Targeted drug delivery system, Sem-VII, As per PCI Syllabus

Targeted drug delivery implies for selective
and effective localization of pharmacologically
active moiety at pre-selected target(s)
therapeutic in concentration.

2. Concept of targeted drug delivery
•The concept of targeted drug delivery system
given by "Paul Ehrlich", proposed drug
delivery as a "magic bullet“.
•Targeted drug delivery implies for selective
and effective localization of pharmacologically
active moiety at pre-selected target(s)
therapeutic in concentration.
•It restrict the entry of drug in non-targeted
cells, thus minimizing toxic effects.

3. Ideal characteristics of TDDS

6. Advantages

7. Disadvantages
• Rapid clearance of targeted systems.
• Immune reactions against intravenous administered carrier
systems.
• Insufficient localization of targeted systems into tumour cells.
• Diffusion and redistribution of released drugs.
• Requires highly sophisticated technology for the formulation.
• Requires skill for manufacturing storage, administration.
•Drug deposition at the target site may produce toxicity symptoms.
• Difficult to maintain stability of dosage form.
• Drug loading is usually law.

8. Components of Targeted Drug Delivery
System
Components Purpose
The active moiety To achieve the therapeutic
effect.
The carrier system (which
can be either soluble or
particulate)
To effect a favorable
distribution of the drug.
To protect the drug from
metabolism.
To protect the drug from
early clearance.
A "homing device“ To specifically target the
drug to the target cells or
target tissue

9. Carrier or Markers
•Targeteddrugdeliverycanbeachievedbyusing
carriersystem.
•Carrierisoneofthespecialmoleculeorsystem
essentiallyrequiredforeffectivetransportationof
loadeddruguptothepre-selectedsites.
•Theyareengineeredvectors,whichretaindrug
insideorontothemeitherviaencapsulationand/
orviaspacermoietyandtransportordeliverit
intovicinityoftargetcell.

10. Carrier System Used For Targeted Drug Delivery
Colloidal Carriers
Vesicular system:
Liposomes
Niosomes
Virosomes
Immunoliposomes
Microparticulatesystem:
•Microspheres
•Nanoparticles
Cellular Carriers
•Resealed erythrocytes
•Serum albumin
•Antibodies
•Platelets Leukocytes
Macro molecular Carriers
•Proteins,
•Glycoprotein,
•Neo-glycoprotein
•Polysaccharides

11. Types of targeted drug delivery system
•NanoTubes:
Theyarehollowcylindermadeofcarbon,atomswhich
canbefilledandsealedforpotentialdrugdelivery.

12. Nano shells
Nanoshellsarehollowsilicaspherescoveredwithgold.
Scientistscanattachantibodiestotheirsurfaces,
enablingtheshellstotargetcertainshellssuchas
cancercells.Absorptionoflightbynanoshellscreates
anintenseheatthatislethaltocells.

13. Gold Nano
ParticleScientistusesgoldnanoparticletodevelop
ultrasensitivedetectionsystemforDNAand
proteinmarkersassociatedwithmanyformsof
cancer,includingbreast,prostratecancer.

14. Dendrimers
Dendrimerspreciselydefined,syntheticnanoparticles
thatareapproximately510nmindiameter.Theyare
madeupoflayersofpolymersurroundingacontrolcore.
Thedendrimerssurfacecontainsmanydifferentsitesto
whichdrugsmaybeattach.Dendrimershaveatree-like
structurewithmanybrancheswhereavarietyof
molecules,includingdrugscanbeattached.

15. Liposomes
Liposomesaresimplemicroscopicvesiclesinwhichanaqueous
volumeisentirelycomposedbymembraneoflipidmolecule
variousamphiphilicmoleculeshavebeenusedtoform
liposomes.Thedrugmoleculescaneitherbeencapsulatedin
aqueousspaceorintercalatedintothelipidbilayersTheextent
oflocationofdrugwilldependuponitsphysico-chemical
characteristsandcompositionoflipids.

16. Niosomes
Niosomesarenonionicsurfactantvesicleswhichcan
entrapbothhydrophilicandlipophilicdrugseitherin
aqueousphaseorinvesicularmembranemadeupoflipid
materialsItisreportedtoattainbetterstabilitythan
liposome's.Itmayproveveryusefulfortargetingthe
drugsfortreatingcancer,parasitic,viralandother
microbialdiseasemoreeffectively.

17. Virosomes
•Virosomesareimmunemodulatingliposomes
consistingofsurfaceglycoproteinofinfluenzavirus
(immunestimulatingreconstitutedinfluenzavirosome)
muramyldipeptideetc.
•Virosomesmustbetargetorientedandtheirfusogenic
characteristicscouldbeexploitedingenomegrafting
andcellular.

18. Nano robots
•Nanoroboticsisthetechnologyofcreating
machinesorrobotsatorclosetothemicroscopic
scaleofananometre(10-meters).
•Morespecifically,Nanoroboticsreferstothestill
largelyhypotheticalnanotechnologyengineering
disciplineofdesigningandbuilding.

