Drug Transport Through the Blood Brain Barrier
•
5 likes•1,820 views
Invasive approaches to bypassing the blood-brain barrier include direct intracerebral implantation, intraventricular infusion, and blood-brain barrier disruption. Intracerebral implantation involves direct injection or implanting controlled release matrices in the brain parenchyma. Intraventricular infusion uses an implanted reservoir to infuse drugs into the ventricles. Blood-brain barrier disruption temporarily opens tight junctions using hyperosmotic solutions, irradiation, or focused ultrasound to increase drug delivery. However, these invasive methods require anesthesia and surgery and risk neuronal damage from blood components entering the brain.
Recommended
More Related Content
What's hot
What's hot (20)
Similar to Drug Transport Through the Blood Brain Barrier
Similar to Drug Transport Through the Blood Brain Barrier (20)
Recently uploaded
Recently uploaded (20)
Drug Transport Through the Blood Brain Barrier
- 2. Content 1) Introduction 2) Structure of the BBB 3) Functions of the BBB 4) Drug transport across the BBB 5) Approaches used to bypass the BBB 6) Models to study drug transport across the BBB 7) Recent advances 8) Conclusion and prospective 9) References 2
- 6. What is the Blood Brain Barrier? A physiological boundary between the bloodstream and central nervous system, preventing transfer of substances from plasma to brain. Yentis et al, Anaesthesia and Intensive Care A‐Z BBB ‐ Definition 6
- 8. Brain Microvascular Endothelial Cells (BMEC): Tight junctions (zonula occludens) Absence of fenestrations High content of mitochondria Astrocytes Pericytes Other cellular components like neurons and microglia play significant role (immune function) BBB – Morphology 8
- 9. BBB – Morphology 9 Cellular component Function 1. Endothelial cells (EC) • Resides on the BM • Forms a continuous sheet • Covering the capillary surface • Interconnected by TJs 2. Astrocytes • Supportive and nutritive functions to the neurons • Formation of the BBB and CNS injury repair (gliosis) • Reuptake and processing of NTs 3. Pericytes • Engulfed in the BM • Regulate endothelium proliferation, angiogenesis & inflammatory processes • Induce polarization of astrocyte endfeet • In the absence of pericytes abnormal vasculogenesis, endothelial hyperplasia and increased permeability
- 11. Brain capillaries vs. general capillaries Characteristic BBB Capillaries 1. Tight junction resistance 5 ‐ 10 ohm/cm² 2000 ohm/cm² 2. Fenestration/clefts No Yes 3. Vesicular transport Deficient Abundant 4. Pinocytosis Rare Abundant 5. Mitochondria Abundant (5 times greater) Rare 6. Tight junction ++++++ (x50‐100 tighter than periphery) + 7. Selective transport ++++++ ‐ 8. Astrocyte foot process ++++++ ‐ 11
- 15. 15
- 16. BBB – Dual Function Barrier function and a Carrier function BBB Function Description A. Carrier function • Small lipid molecules and blood gases like O2 and CO2 diffuse passively • Glucose and amino acids require active transport (transport proteins) B. Barrier function 1. Paracellular barrier • Made by endothelial TJ • Restricts the free movement of H2O sol subs. 2. Transcellular barrier (low level of endo‐& transcytosis) • Made by the absence of microvesicles • Inhibits transport into the cytoplasm 3. Enzymatic (metabolic) barrier • Enzymes (esterase, phosphatase, peptidase, MAO) • Degrading different compounds 4. Cerebral endothelium • Large no. of efflux transporters (ABC, P‐gp) 16
- 19. Selectivity of the BBB General Properties of the BBB 1. Large molecules do not pass through the BBB easily. 2. Low lipid (fat) soluble molecules do not penetrate into the brain. (lipid soluble molecules rapidly cross the BBB into the brain) 3. Molecules that have a high electrical charge to them are slowed. 19
- 26. Overall transport routes across the BBB 26 Transport mechanism Description 1. Paracellular (aqueous) diffusion • Diffusion of subs between the cells • Non‐saturable & non‐competitive • Due to the TJ, only small H2O‐ soluble molecules can diffuse 2. Transcellular (lipophilic) diffusion • Diffusion of subs across the cells • Similar to paracellular diffusion • High lipophilic subs with a molecular weight < 450 greater diffusion • Hydrogen bonding is a major factor (if sum of O & N atoms in a molecule is 5 or less high probability of entering the CNS
