Brain Specific Delivery, Blood Brain Barrier

Brain-specific drug delivery, a part of targeted drug delivery systems, focuses on delivering drugs directly to the brain, bypassing the blood-brain barrier (BBB) to achieve targeted therapeutic effects with reduced side effects. 
How it works?
Bypassing the BBB: The primary challenge is the BBB, a protective barrier that restricts the passage of most substances into the brain.
Targeted Delivery: Brain-specific delivery aims to overcome this barrier by using specific strategies to transport drugs across the BBB or directly into the brain parenchyma.
Lipid-mediated diffusion
 Lipid-soluble molecules can passively diffuse across the BBB due to their ability to dissolve in the lipid-rich cell membranes of the brain's endothelial cells.
 This process is non-saturable, meaning that the rate of transport is directly proportional to the concentration gradient of the drug.
 Small molecules with a molecular weight below 400 Da and high lipid solubility are best suited for this type of transport.
Carrier- or receptor-mediated transport
 Specific transporters or receptors on the BBB can facilitate the entry of certain drugs. Transporters like glucose transporters (GLUT), large neutral amino acid transporters (LAT), and monocarboxylic acid transporters (MCT) are involved in CMT.
receptor-mediated transport
For receptor-mediated transport across the blood-brain barrier (BBB), key receptors involved include the transferrin receptor (TfR), insulin receptor (IR), and low-density lipoprotein receptor (LDLR), as well as related proteins.
Drug Delivery Systems (DDs)
Nanoparticles can facilitate brain-specific drug delivery by leveraging mechanisms like receptor-mediated transcytosis, transporter-mediated transcytosis, and adsorptive-mediated transcytosis, enabling them to cross the blood-brain barrier (BBB) and reach target tissues.

1. Brain Specific Delivery Manthan Chauhan 1 2403313002

2. Content Brain anatomy Introduction Barriers in Brain targeted Drug Delivery Blood Brain Barrier (Structure & Anatomy) Disease related to BBB Mechanism of transfer drug via BBB Approaches for Drug delivery through the BBB Marketed formulation 2 2403313002

3. Brain Anatomy 3 The human brain is composed of several key parts, including the  cerebrum (responsible for higher functions), cerebellum (coordinating movement), brainstem (connecting the brain to the spinal cord), and various lobes (frontal, parietal, temporal, and occipital)  with specialized functions.  2403313002

4. 2. Introduction What is Brain Specific Delivery? How Brain specific drug delivery works? Mechanism of drug transport Factors affecting Brain specific Drug Delivery 4 2403313002

5. What is Brain Specific Delivery? Brain-specific drug delivery, a part of targeted drug delivery systems, focuses on delivering drugs directly to the brain, bypassing the blood-brain barrier (BBB) to achieve targeted therapeutic effects with reduced side effects.  5 2403313002

6. How it works? Bypassing the BBB: The primary challenge is the BBB, a protective barrier that restricts the passage of most substances into the brain.  Targeted Delivery: Brain-specific delivery aims to overcome this barrier by using specific strategies to transport drugs across the BBB or directly into the brain parenchyma.  The brain is the complex organ responsible for controlling thought, memory, emotions, and all bodily functions, forming the central nervous system along with the spinal cord.  6 2403313002

7. Mechanism 7 2403313002

8. Lipid-mediated diffusion Lipid-soluble molecules can passively diffuse across the BBB due to their ability to dissolve in the lipid-rich cell membranes of the brain's endothelial cells.  This process is non-saturable, meaning that the rate of transport is directly proportional to the concentration gradient of the drug.  Small molecules with a molecular weight below 400 Da and high lipid solubility are best suited for this type of transport.  8 Mechanism 2403313002

9. Lipid-mediated diffusion 9 2403313002

10. Carrier- or receptor-mediated transport Specific transporters or receptors on the BBB can facilitate the entry of certain drugs.  Transporters like glucose transporters (GLUT), large neutral amino acid transporters (LAT), and monocarboxylic acid transporters (MCT ) are involved in CMT. 10 Mechanism 2403313002

11. Carrier-mediated transport 11 Mechanism 2403313002

12. receptor-mediated transport 12 Mechanism For receptor-mediated transport across the blood-brain barrier (BBB), key receptors involved include the  transferrin receptor ( TfR ), insulin receptor (IR), and low-density lipoprotein receptor (LDLR), as well as related proteins.  2403313002

13. receptor-mediated transport 13 2403313002

14. Drug Delivery Systems (DDs) 14 Nanoparticles can facilitate brain-specific drug delivery by leveraging mechanisms like receptor-mediated transcytosis, transporter-mediated transcytosis, and adsorptive-mediated transcytosis, enabling them to cross the blood-brain barrier (BBB) and reach target tissues.  Nanoparticles Mechanism 2403313002

