MOlecular basis of drug targeting

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MOLECULAR BASIS OF
TARGATED DRUG DELIVERY
SYSTEM

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 Introduction
 Reasons for site specific drug delivery
 Anatomy & Physiology Of Cell
 Types Of Blood Capillaries
 Anatomical & Physiological considerations For Targeting
 Ideal Characteristics Of DDTS
 Components Of DDTS
 Levels Of Drug Targeting
 Ligend driven receptor mediated drug delivery
 Future perspective
 Conclusion
 References
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3. 3
 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 preselected target(s) in therapeutic
concentration.
 It restrict the entry of drug in non-targeted cells,
thus minimizing toxic effects.

4.  Targeting is signified if target compartment is distinguished
from other compartment.
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Target site
Non target
site
Affinity -
toxicity
No affinity-
low effect
Bio-environmental factors
Target site Non target
site
Inactivation/
Less
therapeutic
effect
More
therapeutic
effect
No affinity-
low effect
Targeted
effect
Drug Drug in carrier

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Reasons For Site-Specific Drug Delivery
Properties Factors
Pharmaceutical Solubility
Drug stability
Biopharmaceutical Low absorption
Pharmacokinetic &
pharmacodinemic
Short half-life
Large volume of distibution
Low specificity
Clinical Low therapeutic index
Anatomical & cellular barrier

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Anatomy & Physiology Of Cell

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Extravasation

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Types Of Blood Capillaries
(1) Continuous capillary (as found in the general circulation). The endothelium is continuous
with tight junctions between adjacent endothelial cells. The subendothelial basement
membrane is also continuous.
(2) Fenestrated capillary (as found in exocrine glands and the pancreas). The endothelium
exhibits a series of fenestrae which are sealed by a membranous diaphragm. The
subendothelial basement membrane is continuous.
(3) Discontinuous (sinusoidal) capillary (as found in the liver, spleen and bone marrow). The
overlying endothelium contains numerous gaps of varying size. The subendothelial basement is
either absent (liver) or present as a fragmented interrupted structure (spleen, bone marrow)

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Lymphatic System
Solid tumors lack lymphatic system,so the macromolecules drugs
enters tumor interstitium by extravasation & remain there,known as
EPR effect.

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Anatomical & Physiological considerations For Targeting
Phagocytic uptake by the cells of the mononuclear phagocyte
systems (MPS; also sometimes known as the reticuloendothelial
system, RES)
• fixed cells: macrophages in liver (also known as Kuppfer cells),
spleen, lung, bone marrow and lymph nodes
• mobile cells: blood monocytes and tissue macrophages
MPS System
Factors Affecting MPS Clearance
1. Particle size :
2. Particle charge :
3. Surface hydrophobicity : Hydrophobic particles rapidly taken up by MPS system.
Particulates in the size range of 0.1−7 μm tend to be cleared by the
MPS, localizing predominantly in the Kuppfer cells of the liver.
Negatively charged vesicles tend to be removed relatively
rapidly from the circulation whereas neutral vesicles tend to
remain in the circulation for longer periods.

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• specifically target the drug to target cells or target tissue;
• keep the drug out of non-target organs, cells or tissue;
• ensure minimal drug leakage during transit to target;
• protect the associated drug from metabolism;
• protect the associated drug from premature clearance;
• retain the drug at the target site for the desired period of time;
• facilitate transport of the drug into the cell;
• deliver the drug to the appropriate intracellular target site;
• Should be biodegradable and non-antigenic.
Ideal Characteristics Of TDDS

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Components Of TDDS
TDDS Component 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

14. Carriers are the drug vectors which protect,transport
and retain drug “an route” and deliver it to target
site.
 It must be able to cross anatomical barriers.
 It must be recognized selectively by target cell.
 Carrier should be non-toxic, non-immunogenic,
biodegradable particulate.
 After internalization carrier should release the drug
moiety inside target organ.
 Extravasation and Passive delivery 14
Carriers
Ideal characteristics of carrier

