Brain specific drug targetting stratergies
- 1. BRAIN SPECIFIC DRUG TARGETTING STRATERGIES PRESENTED BY KOORISHMA J RA1412014010001 M.Tech (BIOTECHNOLOGY)
- 3. INTRODUCTION • drugs, when injected intravenously, fail to reach brain and spinal cord, • but the same drugs, when injected into the ventricles, enter the brain substances easily. • This indicates that a barrier exists at the capillary level between the blood and nerve cells. So, the blood brain barrier can be defined as the separation of the circulating blood and the brain extracellular fluid in the Central Nervous System (CNS).
- 4. FUNCTIONS OF BBB • Maintaining the internal environment of brain. Eg: maintaining brain interstitial fluid & cerebrospinal fluid. • BBB protects brain from fluctuation. • Main function of BBB is neroprotection.
- 5. FACTORS AFFECTING PARTICULAR SUBSTRATE TO CROSS BBB Drug related factors at BBB 1. Conc at the BBB & the size 2. Flexibility 3. Conformation 4. Ionization 5. Lipophilicity 6. Hydrogen bonding potential
- 6. ROUTES FOR THE TRANSPORT OF MOLECULES ACROSS THE BBB • Paracellular hydrophilic diffusion • Transcellular lipophilic diffusion • Receptor mediated endocytosis • Carrier mediated transcytosis • Adsorptive mediated endocytosis • Efflux pump
- 7. RECENT ADVANCES IN BRAIN DRUG DELIVERY RESEARCH • Nano particles • Receptor-mediated transport (RMT) • Transporter-independent mechanisms to circumvent the BBB. 1)Intranasal Delivery. 2)Convection-enhanced drug delivery (CED) 3)Osmotic BBB Disruption (BBBD). 4)Ultrasound-mediated BBB opening • Imaging in brain drug targeting. 1)Magnetic resonance imaging 2)Imaging delivery techniques. 3)Positron Emission Tomography. • BBB genomics. • P-glycoprotein inhibitors
- 8. Nano particles Nanotechnology may also help in the transfer of drugs across the BBB. Recently, researchers have been trying to build nanoparticles loaded with liposomes to gain access through the BBB.
- 10. RECEPTOR MEDIATED TANSPORT The BBB expresses RMT systems for the transport of endogenous peptides, such as insulin or transferrin. The RMT systems operate in parallel with the classical carrier-mediated transporters (CMT), which transport certain small molecule nutrients, vitamins, and hormones.
- 11. Transporter-independent mechanisms to circumvent the BBB 1)Intranasal Delivery. (not effective) This method allows drugs that do not cross the blood-brain barrier to be delivered to the olfactory cerebrospinal fluid via transport across the olfactory region of the nasal epithelium. The surface area of the olfactory region of the nasal epithelium in rodents is large, about 50%, and is small in humans, about 5%, therefore intranasal delivery is not expected to achieve therapeutic drug levels in most brain regions. 2)Convection-enhanced drug delivery (CED) CED is a method for local/regional micro infusion targeted directly to brain tissue. A continuous infusion pressure gradient over hours to days results in distribution of therapeutic agents into the interstitial space. The CED technique is used primarily for large molecular weight agents that show minimal leakage across the BBB and/or have significant systemic toxicity, including viruses, oligonucleotides, nanoparticles, liposome, and targeted immunotoxins.
- 12. 3)Osmotic BBB Disruption (BBBD) Transient osmotic disruption of the blood-brain, blood-CSF, and blood-tumor barriers can be achieved throughout a vascular circulation by intra arterial infusion of a hyper osmotic agent, usually mannitol. Osmotic BBBD reversibly opens the BBB by shrinking the cerebro vascular endothelial cells with transient opening of the tight junctions between cells. 4)Ultrasound-mediated BBB opening BBB disruption by MRI-guided focused ultrasound can achieve focal CNS delivery in animal models. Consistent vascular leak without tissue damage was achieved by localizing cavitation-generated mechanical stresses to blood vessel walls by IV injection of preformed gas bubbles just prior to pulsed ultrasound treatment.
- 13. Imaging in brain drug targeting Imaging has made important contributions in drug discovery and brain drug targeting, particularly in areas of pharmacokinetics and in quantifying therapeutic response.
- 14. • a. Magnetic resonance imaging Brain structural imaging data provide important metrics regarding the extent of brain disease and objective surrogate markers for evaluation of therapies. MRI has played an important role in evaluating new CNS therapies. b. Imaging delivery techniques. The distribution of drug within the brain using any of the BBB strategies is complex and imaging information can be used to optimize individual therapies. Contrast enhanced MRI has been used to monitor CED drug delivery and revealed complex distribution patterns resulting from anisotropic diffusion, vascular efflux, and other factors. c. Positron Emission Tomography. PET is non-invasive, has excellent sensitivity and specificity. Advanced PET techniques have been used to determine pharmacokinetics of brain drugs pharmacodynamic response following anti-cancer therapy.
- 15. Other methods a. BBB genomics. BBB genomics is the application of gene micro-array technologies. The endothelial cells occupy a very small volume of the brain, about 0.1%, or 10-3 parts. The sensitivity of gene micro-array is about 10-4 parts. Therefore, most BBB specific transcripts may not be detected in whole brain gene microarray. b. P-glycoprotein inhibitors. Inhibitors of BBB active efflux transporters, such as Pglycoprotein, have been developed. Such inhibitors may act as co-drugs to increase the brain penetration of P-glycoprotein substrates. Eg:paclitaxel by co-administration of the Pglycoprotein inhibitor.
- 16. applications of targeted brain delivery 1. neurodegeneration / neuroinflammation (Stroke, Alzheimers, Parkinsons, ALS, MS)- protein drugs (growth factors, antibodies, enzymes) – gene / antisense therapy- small molecules. 2. lysosomal storage diseases- enzyme replacement therapies-gene therapy 3. brain tumors / metastasis- anti-cancer drugs- protein drugs (antibodies, cytokines)- gene / antisense therapy
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