15. Nanoparticles 15 2403313002

16. Drug Delivery Systems (DDs) 16 Viral vectors Mechanism 2403313002

17. Viral vectors 17 2403313002

18. Drug Delivery Systems (DDSs) 18 Exosomes Mechanism Exosomes, naturally occurring nanoscale vesicles, can cross the blood-brain barrier (BBB) via various mechanisms, including endocytosis, direct fusion, and receptor-mediated interactions, enabling brain-specific drug delivery.  Abdelsalam, M.; Ahmed, M.; Osaid , Z.; Hamoudi, R.; Harati, R. Insights into Exosome Transport through the Blood–Brain Barrier and the Potential Therapeutical Applications in Brain Diseases. Pharmaceuticals 2023, 16, 571. https://doi.org/10.3390/ph16040571 2403313002

19. Exosomes 19 Abdelsalam, M.; Ahmed, M.; Osaid , Z.; Hamoudi, R.; Harati, R. Insights into Exosome Transport through the Blood–Brain Barrier and the Potential Therapeutical Applications in Brain Diseases. Pharmaceuticals 2023, 16, 571. https://doi.org/10.3390/ph16040571 2403313002

20. Cell-penetrating peptides(CPPs) 20 Mechanism CPPs are short, typically cationic peptides (5-30 amino acids) that can penetrate cell membranes and deliver various cargoes, including drugs, proteins, and nucleic acids.  2403313002

21. Cell-penetrating peptides(CPPs) 21 2403313002

22. Factors affecting Brain specific Drug Delivery 22 2403313002

23. Barriers in Brain targeted Drug Delivery Difference between normal & brain capillaries What are the factors? Structure and anatomy of barriers Functions of barriers 23 2403313002

24. Barriers in Brain targeted Drug Delivery Difference between normal & brain capillaries 24 2403313002

25. 25 2403313002

26. Structure and anatomy of barrier The blood – brain barrier (BBB) is a highly selective permeability barrier that separates the circulating blood from the brain extracellular fluid in the central nervous system. 26 2403313002

27. 27 2403313002

28. Blood Brain Barrier Basal membrane and brain cells, such as pericytes and astrocytes, surrounding the endothelial cells further form and maintain as enzymatic and physical barrier known as the blood-brain barrier (BBB). BBB tight junctions are formed between endothelial cells in brain capillaries, thus preventing paracellular transport of molecules into the brain. 28 2403313002

29. Blood Brain Barrier Astrocytes are necessary to create the blood – brain barrier. It is estimated that more than 98% of small molecular weight drugs and practically 100% of large molecular weight drugs (mainly peptides and proteins) developed for CNS pathologies do not readily cross the BBB. Endothelial cells restrict the diffusion of microscopic objects (e.g. bacteria) and large or hydrophilic molecules into the cerebrospinal fluid (CSF), while allowing the diffusion of small hydrophobic molecules (e.g. O2, CO2, hormones, etc.) 29 2403313002

30. Disease related to BBB Meningitis : A serious disease in which there is inflammation of the meninges, caused by viral or bacterial infection, and marked by intense headache and fever, sensitivity to light, and muscular rigidity. Brain abscess : Brain abscess is an abscess caused by inflammation and collection of infected material. Epilepsy : A neurological disorder marked by sudden recurrent episodes of sensory disturbance, loss of consciousness, or convulsions, associated with abnormal electrical activity in the brain. 30 2403313002

31. Multiple sclerosis : a chronic, typically progressive disease involving damage to the sheaths of nerve cells in the brain and spinal cord, whose symptoms may include numbness, impairment of speech and of muscular coordination, blurred vision, and severe fatigue. De Vivo disease : De Vivo disease or Glucose transporter type 1 deficiency syndrome, is an autosomal dominant, genetic metabolic disorder associated with a deficiency of GLUT1, the protein that transports glucose across the blood brain barrier. Alzheimer's disease : Progressive mental deterioration that can occur in middle or old age, due to generalized degeneration of the brain. Itis the commonest cause of premature senility. Cerebral oedema : is the excess accumulation of water in the intra-and/or extracellular spaces of the brain 31 Disease related to BBB 2403313002

32. Functions of BBB The BBB acts very effectively to protect the brain from many common bacterial infections . Infections of the brain that do occur are often very serious and difficult to treat. Antibodies are too large to cross the blood-brain barrier and only certain antibiotics are able to pass. The blood-brain barrier becomes more permeable during inflammation . This allows some antibiotics and phagocytes to move across the BBB. However, this also allows bacteria and viruses to infiltrate the BBB. An exception to the bacterial exclusion is the diseases caused by spirochetes, such as Borrelia, which causes Lyme disease, and Treponema pallidum, which causes syphilis. These harmful bacteria seem to breach the blood-brain barrier by physically tunneling through the blood vessel walls. 32 2403313002

33. Structure and anatomy of barrier 33 Cerebrospinal fluid (CSF) influences the blood-brain barrier (BBB) by acting as a transport system and a sink for substances, helping to maintain a stable environment for the brain and regulate the exchange of molecules between blood and brain tissue.  choroids plexus 2403313002