- 27. Overall transport routes across the BBB 27 Transport mechanism Description 3. Carrier‐mediated transport (transport proteins) • Solutes (glucose or aa) bind to protein transporters (GLUT1, LAT, MCT & nucleoside transporter) • Efflux pump (ABC & MRP) is a major obstacle for the accumulation of various active molecules 4. Receptor‐mediated transcytosis (RMT) • IGF‐I & II, angiotensin II, ANP & BNP, IL‐1, LDLR and transferrin • Insulin, cytokines, transferrin & leptin 5. Adsorptive‐mediated transcytosis (AMT) • Initiated by charge‐charge interaction between cationic subs & negative charges on the surface of ECs • Starts with uptake via Clathrin‐coated pits or Caveolae (ATP‐dependent)
- 29. Ligands Targeting Transcytosis for Drug Delivery across the BBB 29 No. ligand Target receptor 1 Transferrin TfR 2 Melanotransferrin (p97) LDLR 3 Insulin Insulin receptor 4 LDL LDLR 5 Lactoferrin, tissue plasminogen activator (tPA) Low‐density lipoprotein receptor‐related protein (LRP) 1 & 2 6 Leptin (regulator of body weight) specific receptor ObR 7 Thiamin (3H or Vit B1) Thiamin transportr 8 Glutathione 9 Synthetic Opioid Peptides specialized Peptide Transport System (PTS) 10 Rabies virus glycoprotein (RVG) N‐acetylcholine receptor 11 Tetanus Toxin, Tet1 and G23 GT1b, the receptor for TeNT 12 non‐toxic analog of the diphteria toxin (DT), CRM197 HB–EGF (membrane‐bound precursor of heparin‐binding epidermal growth factor) 13 TAT peptide (CPP) CPPs adsorb strongly to the negatively charged cell surface
- 33. 33
- 35. A‐ Invasive Approaches 35 • Wide range of compound and formulation can be considered for ICV or IC administration. • Both large and small molecules can be delivered.
- 36. A‐ Invasive Approaches I. INTRA CEREBRAL IMPLANTS Delivery of drugs directly into the brain parenchymal space Drugs can be administered by: ‐ Direct injection via intrathecal catheter ‐ Control release matrices & Microencapsulated chemicals. The basic mechanism is diffusion. Useful in the treatment of brain tumor and Parkinson’s Disease, etc. Example: 1. Intrathecal injection of baclofen for spasticity 2. Infusion of opioids for severe chronic pain 36
- 37. A‐ Invasive Approaches I. INTRA CEREBRAL IMPLANTS Limitations: 1. Distribution in the brain by diffusion decreases exponentially with distance. 2. The injection site has to be very precisely mapped to get efficacy and overcome the problem associated with diffusion of drugs in the brain. 37
- 38. A‐ Invasive Approaches II. INTRA CEREBRO VENTRICULAR INFUSION Drug is infused using an ommaya reservoir, a plastic reservoir implanted S.C.ly in the scalp and connected to ventricles 38 Example: Glycopeptide and aminoglycoside antibiotics used in meningitis.
- 39. A‐ Invasive Approaches II. INTRA CEREBRO VENTRICULAR INFUSION Limitations: 1. The diffusion of the drug in the brain parenchyma is very low. 2. Unless the target is close to the ventricles, it is not an efficient method of drug delivery. 39
- 40. A‐ Invasive Approaches III. BBB DISRUPTION i. Exposure to X‐irradiation and infusion of solvents such as dimethyl sulfoxide, ethanol. ii. Osmotic disruption: 40 Example: Intracarotid administration of a hypertonic mannitol solution with subsequent administration of drugs increase drug concentration in brain and tumor tissue
- 41. A‐ Invasive Approaches III. BBB DISRUPTION i. Exposure to X‐irradiation and infusion of solvents such as dimethyl sulfoxide, ethanol. ii. Osmotic disruption. iii. MRI‐guided focused ultrasound BBB disruption: 41 Example: distribution of Herceptin is increased in brain tissue by 50% in a mice model
- 42. A‐ Invasive Approaches Limitations of Invasive Approaches: i. Relatively costly ii. Require anaesthesia and hospitalization. iii. It may enhance tumor dissemination after successful disruption of the BBB iv. Neurons may be damaged permanently from unwanted blood components entering the brain 42
- 43. • Opening BBB’s TJ can occur in: a) Traumatic brain injury, b) Ischaemic stroke, c) Septic encephalopathy & Tumor increased BBB permeability Cerebral Edema 43
- 44. Altered blood–brain barrier transport Inflammation and immune‐related events are amongst the best described processes that cause disruption of the BBB. Associated with CNS disorders such as Alzheimer’s disease, stroke, and multiple sclerosis. 44