19. Monoclonal Antibodies
Thesearehomogenouspreparationsofantibodies
(orfragmentsofantibodies)inwhichevery
antibodyintheproductisidenticalinitsprotein
sequence,andthuseveryantibodyisexpectedto
havethesameantigenrecognitionsite,affinity,
biologicinteractions,anddownstreambiologic
effects.

20. Preparation of Monoclonal Antibodies
•MonoclonalAntibodyproductionormAbisproduced
bycelllinesorclonesobtainedfromtheimmunized
animalswiththesubstancestobestudied.Celllines
areproducedbyfusingB-cellsfromtheimmunized
animalwithmyelomacells.
•ToproducethedesiredmAB,thecellsmustbegrown
ineitheroftwoways:byinjectionintotheperitoneal
cavityofasuitablypreparedmouse(invivomethod)or
byinvitrotissueculture.
•Thevitrotissuecultureisthemethodusedwhenthe
cellsareplacedincultureoutsidethemousethe
mouse'sbodyinflask.

22. Practical steps for production
1.Immunize animal
2.Isolate spleen cells (containing antibody-producing B cell)
3.Fuse spleen cells with myeloma cell (using PEG)
4.Allow unfusedB cell to die
5.Add aminopterinto culture and kill unfusedmyeloma cells
6.Clone remaining cells (place 1 cell/well and allow each cell
to grow into a clones of cell)
7.Screen supernatant of each clone for presence of desired
antibody
8.Grow chosen clone of cells in tissue culture indefinitely
9.Harvest antibody from the culture.
10.$ 1000-2000 per mg

24. Applications
Major Applications:
(1) Diagnostic Applications
•Biochemical analysis
•Diagnostic Imaging
(2) Therapeutic Applications
• Direct use of MAbsas therapeutic agents
• MAbsas targeting agents.
(3) Protein Purification

25. 1a. Biochemical analysis
•Routinelyusedinradioimmunoassay(RIA)and
enzyme-linkedimmunosorbentassays(ELISA)inthe
laboratory.
•Theseassaysmeasurethecirculatingconcentrationsof
hormones(insulin,humanchorionicgonadotropin,
growthhormone,progesterone,thyroxine,
triiodothyronine,thyroidstimulatinghormone)and
severalothertissueandcellproducts(bloodgroup
antigens,bloodclottingfactors,interferon's,
interleukins,tumormarkers).

26. 1b. Diagnostic imaging
•Radiolabeled-MAbsareusedinthediagnosticimaging
ofdiseases,andthistechniqueisreferredtoas
immunoscintigraphy.Theradioisotopescommonly
usedforlabelingMAbareiodine-131andtechnetium-
99.TheMAbtaggedwithradioisotopeareinjected
intravenouslyintothepatients.
•TheseMAbslocalizeatspecificsites(sayatumor)
whichcanbedetectedbyimagingtheradioactivity.In
recentyears,singlephotonemissioncomputed
tomography(SPECT)camerasareusedtogiveamore
sensitivethreedimensionalappearanceofthespots
localizedbyradiolabeled-MAbs.
•Myocardialinfarction,DVT,atherosclorosisetc.

27. 2a.DirectuseofMAbsastherapeuticagents
•Indestroyingdisease-causing
organisms:MAbspromoteefficient
opsonizationofpathogenicorganisms(bycoatingwith
antibody)andenhancephagocytosis.
•Intheimmunosuppressionoforgantransplantation:
Inthenormalmedicalpractice,immunosuppressive
drugssuchascyclosporinandprednisoneare
administeredtoovercometherejectionoforgan
transplantation.Inrecentyears,MAbsspecifictoT-
lymphocytesurfaceantigensarebeingusedforthis
purpose.

28. 2b. MAbsas targeting agents.
•ThedrugscanbecoupledwithMAb(directed
againstacellsurfaceantigenofthecells,saya
tumor)andspecificallytargetedtoreachthesite
ofaction.
•Eg.Alkalinephosphatasefortheconversionof
phosphatepro-drugs.
•Carboxypeptidaseforconvertinginactive
carboxylpro-drugstoactivedrugs.
•Lactamaseforhydrolyzingẞ-lactamring
containingantibiotics.

29. 3. Protein Purification
•Monoclonalantibodiescanbeproducedforanyprotein.And
thesoproducedMAbcanbeconvenientlyusedforthe
purificationoftheproteinagainstwhichitwasraised.
•MAbscolumnscanbepreparedbycouplingthemtocyanogen
bromideactivatedSepharose(chromatographicmatrix).The
immobilizedMAbsinthismannerareveryusefulforthe
purificationofproteinsbyimmunoaffinitymethod.
•TherearecertainadvantagesofusingMAbsforprotein
purification.TheseincludethespecificityoftheMAbtobindto
thedesiredprotein,veryefficientelutionfromthe
chromatographiccolumnandhighdegreeofpurification.