34. Structure and anatomy of barrier 34 2403313002

35. Mechanisms of Transfer of Drug via BBB 35 2403313002

36. Transmembrane Diffusion 36 Gite, V. Z., Ghume , V. K., & Kachave , D. R. N. (2020). Brain Targeted Drug Delivery System. World Journal of Pharmaceutical and Medical Research, 6 (11), 45-57. Transmembrane diffusion is the movement of molecules across a cell membrane, driven by concentration or electrochemical gradients, without requiring cellular energy, and can occur through simple or facilitated diffusion.  A low molecular weight and high degree of lipid solubility favor crossing by this mechanism. 2403313002

37. Transmembrane Diffusion 37 2403313002

38. Saturable Transport System Saturable transport systems are a type of transport mechanism where the movement of a substance across a cell membrane is mediated by specific proteins (transporters). These transporters bind to the substance, facilitating its transport across the membrane.  38 Gite, V. Z., Ghume , V. K., & Kachave , D. R. N. (2020). Brain Targeted Drug Delivery System. World Journal of Pharmaceutical and Medical Research, 6 (11), 45-57. Definition 2403313002

39. Saturable Transport System 39 2403313002

40. Approaches for Drug delivery through the BBB 40 2403313002

41. Localized Delivery 41 Injection/ infusion Convection enhanced delivery Implants Intranasal delivery 2403313002

42. 42 2403313002

43. Localized Delivery 43 2403313002

44. Transport across BBB 44 2403313002

45. Osmotic disruption of BBB 45 Osmotic blood-brain barrier disruption (BBBD) works by using hyperosmotic agents, like mannitol, to temporarily shrink brain endothelial cells, causing the tight junctions between them to loosen and widen, thus increasing permeability and allowing therapeutic agents to enter the brain more easily.  2403313002

46. Osmotic disruption of BBB 46 2403313002

47. Focus ultrasound mediated disruption of BBB BBB permeation can be achieved by using focused ultrasound (FUS) in combination with intravenous microbubbles. This method has several advantages over other methods. It is reproducible, non-invasive, and targeted opening of the BBB can be achieved. In addition, the BBB opening is transient which can be restored within 6 to 24 h allowing accumulation of therapeutics in the region of interest for a desired time window . 47 2403313002

48. Focus ultrasound mediated disruption of BBB 48 2403313002

49. Non-invasive transport across BBB 49 2403313002

50. Receptor-mediated ranscytosis (RMT)(e.g. TfR targeting NPs) Receptor-mediated transcytosis (RMT) is a process where specific receptors on the surface of cells bind to specific ligands , which are then internalized and transported across the cell to the opposite side, a key mechanism for transporting macromolecules like insulin and transferrins across the blood-brain barrier.  50 2403313002

51. Receptor-mediated ranscytosis 51 2403313002

52. Carrier-mediated transcytosis (CMT)(e.g. L-DOPA via LAT) Carrier-mediated transcytosis is a process where molecules, often small and hydrophilic, are transported across the BBB by binding to specific carrier proteins (transporters) located on the luminal (blood-facing) and abluminal (brain-facing) membranes of the endothelial cells that form the BBB.  52 2403313002

53. 53 2403313002

54. Carrier-mediated transcytosis (CMT)(e.g. L-DOPA via LAT) 54 2403313002

55. Adsorption-mediated transcytosis (AMT)(e.g. cationic NPs) Adsorption-mediated transcytosis (AMT) is a non-specific process where  positively charged molecules (like cationic proteins or peptides) cross the blood-brain barrier (BBB) via electrostatic interactions with the negatively charged BBB membrane , leading to endocytosis and subsequent transport across the cell.  55 2403313002

56. Adsorption-mediated transcytosis (AMT)(e.g. cationic NPs) 56 2403313002

57. Cell mediated transport (e.g. Neutrophil) Cell-mediated transport involves specialized membrane proteins (transporters) that facilitate the movement of molecules across cell membranes, including passive and active transport mechanisms.  57 2403313002

58. Cell mediated tranport (e.g. Neutrophil) 58 2403313002

59. Non-invasive transport across BBB 59 2403313002

60. Magnetic field assisted 60 Magnetic fields can assist in blood-brain barrier (BBB) crossing by using magnetic nanoparticles (MNPs) that, when exposed to an external magnetic field, can be guided to the brain and facilitate drug delivery or even transiently open the BBB.  2403313002

61. Magnetic field assisted 61 2403313002

62. Marketed Formulations Drug Condition Delivery System Gliadel® Wafer Brain tumors Implantable biodegradable polymer Doxil® (Doxorubicin Liposome) Brain tumors Liposomal formulation L-DOPA (Levodopa) Parkinson’s disease Carrier-mediated transport Insulin Nasal Spray Alzheimer’s disease Intranasal delivery Zolgensma® Spinal Muscular Atrophy Gene therapy Sumatriptan Nasal Spray Migraine Nasal route 62 2403313002

63. 63 THANK YOU 2403313002