Use Of Liposomes & Nanoparticles In Brain Drug Targeting

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Use of Liposomes & Nanoparticles in Brain Drug Targeting - Recent Trends

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Use Of Liposomes & Nanoparticles In Brain Drug Targeting

  1. 1. Use of Liposomes & Nanoparticles in Brain Drug Targeting - Recent Trends Presented by Debanjan Das
  2. 2. Changing face of CNS drug development  Chemically driven to biologically driven  Delivery of large molecule pharmaceuticals(>500 Daltons) such as recombinant proteins,monoclonal antibodies,antisense drugs,gene medicines  The horse & the cart science,where horse is the carrier dosage form and the cart is the large molecule pharmaceutical
  3. 3. Application of Liposomes  Remarkable structural versatility  Targeting to specific organs or cells by coupling with a carrier moiety  Biodegradable,shows good drug entrapment(water & oil soluble drugs),and physicochemically stable  Inherent efficiency of CNS drug development is increased by incorporating structure transport relationship(STR) during formulation development phase
  4. 4. Recent trends: PEGylation  Brain cancer treatment,AIDS related Kapsoi’s sarcoma,solid brain tumors  Coating with PEG which confers optimal protection from RES mediated clearance; long acting type  Bilayer rigidification using phospholipid reduces chances of leakage  Localization in brain tumors due to enhanced extravasations through abnormally permeable microvasculature and impaired lymphatic drainage
  5. 5. ATP supply to brain  Potential application in human resuscitation from deep brain hypogeric states  Experimented intracarotidally & cerebroventricularly into rats subjected to brain ischaemia  ATP entrapped in liposomes decreases ischaemic episodes in brain
  6. 6. Transfecting neurons & glia  Use of pH sensitive immunoliposomes  Effective transfection system for gene delivery to brain  Liposomes constructed with N-glutaryl- phosphatidylethanolamine conjugated antibodies & a beta galactosidase plasmid under the control of cytomegalo virus
  7. 7. AZT oral dosage  Chemical delivery of AZT (AZT-CDS) orally shows poor bioavailability in brain due to its acid lability in the intestine  AZT-CDS in Dimethyl Sulfoxide did not reach brain  Liposome formulation of AZT was absorbed from jejunum  Liposome formulation in enteric coated AZT- CDS might be promising for oral dosage
  8. 8. Cationic liposome complex for gene transfer  Improvement over previously done direct in vivo gene transfer by continuous injection of plasmid DNA  Plasmid DNA-cationic liposome complex contained a reporter gene coding for E.Coli beta galactosidase  Improved liposome mediated gene transfer technology helpful for treating brain disorders & analysis of gene functions
  9. 9. Vector mediated brain drug delivery  Chimeric peptide technology where a non- transportable drug is conjugated to a BBB vector  Vector can be receptor specific Mabs which will undergo receptor mediated transcytosis across BBB  Delivery of wide variety of liposomes such as peptide based pharmaceuticals,brain derived neutropic factors,anti sense therapeutics etc
  10. 10. Application of Nanoparticles  Like liposomes nanoparticles are rapidly cleared from blood  PEGylation is done to prolong circulation time in blood  Unexpected finding with dalargin,where 230nm nanoparticles crossed BBB,whereas 40-80 nm liposomes doesn't  Recent studies show that detergents like Tweens enhance BBB transport
  11. 11. Recent trends-use of surfactants  Drug+nanoparticles+Tween complexes cross BBB  Polysorbate 20/40/60/80 were tested for efficiency,of which 80 showed best effect  Experiment done in rats where these complexes were injected i.v. & nociceptive analgesia was measured by tail flick test
  12. 12. Use of surfactants (Continued)  Formulation consisted of dalargin bound to poly butyl cyanoacrylate nanoparticles by sorption,then coated with polysorbate 80  Simple mixture of the above three components showed no effect  Fluorescent & electron microscopic studies show that the passage of particle bound drug occurred by phagocytic uptake of polysorbate 80 coated nanoparticles by brain blood vessel endothelial cells
  13. 13. Enhanced brain targeting using DO-FudR-SLN  DO-FudR-SLN is 3,5-dioctanoyl-5-fluro-2 deoxyuridine,conjugated into solid lipid nanoparticles(SLN)  Prepared by thin layer ultrasonication technique with median particle size of 76nm,drug loading of 29.02% & entrapment efficiency of 96.62%  Excellent penetration through BBB  Promising drug targeting system to treat brain disorders
  14. 14. Use of SLN  SLN loaded with tobramycin showed increased concentration in brain  However,concentration was much less when given intraduodenally than via iv route  Hence,oral route seems unsuitable but iv route provided much greater tissue distribution of SLN in brain
  15. 15. Delivery of AZT by oral route  Use of hexacyanoacrylate nonaparticles as colloidal drug carriers of AZT to brain  The AUC for treated nanoparticles when used in above formulation showed 30% increase than the control confirmed by use of 14C radioactive tracers  Shows promising delivery system for nucleoside analogs  Abundance of macrophages in BBB actually helps in greater uptake,and hence lowers the dosage & systemic toxicity
  16. 16. Use of magnetic materials  Nanodisperesed iron preparations accumulated in brain following iv injection to rats  Magnetite-dextran nanoparticle injection in carotid artery  Penetration of particles in brain tumor & peritumoral tissue of rats bearing glial brain tumor  Accumulation in brain confirmed by MRI imaging
  17. 17. Lipid Drug Conjugate Liposomes (LDC)  Particles incubated in mouse & human serum for adsorption of plasma proteins  Showed preferential adsorption of apolipoproteins,specially ApoE,which proves to be a decisive factor for brain uptake  In vivo localization in brain confirmed by marker Nile Red & confocal laser scanning microscopy
  18. 18. Summary  Liposomes show steric stabilization,remote loading of drugs by pH & ionic gradients, form lipoplexes based on complexes of cataionic liposomes with anionic nucleic acids or proteins  Excellent vehicle for delivery of large volume pharmaceuticals to brain  Do not cross BBB inherently excepting BBB disruption or structural modifications(STR)
  19. 19. Summary (Continued)  Nanoparticle mediated transport depends on overcoating of particles with polysorbates, which provides an anchor for plasma protein  They mimic LDL particles & interact with LDL receptors leading to accumulation in brain by diffusion or transcytosis  BBB tight junctions are modified by phosphoglycoprotein inhibition  Above mechanisms run in parallel or in combination for brain drug uptake
  20. 20. Conclusion  Nanoparticles can be regarded as better tools of brain drug targeting  They cross BBB with little modifications  Drugs successfully tried out are dalargin, loperamide, tubocurarine, doxorubicin & NMDA receptor antagonist MRZ2/576  However,more studies need to be done in finding its ability to carry large volume pharmaceuticals

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