- 45. Altered blood–brain barrier transport 1. Alzheimer’s Disease (AD): • Associated with the loss of cholinergic input (low availability of acetylcholine receptor). • Current AD therapy: Donepezil (an acetylcholinesterase inhibitor) improves cognition by enhancing acetylcholine bioavailability. • Donepezil crosses the BBB through the organic cation transporter, although P‐gp limits therapeutic concentrations of acetylcholinesterase inhibitors in the brain. 45
- 47. Altered blood–brain barrier transport 2. Multiple Sclerosis (MS): • A chronic inflammatory disease of the CNS, marked by infiltration of monocyte‐derived macrophages in the brain parenchyma. • Characterized by massive influx of activated monocyte‐derived macrophages, which subsequently induce BBB breakdown (leakage and alterations of TJ proteins high BBB permeability). 47
- 49. Altered blood–brain barrier transport 3. Parkinson’s disease (PD): • Increased permeability of the BBB has been shown in PD patients. 4. Stroke: • Increased endocytotic activity has been observed in stroke models. 5. Meningitis: • Inflamed meninges disrupt blood‐brain barrier • This increase penetration of various substances (including antibiotics) into the brain • 3rd generation cephalosporin or 4th generation cephalosporin is preferred. 49
- 50. Altered blood–brain barrier transport 6. Tumours: • Leaky BBB • Increased nutrients, increased growth 7. Infiltration: • Infection • Increased antibiotic permeability 8. Ischaemia: • Cellular damage • Increased water, oedema 50
- 51. Altered blood–brain barrier transport Summary • In CNS diseases, induction of endocytotic activity is plausible. • Changes in endocytotic activity of diseased CNS endothelial cells may affect adsorptive mediated endocytosis and the receptor‐mediated endocytosis as well. • Several transporters at the BBB are altered or modulated by immune‐related and inflammatory‐related events. 51
- 52. B‐ Non Invasive Approaches I. Chemical Approaches i. Prodrug 52 Esterification or amidation of hydroxy‐, amino‐, or carboxylic acid‐ containing drugs, may greatly enhance lipid solubility and, hence, entry into the brain
- 53. B‐ Non Invasive Approaches I. Chemical Approaches i. Prodrug Improve solubility and membrane permeability. Examples: levodopa, valproate Heroin, a diacyl derivative of morphine, is a notorious example that crosses the BBB about 100 times more easily than its parent drug just by being more lipophilic. Limitations: Adverse pharmacokinetics and increased molecular weight 53
- 54. BBB – Dual Function Unable to use DOPAMINE to treat Parkinson’s Disease 54 ‐ Ionized at pH 7.4 ‐ Metabolized by MAO L‐Dopa + Dopa decarboxylase inhibitor (Unionized) (Ionized)
- 55. B‐ Non Invasive Approaches I. Chemical Approaches ii. Co‐drug Co‐administration of BBB AET inhibitors increased brain permeability of drug that is normally excluded from brain by a BBB AET. Example: Increased brain penetration of paclitaxel (taxol®) by co‐ administration of the P‐gp inhibitor, psc‐833(valspodar) 55
- 57. B‐ Non Invasive Approaches II. Biological Approaches i. Carrier‐Mediated Transport Example of drugs transported via LAT1: ‐ Melphalan for brain cancer ‐ Alpha methyl dopa for high blood pressure ‐ Gabapentin for epilepsy ‐ L dopa for parkinsonism 57
- 59. B‐ Non Invasive Approaches II. Biological Approaches ii. Receptor/Vector‐Mediated Transport Chimeric peptides are transported to brain by transcytosis through peptide specific receptor 59
- 60. B‐ Non Invasive Approaches III. Colloidal (vsesicular) Systems i. Nanoparticles Nanocapsules (a reservoir system) and nanospheres (a matrix system) Polysorbate coated nanoparticles can mimic LDL to cross BBB Polyoxyethylene sorbitan monooleate coated nanoparticles containing drug easily cross BBB. 60
- 61. B‐ Non Invasive Approaches III. Colloidal (vsesicular) Systems i. Nanoparticles Mechanisms of transport: 1. Adhesion 2. Fluidization of BBB endothelium by surfactants 3. Opening of TJ 4. Transcytosis / endocytosis 5. Blockage of P‐gp 61
- 62. B‐ Non Invasive Approaches III. Colloidal (vsesicular) Systems i. Nanoparticles Advantages of using nanoparticles for Targeting CNS 1. Protect drugs against chemical and enzymatic degradation 2. Small size ‐‐‐ penetrate into even small capillaries ‐‐‐ taken up within cells ‐‐‐ drug accumulate at the targeted sites 3. Biodegradable materials ‐‐‐ allows sustained drug release at the targeted site 62
