BRAIN TARGETING DRUG DELIVERY SYSTEM

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BRAIN TARGETING DRUG DELIVERY SYSTEM: AN OVERVIEW :

BRAIN TARGETING DRUG DELIVERY SYSTEM: AN OVERVIEW OMOTOSO, KAYODE SUNDAY 010702027 14 TH APR, 2011

TABLE OF CONTENT:

TABLE OF CONTENT INTRODUCTION THE BLOOD BRAIN BARRIER APPROACHES TO CNS DRUG DELIVERY CONCLUSION.

INTRODUCTION:

INTRODUCTION In spite of an impressive increase CNS drug discovery, the biggest impediment remains the effective delivery of these agents across the blood brain barrier (BBB). Despite aggressive research, patients suffering from fatal or debilitating CNS diseases far outnumber those dying of all types of systemic cancers or heart diseases. (Ricci et al, 2006) The BBB represents an insurmountable barrier for the majority of drugs. ( Cornford , 1985; Hawkins and Davis, 2005)

CONT’D:

CONT’D BBB is a major bottleneck in developing brain drug delivery and the most prominent factor limiting the future growth of neurotherapeutics ( Pardridge , 2005). General methods that can enhance drug delivery to the brain are therefore of great pharmaceutical importance. Our aim here is to review the various drug delivery strategies that have been developed to circumvent the BBB.

THE BLOOD BRAIN BARRIER:

THE BLOOD BRAIN BARRIER The brain is shielded internally against potentially toxic substances by the presence of two barrier systems: the blood brain barrier (BBB) and the blood cerebrospinal fluid barrier (BCSFB) . ( Pardridge , 2003) The term “blood brain barrier” was first coined in 1900 by Lewandowsky . ( Brightman , 1992)

BBB cont’d:

BBB cont’d The presence of tight junction, few endocytic vesicles and efflux transporters (e.g. P- glycoproteins ) in the CNS capillaries form the barrier that occlude the free uptake of into the interstitium . ( Nabeshima , 1975; Lewin , 1980; Habgood et al, 2000) As a result, a significant number of CNS diseases have poorly met therapy. ( Pardridge , 1995)

BBB cont’d:

BBB cont’d The parameters considered optimum for a compound to transport across the BBB are: (a) Non-ionization. (b) Log P value near to 2. (c) Molecular weight less than 400 Da. (d) Cumulative number of hydrogen bonds between 8 to10.

BBB cont’d:

BBB cont’d The Brain Microvasculature Additionally, circumventricular organs (CVO) are present adjacent to the brain ventricles in some regions of central neuron system (CNS). The CVO have an incomplete blood-brain barrier and the BBB capillary endothelial tight junctions are absent. They are highly vascularised and lack of BBB because capillary system supplying the CVOs contains fenestrated endothelial cells instead of epithelial tight junction (Cottrell and Ferguson, 2004).

APPROACHES TO CNS DRUG DELIVERY:

APPROACHES TO CNS DRUG DELIVERY To overcome the multitude of barriers restricting CNS drug delivery of potential therapeutic agents, numerous drug delivery strategies have been developed. These strategies generally fall into one or more of the following categories: invasive, non-invasive or miscellaneous techniques. ( Misra et al , 2003; Kabanov and Batrakova , 2004)

APPROACHES cont’d:

APPROACHES cont’d

APPROACHES cont’d:

APPROACHES cont’d INVASIVE METHODS Generally, only low molecular weight, lipid-soluble molecules and a few peptides and nutrients can cross this barrier to any significant extent, either by passive diffusion or using specific transport mechanisms. (Grieg, 1987) However, these methods entail that drugs are administered directly into the brain tissue. (Wang, et al , 2002; Graff and Pollank , 2005)

APPROACHES cont’d:

APPROACHES cont’d Biochemical BBB Distruption ( Neuwelt , 1989) Temporary breakdown of the BBB by sugar solution ( mannitol ). The endothelial cells shrink opening the tight junctions. (Miller, 2002) The effects last for 20-30min during which drugs diffuse freely.

APPROACHES cont’d:

APPROACHES cont’d Useful in cerebral lymphoma, malignant, glioma and disseminated CNS germ cell tumours . ( Torchilin , 2001; Rosler et al, 2001) Side effects include physiological stress, transient increase in intracranial pressure and unwanted delivery of anticancer agents to normal brain tissues.

APPROACHES cont’d:

APPROACHES cont’d INTRAVENTRICULAR INFUSION Used extensively in clinical trials. Infusion is done using a plastic reservoir ( Ommaya reservoir) implanted SC in the scalp and connected to the ventricles within the brain via an outlet catheter. Only suitable for sites close to the ventricles.

APPROACHES cont’d:

APPROACHES cont’d Continuous infusion may be necessary for drugs that need to be at elevated levels for a long period. Gilbert (2007) developed a new and useful device and method for the needle-free delivery of drugs with minimal trauma to the tissue.