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Carrier System Used For Targeted Drug Delivery
Colloidal Carriers 1)Vesicular system:
liposomes,niosomes,virosomes,immunoliposomes
2)Microparticulate system:
microspheres,nanoparticles
Cellular carriers Resealed erythrocytes,serum
albumin,antibodies,platlets,leukocytes
Supramolecular
delivery
Micelles,reverse micelle,liquid crystals,lipoprotein
(VLDL,LDL)
Polymer based
delivery
Muco-adhesive,biodegradable,bioerodible,soluble
synthetic carriers
Macromolecular
carriers
1)proteins,glycoprotein,neo-glycoprotein
2)Mabs
3)Polysaccharides

16. Targeting occurs because of the body‟s
natural response to the physiological
characteristics of the drug-carrier system.
colloidal carriers are taken up by RES in liver &
spleen.
:extravasation is poor with
microparticulate system.
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Levels Of Drug Targeting
Macrophage related infected cell lines Drug proposed for
encapsulation
INTRACELLULAR PARASITES:
Leismaniasis,Brucellosis, Candidiasis
Antimalarial &
Antiinfective
NEOPLASM: lukemia,hodgkin’s disease,viral
infected disease
Cytotoxic & antiviral
drugs
Disadvantage
Passive Targeting

17. It is based on successful attempts to avoid passive
uptake of colloidal carrier by reticuloendothelial
system.
Phospholipid microsphere emulsified with poloxamer
338 showed the lowest RES uptake in mouse. 17
Inverse Targeting
Inverse Targeting
Pre injection of blank
colloidal carrier
Change in size, surface charge,
hydrophilicity of carrier
Blockade of RES
Methods For Inverse Targeting

18. The natural distribution pattern of the drug carrier
composites is enhanced using chemical,biological
& physical method.
Active targeting devided in two types:
1)Ligand mediated targeting
2)Physical targeting 18
Active Targeting
Active Targeting
First order targeting Second order targeting Third order targeting
Organ targeting Cellular targeting Intracellular targeting
pH sensitive
Temperature sensitive

19. Drug targeting employs carrier molecules,which have their
own effect thus synergies the active ingradient effect.
Targeting can be achieved via physical(pemeation
enhancer),chemival(prodrug),or carrier encapsulation
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Dual Targeting
Double Targeting
Controlled release of drug
Sustained release
Stimuli responsive release
Self-regulating release
Drug targeting
Active/passive
targeting
Double
targeting
Combination Targeting

20.  Rapid clearance of targeted systems specially
antibody targeted system.
 Immune reactions against intravenous administered
carrier system.
 Problems of insufficient localization of targeted
systems into tumour cells.
 Down regulation of surface epitopes.
 Diffusion and Redistribution of released drug
leading to non-specific accumulation.
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Problems Associated With Targeted Drug Delivery System

21. Cell Surface Biochemistry & Molecular Targets
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Distinctive cellular elements present on the surface of the
target cells are important for targeting.
• Cell surface antigen
• Cell specific antibodies
• Cell surface receptors
Types of receptors present on
biocell,
• lectin like receptors
• Monoclonal antibody
• Hormone
• MHC-1
Receptor as drug delivery

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Ligand As Drug Delivery
 Types of ligand internalized via receptor mediated
endocytosis.
1. The endogenously produced ligands may compete with
exogenously delivered ligand.
2. Ligands may elicit immunological response.
3. Bind to multi receptor types.
Endogenous
ligand
Immunological
ligand
Glycoconjugate Antibodies
Transferin Interferons Glycolipid Haptens
Folate MHC-peptides Glycosides Mabs
Lipoprotein Interlukins Polysaccharides Immunotoxins
Limitations of natural ligands

23. LIGAND DRIVEN RECEPTOR MEDIATED
DRUG DELIVERY
Endocytosis:
(1) Recognition: Coating mediated by blood components
(2) Adhesion: Attachment of ligand to macrophage cells of
RES
(3) Digestion: Particle transfer to phagosome,phago-
lysosome,digestive vacuoles.
Cellular Processes
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Endocytosis Processes

