic window forneuroprotection is the first 3 hours after stroke. The latter is an endogenous peptide. 16. Therefore. 33] Neuroprotection with peptide radiopharmaceuticals:The practice of brain imaging uses small-molecule radio chemicals that bind to monoamine or amino acid neurotransmitter systems. the use of peptide radiopharmaceuticals could greatly increase the diagnostic potential ofneuroimaging technology. a drug ismonobiotinylated in parallel with the production of a vector/ avid in or a vector/streptavidin (SA) fusion protein. Iron oxide is a contrast agent used to enhance magnetic resonance imaging (MRI) Chimeric peptide technology:Chimeric peptides are formed when a drug that is normally not transported through the BBB is conjugated to a brain drug-targeting vector.Researchers incorporated a drug calledPhotofrin along with iron oxide intonanoparticles that would target cancerous brain tumors. Therefore. but at this time. 37. The BBB is disrupted in later stages following stroke. [11. Thebiotinylated drug is produced in one vial and the vector/avid in fusion protein is produced in another vial. if effectiveneuroprotective agents for stroke are to be developed. these molecules must have favorable safety profiles and must be able to cross the BBB. and the BDNFchimeric peptide isneuroprotective following delayed intravenous administration in either regional or global brain ischemia. Owing to the extremely high affinity of avid in or SA binding of biotin.42-45] .  Potential candidates forneuroimaging include epidermal growth factor (EGF) peptide radiopharmaceuticals for the early detection of brain tumors and A_ peptide radiopharmaceuticals as a diagnostic brain scan for Alzheimer disease. 41. modified protein. and the 2 vials are mixed before administration. Brain drug delivery in humans is possible with the genetically engineeredchimeric HIRmab. was reformulated to enable BBB transport. orpeptidomimetic monoclonal antibody (mab) that undergoes RMT(Rapid metabolic transfer) through the BBB on endogenous receptor systems such as the insulin receptor or the tfr. Brain drug delivery in rats is possible with the OX26 mousemab to the rat tfr. [34.Photofrin is a type of photodynamic therapy (PDT). the BBB is intact.
the olfactory mucosa may be reached and drug transport into the brain and/or CSF via the olfactory receptor neurons may occur.  Axonal transport is considered a slow route whereby an agent enters the olfactory neuron via endocytotic orpinocytotic mechanisms and travels to the olfactory bulb by utilizing the same anterograde axonal transport mechanisms the cell uses to transport endogenous substances to the brain. Then the molecules can diffuse into the brain tissue or will be cleared by the CSF flow into the lymphatic vessels and subsequently into the systemic circulation. Depending on the substance administered. whereby compounds passparacellularly across the olfactory epithelium into theperineural space.  The epithelial pathway is a significantly faster route for direct nose-to-brain transfer. [46-55] . problem of BBB-mediated exclusion of brain-therapeutic agents to be of greater immediate concern. olfactory mucosa..  When a nasal drug formulation is delivered deep and high enough into the nasal cavity. and absorption through trancytosis.Intranasal and olfactory rout of administration:- Figure 5:. carrier-mediated transport. epinephrine or vasopressin). The olfactory pathways may be broadly classified into two possible routes: the olfactory nerve pathway (axonal transport) and the olfactory epithelial pathway. the remainder of this article will deal primarily with the transport of drugs to the CNS by way of the olfactory epithelium. where compounds can be absorbed into the systemic circulation utilizing the same pathways as any other epithelia in the body: Tran cellular and Para cellular passive absorption.g. Although absorption across the respiratory epithelium is the major transport pathway for nasally-administered drugs and may represent a potentially time saving route for the administration of certain systemic drugs delivered in cryonics medication protocols (e.  Nasal transport routes:After nasal delivery drugs first reach the respiratory epithelium.1-4 mm/day.The olfactory bulb. axonal transport rates range from 20-400 mm/day to a slower 0. which is continuous with the subarachnoid space and in direct contact with the CSF. and olfactory nerve cells in humans. Accordingly.
