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Use of Liposomes &
Nanoparticles in Brain Drug
Targeting - Recent Trends
Presented by Debanjan Das
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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)
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
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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Use Of Liposomes & Nanoparticles In Brain Drug Targeting

  • 1. Use of Liposomes & Nanoparticles in Brain Drug Targeting - Recent Trends Presented by Debanjan Das
  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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