- 63. B‐ Non Invasive Approaches III. Colloidal (vsesicular) Systems i. Nanoparticles Limitations of using nanoparticles for CNS targeted delivery: 1. Small size and large surface area ‐‐‐ particle‐particle aggregation ‐‐‐ physical handling of nanoparticles difficult in liquid and dry forms 2. Small particles size and large surface area readily result in limited drug loading and burst release. 63
- 64. B‐ Non Invasive Approaches III. Colloidal (vsesicular) Systems ii. Liposomes Lipid based unilamellar or multilamellar vesicles 64 Transport: receptor/adsorptive mediated transport
- 65. B‐ Non Invasive Approaches III. Colloidal (vsesicular) Systems ii. Liposomes 65 If coated with mannose reaches brain tissue where mannose coat assists transport Addition of sulphatide to liposome increases availability
- 68. C‐ Miscellaneous Approaches II. Iontophoretic Delivery Introduction of ionized molecules into tissues by means of an electric current Known as transnasal iontophoretic delivery 68
- 69. C‐ Miscellaneous Approaches III. Monocytes Used as a Trojan Horse Ideal endogenous carriers Express certain receptors involved in RME upon interaction with suitable ligands 69
- 73. Recent Advances 1) Dendrimers 2) Polyanhydrides 3) Lipoplexes and Polyplexes 4) Scaffolds 5) Convection‐enhanced delivery 6) Modified nanoparticles: Multifunctional nanoparticles Magnetic nanoparticles 73
- 76. A‐ In vitro techniques 76 1. Primary Brain Microvessel Endothelial Cells: Bovine and porcine brain microvessel endothelial cells, BBMECs and PBMECs (most common) Two systems: a. Side‐by‐side diffusion chamber Cells are isolated from bovine brain, grown on polycarbonate membrane and mounted between two water‐jacketed, thermally controlled chambers
- 82. A‐ In vitro techniques 82 Item Primary cells Immortalized Cell Lines 1. Time for confluency 14 days 7 days 2. Isolation Yes Not 3. Workload Much (time and labor intensive) Less 4. TJs Complete Incomplete (leaky)
- 83. B‐ In vivo techniques 83 1. Intravenous Injection Methods (most common): I.V. adminstaration of drug to animal drug conc. is determined at different times in the brain, plasma, and CSF
- 84. B‐ In vivo techniques 84 2. Brain Perfusion Techniques: • Using perfusion pump drug is infused into the heart or a major vessel leading directly to the brain animal decapitated and drug amount is determined in the brain • Inhibitors for metabolic enzymes and/or efflux transporters can be introduced into the perfusate to clarify their role • Effect of protein binding can be evaluated by controlling the albumin conc. in the perfusate
- 85. B‐ In vivo techniques 85 3. Tomographic Methods: • Using positron emission tomography (PET) • To study brain uptake kinetics, cerebral blood flow, BBB integrity, and efflux mechanisms
- 86. B‐ In vivo techniques 86 4. Microdialysis Sampling: to investigate drug transport and metabolism of at the BBB
- 88. Conclusions 88 • The treatment of brain diseases is particularly challenging because the delivery of drug molecules to the brain is often precluded by a variety of physiological, metabolic and biochemical obstacles that collectively comprise the BBB. • Drug delivery directly to the brain has recently been markedly enhanced through the rational design of polymer‐based drug delivery systems.
- 89. Future Prospective 89 • Lack of training to brain drug targeting specialists and lack of prominence in pharmaceutical industries are some of the obstacles in future progress in this area. • Future developments include identification of new BBB transporters, application of genomics and proteomics and stem cell therapy and emphasizing on development of novel imaging agents. • This area requires innovative approach and constant research.
- 90. 90 References
- 91. Reference 1. Zlokovic, B.V., 2008. The blood‐brain barrier in health and chronic neurodegenerative disorders. Neuron, 57(2), pp.178‐201. 2. Mehmood, Y., Tariq, A. and Siddiqui, F.A., 2015. Brain targeting Drug Delivery System: A Review. International Journal of Basic Medical Sciences and Pharmacy (IJBMSP), 5(1). 3. Misra, A., Ganesh, S., Shahiwala, A. and Shah, S.P., 2003. Drug delivery to the central nervous system: a review. J Pharm Pharm Sci, 6(2), pp.252‐273. 4. Reichel, A., Begley, D.J. and Abbott, N.J., 2003. An overview of in vitro techniques for blood‐brain barrier studies. In The Blood‐Brain Barrier (pp. 307‐324). Humana Press.2. 91
- 95. 95