Brain targeting

Brain Targeted Drug Delivery System
Prepared by :
Surbhi
M.Pharmacy II sem

Submitted to :
Dr. Anupama Diwan
MAGIC BULLET : CONCEPT OF PAUL EHRLICH
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.
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 conditions
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. 

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.

1. Brain Targeted D rug D elivery S ystem Prepared by : Surbhi M.Pharmacy II sem Submitted to : Dr. Anupama Diwan 4/18/2019 1 Apeejay Stya University

2. What is Drug targeting ! Drug targeting is the ability of the drug to   accumulate in the target organ or tissue    4/18/2019 2 Apeejay Stya University

3. Need of Targeted Drug Delivery S ystems The main complications currently associated with  systemic drug administration are: 4/18/2019 3 Apeejay Stya University

4. MAGIC BULLET : CONCEPT OF PAUL EHRLICH 4/18/2019 4 Apeejay Stya University

5. MAGIC BULLET: Two components Currently, the concept of magic bullet includes a coordinated behavior of three components: 4/18/2019 5 Apeejay Stya University

6. Drug targeting may resolve many of these problems !   4/18/2019 6 Apeejay Stya University

7. 4/18/2019 7 Apeejay Stya University

8. Advantages 4/18/2019 8 Apeejay Stya University

9. Targeting Moieties Antibodies Lectins and other proteins Lipoproteins Hormones Charged molecules Polysaccharides Low-molecular-weight ligands polymers microcapsules microparticles Nanoparticles lipoproteins liposomes micelles Pharmaceutical carriers 4/18/2019 9 Apeejay 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 10 Apeejay 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 11 Apeejay 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 conditions 4/18/2019 13 Apeejay Stya University

14. The P hysicochemical 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 14 Apeejay 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 15 Apeejay 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 16 Apeejay 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 17 Apeejay 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 18 Apeejay 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 19 Apeejay 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   b ased Strategies Psuedo nutrients eg   L-dopa Cationic antibodies.These undergo  Absorption mediated trancytosis through BBB owing  to positive charge . Chimeric peptides. 4/18/2019 20 Apeejay Stya University Strategies for Brain Targeting Mechanisms

21. Pharmacologic Strategies : Chemical Delivery  system: Nanocarriers for active targeting of the  brain. Liposomes Polymeric micelles. Polymeric   nanoparticles Lipid nanoparticles  . Biochemically by the use of vasoactive substances such as bradykinin , Localized   exposure to high intensity focused ultrasound  (HIFU). Cell-penetrating peptides and Brain   transport vectors  4/18/2019 21 Apeejay 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 folic acid   ( over-expressed in cells of cancers with  epithelial origin), LDL (B16 melanoma cell line  shows higher expression of LDL receptors) and, 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 22 Apeejay 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 a denovirus 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 23 Apeejay 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 24 Apeejay Stya University

25. Thanks for your attention! 4/18/2019 Apeejay Stya University 25