Nanoparticulate systems for brain delivery of drugs

This ppt will help to understand in very brief about the nano particulate system for brain delivery of drugs. Various examples and mechanism of penetration is also added

1. Dr. Sheikh Aijaz A.
*
AnuradhaCollege of Pharmacy, Chikhli,
Maharashtra, India
Nanoparticulate systems for brain
delivery of drugs

2. Introduction
ThedeliveryofdrugstotheCNSisofprimeimportancefortreating
variousdegenerativediseasessuchasAlzheimer,Parkinson’sand
tumor.
The major problem in treating suchdisorders isdue to inability to
surpass the natural CNS protective barrier i.e. blood-brain barrier(BBB).
The BBB is a structure formed by a complex system of endothelial
cells, astroglia, pericytesand perivascularmast cells, preventing
the passage of most circulating cells and molecules.

3. The tightness of the BBB is attributed mainly to the brain
capillary endothelial cells which are interconnected side by
side by tight junctions.
A further obstacle for drugs is presence of P-glycoprotein
pump in the BBB, allowing the recognition of molecules
necessary for the brain to enter the brain and expulsion of
other molecules, pharmaceuticals included.
The BBB represents an obstacle for a large number of drugs,
including antibiotics, antineoplasticagents.

4. A number of attempts have been made to over-come the above
barrier including osmotic opening of the tight junctions, use of
prodrugsor carrier systems such as antibodies, liposomes and
nanoparticles.
The opening of the tight junctions by osmotic pressure, however, is a
very invasive procedure that also enables the entry of unwanted
substances into the brain.
Prodrugstake advantage of a higher lipophilicityenabling a better
penetration into the lipophilic endothelial barrier but often the
prodrugapproach is not possible.
The colloidal carriers, on the other hand may take advantage of the
biochemical transport systems that are also present in the BBB.

5. Definition of Nanoparticles
Nanoparticlesaredefinedaspolymericparticlesmadeofnatural
orartificialpolymersrangingbetween10to1000nm(1mm)in
size.Drugscanbeboundintheformofasolidsolutionor
dispersion,orcanbeadsorbedtothesurfaceorbechemically
attached.

6. Advantages of nanoparticles for CNS targeted
drug delivery
Nanoparticlesprotectdrugsagainstchemicalandenzymatic
degradation.
Highchemicalandbiologicalstability.
Feasibilityofincorporatingbothhydrophilicandhydrophobic
pharmaceuticals.
Imagingorsensingagentsmightadditionallybeincorporatedintoa
nanodeliverysystemtogeneratemultifunctionality.
Sustaineddrugreleaseatthetargetedsiteafterinjectionoveraperiod
ofdaysorevenweeks.
Thistechnologydoesnotrequireanymodificationofthedrug
moleculeforthebraindelivery.

7. Ideal properties of nanoparticles for CNS
drug delivery
Nanoparticlesshouldbenontoxic,biodegradableandbiocompatible.
Shouldbephysicallystableinblood(Noaggregation)
Shouldavoidopsonization,therebyprolongedbloodcirculationtime.
Amenabletosmallmolecules,peptides,proteins,nucleicacid.

8. Use of nanoparticles for the CNS targeted
drug delivery
NeutralnanoparticleshavenoeffectonBBBintegrity.
Theextentofbrainuptakeofanionicnanoparticlesatlow
concentrationwassuperiortoneutralorcationicnanoparticles.
Highconcentrationofanionicnanoparticlesandcationic
nanoparticlesweretoxicforBBB,hencenanoparticlessurface
chargesmustbeconsideredfortoxicityandbraindistribution
profile.

9. Different types of nanoparticles used for CNS
targeted drug delivery
Solid lipid nanoparticles
Polymeric nanoparticles
Nanocrystals
Quantum dots
Carbon nanotubes
Polymeric micelles
Dendrimers

10. In vivo brain drug delivery with nanoparticles
The first successful drug delivery across the BBB to the brain was achieved
with poly(butyl cyanoacrylate) nanoparticles of a size of about 250 nm.
This polymer has the advantage that it is very rapidly biodegradable.
Besides the over coating of the poly(butyl cyanoacrylate) nanoparticles
with polysorbate80, overcoatingwith polysorbate20, 40, and 60 also
enabled a transport of the nanoparticle-bound dalarginacross the BBB.
Nano particles made of the biodegradable polymers, such as poly(alkyl
cyanoacrylate) and poly(lactide-co-glycolide) (PLGA), human serum
albumin (HSA), as well as chitosan were also studied.
The biodegradability of core polymers is a main requirement for the safety
of the nanoparticles intended for parenteral use.

11. Mechanism of nanoparticles-mediated drug transport
to the brain
1. An increased retention of the nanoparticles in the blood capillaries of the
brain, combined with an adsorption to the capillary walls could create a
higher concentration gradient that would increase the transport across
the endothelial cell layer and as a result enhanced delivery to the brain.
2. The polysorbate80, used as the coating agent, could inhibit the efflux system.
3. A general surfactant effect characterized by a solubilizationof the endothelial cell
membrane lipids would lead to membrane fluidization and an enhanced drug permeability
across the BBB.
4. The nanoparticles could lead to an opening of the tight junctions between
the endothelial cells.
5. The nanoparticles may be endocytosedby the endothelial cells followed by the release of
the drugs within these cells and delivery to the brain.
6. The nanoparticles with bound drugs could be transcytosedthrough the
endothelial cell layer.
(All these mechanisms could also work in combinations.)

12. Doxorubicinisoneofthemostefficientanticancerdrugs,butit
cannotcrosstheBBBandthereforeisnotusedagainstbrain
tumors.Forthisreason,thedrugwasboundtopoly(butyl
cyanoacrylate)nanoparticlesandtheparticleswerecoated
withpolysorbate80.Thesenanoparticlesachievedveryhigh
braindoxorubicinconcentrations.

13. Drug Typeof
action
Corepolymer Surface
modification
Size
(nm)
DalarginAnalgesic
drug
Poly(butyl
cyanoacrylate)
Polysorbate80230
DoxorubicinAnticancer
drug
Poly(butyl
cyanoacrylate)
Polysorbate80270
CampthotecinAnticancer
drug
SolidlipidnanoparticlesPoloxamer188197
RivastigmineAnti-
Alzheimer's
drug
Poly(butyl
cyanoacrylate)
Polysorbate8041
Drugs bound to nanoparticles for brain delivery

14. The transport of nanoparticles to the brain depends on the coating of the
nanoparticles with polysorbate80. The particles thus seem to mimic LDL
particles and could interact with the LDL receptors leading to their uptake
by the endothelial cells.

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