25. Three internalization mechnisms have been proposed:
1. Fluid phase pinocytosis
2. Adsorptive,receptor mediated pinocytosis
3. Adsorptive,non-receptor (diffusive)mediated pinocytosis
 Clathrin is vesicular coat proteins mediate internalization
of receptor-ligand complex
 They concentrate carriers & receptors in the vesicles.
 They serve to transport & target vesicles from the donor
compartment to appropriate destinations.
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Receptor Madiated Endocytosis
Clathrin Coated Endocytosis
Functions

26. Clathrine Independent Endocytosis
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 It involve the component of cytoskeleton.
 Caveolae are coated investigations of plasma
membrane,they do not separate from the plasma
membrane,known as “POTOCYTOSIS”
 Folate undergo potocytosis.
Clathrine coated
pinocytosis
Non clathrine
coated
micropinosomes
phagosome

27. Ligand Mediated Transcytosis
 receptor-mediated pinocytosis,
the endosomes carrying the
drug actually bypass the
lysosomes and migrate toward
the basolateral membrane,
resulting in the release of the
undegraded drug into the
extracellular space bounded by
the basolateral membrane. This
process, known as transcytosis,
represents a potentially useful
and important pathway for the
absorption of high molecular
weight drugs such as peptides
and proteins.
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INTRACELLULAR DISPOSITION OF DRUG-CARRIER COMPLEX
Receptor Recognition & Ligand-Receptor Interaction
Cell Specific Recognition of Carrier
Binding Of Drug Conjugate
Intracellular release
Cellular Retention
Endocytosis
Influence By Proteine
Kinase C

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Intracellular Complex Of Ligand-Receptor complex
Ligand-Receptor Complex
Transported In Endosome Vesicles
Receptor Ligand
Transported To Cell Surface
Lysosome

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Delivery Of Drug-Carrier complex To Acidic Endosomal & Lysosomal
Compartment
“Lysomotropic Approach”
Vesicle Shunt Model Assumes that early & late endosomes are pre-
existing compartments that communicate through
vesicle-mediate transport
Maturation model Assumes that early endosomes mature gradually into late
endosomes
Delivery Of Drug-Carrier complex To Cytosolic Compartment
Ligand degradation by lysosomal pH decrease by Ammonium Chloride which
neutralise acidic pH of lysosome
Various methods available to target cytosole by exposing the vesicle to adenovirus
& immunotoxins which degrade endosomal vesicles & deliver the content to
cytosol.

31.  The innovation in this field of research on the targeted drug
delivery in the coming years would be a shift from “receptor to
nucleus”.
 This site-specific delivery rotate towards the gene delivery to
nucleus.
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Future Perspective
•In the early days of the 20th century, Paul Ehrlich developed his
“magic bullet” concept: the idea that drugs reach the right site in
the body, at the right time, at the right concentration. It should not
exert side-effects, neither on its way to the therapeutic target, nor at
the target site, nor during the clearance process.
•they are indicated for the treatment of life-threatening diseases
like cancer, and severe infectious diseases.
Conclusion

32. 1. Vyas s. p.,Khar r. k., 2010, „Molecular Basis Of
Targeted Drug Delivery‟ Targeted & Controlled
Drug Delivery System, 6th Edition, CBS Publishers
& Distributors,New Delhi,Page no:38-80
2. Hillery m.,Lloyd w.,2005, „Advanced Drug
Delivery and Targeting: An Introduction‟Drug
Delivery & Targeting, 3rd Edition, Taylor & Francis
Inc,29 West 35th Street, New York,Page no:56-71
3. Banker s. g.,Rhodes t. c.,2002, „Target Oriented
Drug Delivery System‟Modern Pharmaceutics,4th
Edition,United States Of America,Page no:531-580
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REFERENCES

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