effects on event-related-potentials). measurement of drug concentrations in the CSF during surgery. Wei et al. studies of the olfactory pathway as a conduit for transmission of drugs to the CNS have mostly made use of animals having substantially different ratios of olfactory-to-respiratory epithelium than humans. the mechanisms of transfer remain the same and are worthy of thorough investigation. To date.rifampin. however. Because of this limitation.  A growing number of recent reports have demonstrated the effectiveness of intranasal administration ofneuroprotective agents in decreasing ischemic brain injury.Factors Affecting Nasal Drug Delivery to the Brain:The size of the molecule is the major determinant in whether a substance will be absorbed across the nasal respiratory epithelium and/or transported along the olfactory pathway. which plays a significant role in ischemic brain damage. Once a drug is in the brain.  Recent patents:No. NAD+ was observed to reduce infarct formation by up to 86% even when administered at 2 hours after ischemic onset. either employ indirect visualization of drug transfer (e. Such agents are believed to provide neuroprotection by diminishing or abolishing activation of poly (ADP-ribose) polymerase-1 (PARP-1). However. 1 2 3 4 5 6 Document US20080235817 US20080234377 US20080234368 US20080234356 US20080234313 US20080234233 Document title Artificial mammalian chromosome Polyunsaturated fatty acids for treatment of dementia and pre-dementia related conditions Therapeutic compositions and methods of use 2-phenyl-3.  Other factors affecting delivery to the brain include the degree of dissociations and lipophilicity (higherlipophilicity results in better transport). for obvious reasons. Because PARP activation appears to be a downstream ischemic event.3-trifluro-2-hydroxypropionic acid derivatives Novel inhibitors Medicament for treatment of neurodegenerative diseases . it may be worthwhile to also investigate the ability of IN (intranasal) administration of agents such as antiporters or NMDA receptor blockers to provide neuroprotection against the more upstream events of global ischemia such as membrane depolarization and excytotoxicity. Ying et al. more than 50 drugs and drug-related compounds have been reported to reach the CNS after nasal administration in different species..3. (2007) recently reported that intranasal administration of NAD+ profoundly decreased brain injury in a rat model of transient focal ischemia. Graff and Pollack (2003). For example. or simple monitoring of CNS effects. Fisher et al. Demonstrated an almost linear relationship between the log (molecular weight) and the log (% drug absorbed) of watersoluble compounds. Similarly. but they give no clear-cut evidence regarding the role of transfer. Such studies have clearly indicated that drugs can be delivered to the brain in this manner.g. found that uptake into the brain was enhanced when drugs were administered in combination with the P-gp efflux inhibitor. it can be further influenced by BBB efflux transporter systems like P-glycoprotein (P-gp). [48. 49] Nose-to-Brain Research:Researching nose-to-brain transfer of drugs in humans must. (2007) showed that intranasal administration of the PARG inhibitor Gallo tannin decreased ischemic brain injury in rats.
