Brain targeting
- 1. Brain Targeted Drug Delivery System Prepared by : Surbhi M.Pharmacy II sem Submitted to : Dr. Anupama Diwan 4/18/2019 1Apeejay Stya University
- 2. What is Drug targeting ! • Drug targeting is the ability of the drug to accumulate in the target organ or tissue selectively quantitatively, independent of the site & method of its administration. 4/18/2019 2Apeejay Stya University
- 3. Need of Targeted Drug Delivery Systems The main complications currently associated with systemic drug administration are: Even biodistribution of pharmaceuticals throughout the body The lack of drug specific affinity toward a pathological site The necessity of a large total dose of a drug to achieve high local concentration Non-specific toxicity and other adverse side-effects. 4/18/2019 3Apeejay Stya University
- 4. MAGIC BULLET : CONCEPT OF PAUL EHRLICH MAGIC BULLET Drugs would be targeted by virtue of groups having affinity for specific cells A ligand would confer specificity on a non-specific reagent 4/18/2019 4Apeejay Stya University
- 5. MAGIC BULLET: Two components The first one recognizes and binds the target The second one provides a therapeutic action in this target (a) drug (b) targeting moiety (c) pharmaceutical carrier Currently, the concept of magic bullet includes a coordinated behavior of three components: 4/18/2019 5Apeejay Stya University
- 6. Drug targeting may resolve many of these problems ! 4/18/2019 6Apeejay Stya University
- 7. The principal schemes of drug targeting include Direct application of a drug into the affected zone, Passive drug targeting (spontaneous drug accumulation in the areas with leaky vasculature, or Enhanced Permeability and Retention-EPR-effect) Physical targeting (based on abnormal pH value and/or temperature in the pathological zone) Magnetic targeting (or targeting of a drug immobilized on paramagnetic materials under the action of an external magnetic field) Targeting using a specific vector molecules (ligands having an increased affinity toward the area of interest).4/18/2019 7Apeejay Stya University
- 8. Advantages1 Drug administration protocols may be simplified 2 Drug quantity may be greatly reduced as well as the cost of therapy 3 Drug concentration in the required sites can be sharply increased without negative effects on non-target compartments. 4/18/2019 8Apeejay Stya University
- 9. Antibodies Lectins and other proteins Lipoproteins Hormones Charged molecules Polysaccharides Low-molecular-weight ligands polymers microcapsules microparticles Nanoparticles lipoproteins liposomes micelles 4/18/2019 9Apeejay Stya University
- 10. Brain Targeting: Challenges • Blood brain barrier (BBB): Brain is tightly segregated from the circulating blood by a unique membranous barrier. • The brain and spinal cord are lined with a layer of special endothelial cells that lack fenestrations and are sealed with tight junctions that greatly restrict passage of substances from the bloodstream. • These endothelial cells, together with perivascular elements such as astrocytes and pericytes, constitute the BBB. • Rate-limiting factor in determining permeation. 4/18/2019 10Apeejay Stya University
- 11. Characteristics of the BBB (1)tight junctions that seal the pathway between the capillary (endothelial) cells (2) the lipid nature of the cell membranes of the capillary wall which makes it a barrier to water-soluble molecules (3), (4), and (5) represent some of the carriers and ion channels (6) The 'enzymatic barrier 'that removes molecules from the blood (7) the efflux pumps which extrude fat- soluble molecules that have crossed into the cells . 4/18/2019 11Apeejay Stya University
- 12. Schematic view of BBB 4/18/2019 Apeejay Stya University 12
- 13. The factors affecting particular substance to cross BBB • Drug related factors at the BBB • Concentration at the BBB and the size, • Flexibility, • Conformation, • Ionization (nonionized form penetrates BBB) • Lipophilicity of the drug molecule, • Cellular enzyme stability and cellular sequestration, • Affinity for efflux mechanisms (i.e. P-glycoprotein), • Hydrogen bonding potential (i.e. charge), • Affinity for carrier mechanisms, and • Effect on all of the above by the existing pathological conditions4/18/2019 13Apeejay Stya University
- 14. The Physicochemical Characteristics of Drugs • Log Po/w of the therapeutic agent, the rule of 2 is generally accepted i.e. the value of log Po/w nearing 2 is considered optimal. • However, increasing the lipophilicity with intent to increase permeability would increase the volume of distribution (Vd) and also the rate of oxidative metabolism by cytochrome P450 • Peripheral factors including systemic enzymatic stability, • Plasma protein binding affinity, • Uptake of the drug into other tissues, • Clearance rate, and • Effects of existing pathological conditions are also important. 4/18/2019 14Apeejay Stya University
- 15. • The lipophilicity of a given drug is inversely related to the degree of hydrogen bond formation that occurs with surrounding water. • The presence of certain chemical moieties in drug like terminal amide, primary amines or amides and hydroxyl group favors hydrogen bond formation resulting in a decreased lipophilicity. • Thus for a compound to be transported through the BBB, the cumulative number of hydrogen bonds should not go beyond 810. • Therefore for small drugs increasing lipophilicity i.e. decreasing hydrogen bonds has a positive impact on capillary permeability and drug transfer to the brain and for large drug molecules with molecular weight above 400 Da or for those with strong polarity, the capillary permeability will remain low regardless of the lipophilicity 4/18/2019 15Apeejay Stya University
- 16. Transport Mechanisms • Several specialized transport mechanisms of solute transfer across endothelial cells and into the brain interstitium are also present within the BBB Carrier system for monosaccharides, monocarboxylic acid, neutral amino acids, basic amino acid, acidic amino acids, amines, purine bases, nucleosides, vitamins and hormones. • The more lipophilic substances that are present in the blood can diffuse passively directly through the lipid of the cell membrane and enter the endothelial cells and brain by this means. 4/18/2019 16Apeejay Stya University