The Ommaya Reservoir:

The Ommaya Reservoir

APPROACHES cont’d:

APPROACHES cont’d INTRACEREBRAL IMPLANTS Entails delivery of drugs directly into the brain parenchymal space. Drugs can be administered by: Direct injection via intrathecal catheter. (Benoit et al, 2000) Control release matrices. (Yang et al, 1989) Microencapsulated chemicals. ( Nathelie et al, 2004)

APPROACHES cont’d:

APPROACHES cont’d The basic mechanism is diffusion. Useful in the treatment of different CNS diseases e.g. brain tumour , Parkinson’s Disease etc. ( Menei et al, 1994; Be noit et al, 2000)

APPROACHES cont’d:

APPROACHES cont’d NON-INVASIVE APPROACHES A variety of non-invasive brain drug delivery methods have been investigated, that make use of the brain blood vessel network to gain widespread drug distribution. Noninvasive techniques usually rely upon drug manipulations which may include alterations as prodrugs , lipophilic analogues, chemical drug delivery, carrier-mediated drug delivery, receptor/vector mediated drug delivery etc. (Byrne et al, 2002)

APPROACHES cont’d:

APPROACHES cont’d Chemical Methods The main premise for the chemical methods remains the use of prodrugs . Such prodrug approaches were explored for a variety of acid containing drugs, like levodopa . ( Bodor et al, 1987)

APPROACHES cont’d:

APPROACHES cont’d Lipidization of molecules generally increases the volume of distribution, the rate of oxidative metabolism by enzymes and uptake into other tissues, causing an increased tissue burden. (Han and Amidon , 2000; Wu et al, 2002) Chemical approaches for delivering drugs to the brain include lipophilic addition and modification of hydrophilic drugs, (e.g., N-methylpyridinium-2-carbaldoxime chloride; 2-PA). Higush et al, 1975; 1976.

APPROACHES cont’d:

APPROACHES cont’d Biological Approaches Chimeric Peptide Drug substances which are not transported through BBB are combined with a transport vector to form an easily transportable or fused molecule. The conjugated proteins may be endogenous peptides, monoclonal antibodies ( mAbs ), modified protein, etc.

APPROACHES cont’d:

APPROACHES cont’d The chimeric are transported to brain by various transportation pathways like peptide-specific receptor. E.g. insulin and transferrin which undergo trancytosis by their insulin and transferrin receptor present at BBB.

APPROACHES cont’d:

APPROACHES cont’d The vector itself should have pharmacological activity, for example insulin and secondly, the interaction between peptide vectors with its binding receptor site must be highly specific for targeting drug to brain. ( Sood and Panchagnula , 2000; Vandermeulen and Klok , 2003)

APPROACHES cont’d:

APPROACHES cont’d Cationic Proteins Cationic protein is suited method for protein and peptides delivery based on isoelectric point to the brain. BBB transport of large molecule drugs is not possible e.g proteins. ( Pardridge , 2002).

APPROACHES cont’d:

APPROACHES cont’d This method offers an additional benefit for delivering them by making them charged into cationic form, which can go through brain easily by electrostatic interaction with anionic functional groups exists on brain surface. Various cationic proteins have been reported to penetrate the BBB including avidin , histone , protamine , and cationized polyclonal bovine immunoglobulin ( Brasnjevic et al., 2009).

APPROACHES cont’d:

APPROACHES cont’d Monoclonal Antibodies Monoclonal antibodies for targeting are usually prepared by hybridoma technology.

APPROACHES cont’d:

APPROACHES cont’d Combining malenoma (tumor) cells with antitumor antibodies against a particular type of antigens found on malignant cells in animals like rat. But instead of using mAb directly for brain targeting, they are modified structurally to get genetically engineered monoclonal antibodies.

APPROACHES cont’d:

APPROACHES cont’d Liposomes Liposomes are non-toxic, biocompatible and biodegradable lipid body carrier made up of animal lipid like phospholipids, sphingolipids , etc. They have benefits of carrying hydrophilic, lipophilic , as well as amphoteric drug molecules either entrapped inside it or its micellar surface.

APPROACHES cont’d:

APPROACHES cont’d The surface modified liposomes can be employed to encapsulate drug molecules to diseased tissue or organ directly. The basic mechanism is by coupling with brain drug transport vector via receptor-mediated transcytosis or by absorptive-mediated transcytosis . ( Schnyder and Huwyler , 2005).

APPROACHES cont’d:

APPROACHES cont’d Nanoparticles Nanoparticles have attracted interest in targeting drug molecules to brain. Nanosystems employed for the development of nano drug delivery system in the treatment of CNS disorders include polymeric nanoparticles , nanospheres , nanosuspensions , etc. Nanoparticles enter into the brain by crossing the BBB by various endocytotic mechanisms.

APPROACHES cont’d:

APPROACHES cont’d Nanoparticles can be designed from albumin attached with apoliprotein E (Apo E-albumin nanoparticles ). After IV administration, Apo E-albumin nanoparticles are internalized into the brain capillary endothelial cells by transcytosis and release into brain parenchyma. (Park, 2009).

APPROACHES cont’d:

APPROACHES cont’d Intra Nasal Drug Delivery After nasal delivery drugs first reach the respiratory epithelium, compounds can be absorbed into the systemic circulation by Tran cellular and Para cellular passive absorption, carrier-mediated transport, and absorption through trancytosis .

APPROACHES cont’d:

APPROACHES cont’d When a nasal drug formulation is delivered deep and high enough into the nasal cavity, the olfactory mucosa may be reached and drug transport into the brain and/or CSF via the olfactory receptor neurons may occur. ( Chieny et al, 1989; Yamada, 2004)

CONCLUSION:

CONCLUSION Even though a lot of strategies have been developed to deliver drug into brain to treat brain tumors and other abnormalities treatment, none of them have showed to be suitable in each and every case of CNS disorders. This is due to the brain physiology which presents unique challenges, made up of tight regulation of what can enter the brain space and limited distribution of substances along extracellular fluid flow pathways.

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