" Functions ( active drug targeting. " Nanoparticles for tissue engineering. 3. biocompatible and biodegradable. or for coating implants withnanoparticles in biodegradable polymer layers for sustained release. especially for sensitive drugs. e. " Controllable release profiles. Thermotherapy with magnetic particles).g. " User-friendly lab-on-a-chip devices for point-of-care and disease prevention and control at home. "Nanoparticles to improve devices such as implantable devices/nanochips fornanoparticle release. " Devices for detecting changes in magnetic or physical properties after specific binding ofligands on paramagneticnanoparticles that can correlate with the amount ofligand. intelligent drug release devices/bio responsive triggered systems.7 8 US20080234200 US20080233132 Method of treatment of a metabolic disease using intranasal administration ofexendin peptide Multiple sclerosis therapy Future aspects of brain targeting [2. " Technologies for self-assembly. such as biomimetic polymers. And also in the development of: Combined therapy and medical imaging. in developing the following techniques: " Nano . 30]:There are many technological challenges to be met. and stimulate regeneration. intramuscular or per oral drugs " Cell and gene targeting systems.  " Virus-like systems for intracellular delivery.drug delivery systems that deliver large but highly localized quantities of drugs to specific areas to be released in controlled ways.  " Universal formulation schemes that can be used as intravenous.g. 39] . systems interacting with the body.  " Materials fornanoparticles those are " Architectures / structures. smart delivery).nanotubes. For the delivery of cytokines to control cellular growth and differentiation. for example. self-regulated delivery systems. 12. or multi reservoir drug delivery-chips. " Better disease markers in terms of sensitivity and specificity. 29.nanoparticles for diagnosis and manipulation during surgery (e. " Advanced polymeric carriers for the delivery of therapeutic peptide/proteins (biopharmaceutics). on-command delivery . [38.
N.C . 5) Muller-Goymann C. Int. 2000. Harada A. 58. Physicochemical characterization of colloidal drug delivery systems such as reverse micelles.. Int.. 5-28.T. 42.Schnieders J. Journal of Controlled Release. and Langer R. 4) Torchilin V. Richards A.M.27. 100.. 6) Haag R.Cima M.Aminabhavi T. 2004.Angew. In situ formingparenteral drug delivery systems: an overview .. andCharman S. Journal of Controlled Release. 20. 43. 278-82. Drug Development Research.Conclusion:Brain Targeting has got the attention of the many researchers due to its application in various diseases related to CNS. 343-56.Angew. Biodegradable polymericnanoparticles as drug delivery devices .N.C. 2004.. 1-20. Design of Environment-SensitiveSupramolecular Assemblies for Intracellular Drug Delivery: Polymeric Micelles that are Responsive to Intracellular ph Change. vesicles. B. PATEL and for giving constant support. Only few drugs can penetrate the BBB and enters the CNS. Chem.Angew. 2001. This system has clinical benefits like reduced drug dose.. non invasive routes. Chem. 316..J.Mallikarjuna N... J. 1-16. Ed.. Drug Delivery: A Key Factor inRealising the Full Therapeutic Potential of Drugs ..R. 2003. It emerges that the nanotechnology and by using other routes of drug administration like intra nasal technique drug can penetrate the BBB efficiently. Fukushima S.A. based on Polymeric Core-Shell 7) Bae Y.E. 2001. Supramolecular Drug-Delivery Systems Architectures. 4640-43.. European Journal of Pharmaceutics andBiopharmaceutics. 2004. Acknowledgements:I acknowledged my guide DR. 70... Further the modified colloidal particles and various modifiedliposomes enhance exposure of the BBB due to prolonged blood circulation.Finnin B.. European Journal of Pharmaceutics andBiopharmaceutics.-K.. 137-72.Kulkarni A. Ed.Aminabhavi T... 10) Agnihotri S. 1999.based drug delivery systems .A. Journal of Controlled Release. 3) Kopecek J. 2396-407. 2003. Smart and genetically engineered biomaterials and drug delivery systems . liquid crystals andnanoparticles for topical administration .P.. Structure and design of polymeric surfactant.. 9) Packhaeuser C... We still require developing a cost effective system that can be used in various CNS disorders efficiently with minimum side effect. R. 8) SoppimathK. Recent advances on chitosan-based microandnanoparticles in drug delivery . which favors interaction and penetration into brain endothelial cells. References:1) Charman W.. .B. European Journal of Pharmaceutical Sciences. Chem.Scheidt R.C.. 445-55.. 46.S. AndKataoka K.. 39. Int. Ed. and more patient compliance. 2004.. Chan H. 2) SantiniJr. 73. so various systems are developed for drug delivery.M.Rudzinski W. Microchips as Controlled DrugDelivery Devices. 58. decreased side effects.Kissel T..Oster C.G.
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