- 17. • These solutes, and in many cases their metabolites, are actively removed from the CNS by efflux transporters. • Various efflux transport pathways like P- glycoprotein and active organic acid present in choroids plexus may also be active in brain endothelial cells efflux systems are present in the BBB to remove unwanted substances. • On the other hand the presence of the tight junctions and the lack of aqueous pathways between cells greatly restrict the movement of polar solutes across the cerebral endothelium 4/18/2019 17Apeejay Stya University
- 18. • The molecules that can freely diffuse through this capillary endothelial membrane can passively cross the BBB, and this ability is closely related to their lipid solubility (lipophilicity/ hydrophobicity). • Practically all drugs currently used to treat brain disorders are lipid-soluble and can readily cross the BBB following oral administration. • The BBB also has an additional, enzymatic aspect solutes crossing the endothelial cell membrane are subsequently exposed to numerous degrading enzymes within these cells. 4/18/2019 18Apeejay Stya University
- 19. • These cells also contain many mitochondria metabolically active organelles and active transport can significantly alter both inward and outward transport for compounds. • The BBB is highly efficient and makes the brain practically inaccessible to lipid-insoluble compounds. • Brain-delivery of such compounds, therefore, requires a strategy to overcome the BBB. • Delivery of compounds such as neuropeptides or oligonucleotides is further complicated by their metabolic lability. 4/18/2019 19Apeejay Stya University
- 20. • Strategies for Brain Targeting Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB. • Neurosurgical or Invasive Strategies BBB disruption :Disruption of BBB by osmotic means (Hyperosmolar solutions), Intraventricular drug infusion Intracerebral Implants: Biodegradable implants, • Physiologic based Strategies Psuedo nutrients eg L-dopa Cationic antibodies.These undergo Absorption mediated trancytosis through BBB owing to positive charge. Chimeric peptides. 4/18/2019 20Apeejay Stya University Strategies for Brain Targeting Mechanisms
- 21. • Pharmacologic Strategies : 1. Chemical Delivery system: Nanocarriers for active targeting of the brain. 2. Liposomes 3. Polymeric micelles. 4. Polymeric nanoparticles 5. Lipid nanoparticles . 6. Biochemically by the use of vasoactive substances such as bradykinin, 7. Localized exposure to high intensity focused ultrasound (HIFU). 8. Cell-penetrating peptides and 9. Brain transport vectors 4/18/2019 21Apeejay Stya University
- 22. • Use of Ligands: • Ligands or homing devices that specifically bind to surface epitopes or receptors on the target sites, can be coupled to the surface of the long-circulating carriers. • Certain cancer cells over express certain receptors, like 1. folic acid (over-expressed in cells of cancers with epithelial origin), 2. LDL (B16 melanoma cell line shows higher expression of LDL receptors) and, 3. peptide receptors (such as somatostatin analogs, vasoactive intestinal peptide, gastrin related peptides, cholecystokinin, leutanising hormone releasing hormone). • Attaching suitable ligands for these particular receptors on to the nanoparticles would result in their increased selectivity. • It was postulated that the presence of specific ligands on the surface of nanoparticles could lead to their increased retention at the BBB and a consequent increase in nanoparticle concentration at the surface of BBB. • E.g. coated nanoparticles from Brij 78, and emulsifying wax, with thiamine ligand (linked to DSPE via a PEG spacer). 4/18/2019 22Apeejay Stya University
- 23. • Gene targeting technology : • Gene therapy of the brain: Many serious disorders of the CNS that are resistant to conventional small-molecule therapy could be treated, even cured, with gene therapy of the brain. • Current approach include delivery of the therapeutic gene to the brain by drilling a hole in the head followed by insertion of the gene incorporated in a viral vector. • The advantage of craniotomy-based gene delivery is that the gene can be expressed in a highly circumscribed area of the brain with an effective treatment volume of 110 µl. • This craniotomy based delivery does not enable the expression of the therapeutic gene widely throughout the brain or even to a relatively localized area such as a brain tumor, which could have a volume greater than several milliliters. • Viruses have been the vector of choice because the virus-coat proteins trigger endocytosis of the virus into the target brain cell. • The two most commonly used viral vectors are adenovirus or herpes simplex virus (HSV). • The problem with both these viruses is that, because they are common, humans have a pre-existing immunity. This immunity generates an inflammatory response. 4/18/2019 23Apeejay Stya University
- 24. • Immunoliposome: • The surface of the nanocarrier is modified that triggers transcytosis across microvascular endothelial barriers such as the BBB and then endocytosis into target neurons or glial cells in brain. (Targeting through the BBB and neuronal plasma membrane is accomplished by tethering the tips of 12 of the PEG strands with a targeting monoclonal antibody (MAb) to form an immunoliposome). • Owing to expression of the transferrin receptor (TfR) on both the BBB and the neuronal plasma membrane, the use of an anti-TfR MAb causes the pegylated immunoliposome to undergo transport through both the BBB and the neuronal plasma membrane in vivo. • The liposomal lipids fuse with the endosomal membrane inside neurons, which releases the plasmid into the cytosolic space of target neurons, where it can then diffuse to the nuclear compartment. • The only immunogenic component of the formulation is the MAb and the immunogenecity of murine MAbs in humans can be liminated with genetic engineering and humanization of the MAb. 4/18/2019 24Apeejay Stya University
- 25. Thanks for your attention! 4/18/2019 Apeejay Stya University 25