Drug targating

11
Drug Targeting
Mr. Sagar Kishor savaleMr. Sagar Kishor savale
[[Department of Pharmaceutics]Department of Pharmaceutics]
avengersagar16@gmail.comavengersagar16@gmail.com
2015-0162015-016
Department of Pharmacy (Pharmaceutics) | Sagar savale
04/28/1604/28/16 Sagar SavaleSagar Savale

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CONTENTSCONTENTS
 Problems with CDDSProblems with CDDS
 Drug TargetingDrug Targeting
 Types of Drug TargetingTypes of Drug Targeting
 Approaches of Drug TargetingApproaches of Drug Targeting
 Levels of Drug TargetingLevels of Drug Targeting
 Factors affecting Drug TargetingFactors affecting Drug Targeting
 Targeted Drug Delivery SystemTargeted Drug Delivery System
 Problems with TDDSProblems with TDDS
 ReferencesReferences

33
Problems Associated With Conventional DrugProblems Associated With Conventional Drug
Delivery SystemDelivery System
 Difficulty in assessing diseased site (RA, Diseases of CNS,Difficulty in assessing diseased site (RA, Diseases of CNS,
Cancer, Interact able bacterial, fungal & parasitic infection)Cancer, Interact able bacterial, fungal & parasitic infection)
 High dose & frequent administration of drugs leads to toxicHigh dose & frequent administration of drugs leads to toxic
manifestationmanifestation
 Inappropriate pharmacodepositionInappropriate pharmacodeposition
 Inactivation or decomposition of drug by GIT pH, by enzymesInactivation or decomposition of drug by GIT pH, by enzymes
which digest food , metabolism by microbial florawhich digest food , metabolism by microbial flora
 In parentral route deactivation & metabolism of drug, doseIn parentral route deactivation & metabolism of drug, dose
related toxicity frequently observed.related toxicity frequently observed.

44
Ideal Characteristics of Targeted Drug Delivery SystemIdeal Characteristics of Targeted Drug Delivery System
It should beIt should be
 Biochemically Inert ( Non-toxic)Biochemically Inert ( Non-toxic)
 NonimmunogenicNonimmunogenic
 Physically & Chemically stablePhysically & Chemically stable in-vivoin-vivo && in-vitro.in-vitro.
 The carrier must be biodegradable or readily eliminated fromThe carrier must be biodegradable or readily eliminated from
body without problemsbody without problems
 Preparation of the delivery system must be reproducible, cost-Preparation of the delivery system must be reproducible, cost-
effective & simpleeffective & simple
Drug Targeting
Drug targeting means to deliver the drug only to its
site of action & not to the non-target organs, tissues or cells.

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Rational for Targeted Drug DeliveryRational for Targeted Drug Delivery
SystemSystem
 To supply drug selectively to its site of action to provideTo supply drug selectively to its site of action to provide
maximum therapeutic activitymaximum therapeutic activity
 Preventing degradation or inactivation of drugPreventing degradation or inactivation of drug
 Prevention of inappropriate deposition of the drugPrevention of inappropriate deposition of the drug
 For the drugs that have low therapeutic indexFor the drugs that have low therapeutic index

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Types of Drug TargetingTypes of Drug Targeting
First Order TargetingFirst Order Targeting
It involves the delivery of a drug to specific organ or a tissueIt involves the delivery of a drug to specific organ or a tissue
Second Order TargetingSecond Order Targeting
It involves targeting towards the specific cell type within theIt involves targeting towards the specific cell type within the
tissue or organ (e.g. Tumor cells Vs Normal cell)tissue or organ (e.g. Tumor cells Vs Normal cell)
Third Order TargetingThird Order Targeting
It involves a delivery to a specific intracellular compartment inIt involves a delivery to a specific intracellular compartment in
the target cell ( e.g. Lysosomes)the target cell ( e.g. Lysosomes)

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Approaches of Drug TargetingApproaches of Drug Targeting
First ApproachFirst Approach
It involves the use of biologically active agents that areIt involves the use of biologically active agents that are
both potent & selective to a particular site in the bodyboth potent & selective to a particular site in the body
((Magic Bullet Approach of EhrlichMagic Bullet Approach of Ehrlich))
Second ApproachSecond Approach
It involves the preparation of pharmacologically inertIt involves the preparation of pharmacologically inert
form of active drugs, which upon reaching the active sitesform of active drugs, which upon reaching the active sites
becomes activated by a chemical or enzymatic reactionbecomes activated by a chemical or enzymatic reaction
(( Prodrug ApproachProdrug Approach))
Third ApproachThird Approach
Biologically inert macromolecular carrier system thatBiologically inert macromolecular carrier system that
directs a drug to a specific site in the body where it isdirects a drug to a specific site in the body where it is
accumulated & shows its effect (accumulated & shows its effect ( Magic Gun or MissileMagic Gun or Missile
Approach)Approach)

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Levels of Drug TargetingLevels of Drug Targeting
Followings are the levels of drug targetingFollowings are the levels of drug targeting
 Passive TargetingPassive Targeting
 Inverse TargetingInverse Targeting
 Active Targeting ( Ligand Mediated Targeting & PhysicalActive Targeting ( Ligand Mediated Targeting & Physical
Targeting )Targeting )
 Dual TargetingDual Targeting
 Double TargetingDouble Targeting
 Combination TargetingCombination Targeting

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Passive Targeting
Means targeting occurs because of the body’s natural
response to the physicochemical characteristics of the drug or drug
carrier system
e.g.
The ability of some colloids to be taken up by the RES
specially in the liver & spleen
Inverse Targeting
These process involves the reversion of the biodistribution
trend of the carrier & hence the process is referred as inverse
targeting
e.g.
Suppression of the RES by the pre-injection of the large
amount of blank colloidal carriers which leads to impairment of the
host defense system.

1010
Active Targeting
The facilitation of the binding of the drug-carrier to target
cells through the use of ligands or engineered homing devices to
increase receptor mediated localization of the drug & target specific
delivery of drug is referred as active targeting.
.
Active Targeting
Ligand Mediated
Targeting
Physical
Targeting

1111
Ligand Mediated Targeting
Here the carrier for the drug is made specific for the certain cell
or group of cells by incorporating ligands such as antibody, polypeptide,
oligosaccharides etc. on the surface of the carrier.
e.g.
apoprotein coat serves as ligand for the LDL receptors
Physical Targeting
In this mode of targeting ,some characteristics of the
bioenvironment are used either to direct the carrier to particular
location or to cause selective release of its content.
e.g.
Application of the external magnetic stimuli has been
suggested for the localization of the magno-responsive liposomes and
microspheres within a preselective capillary bed.

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Dual Targeting
This classical approach of the drug targeting employs, carrier
molecules which have their own intrinsic anti-viral effect thus
synergies the anti-viral effect of the loaded active drug.
Double Targeting
In this mechanism spatial targeting is combined with temporal
control release .
Sustain release
Stimuli Responsive Release
Self-regulating Release
Active Targeting
Passive Targeting
Double
Targeting
Controlled
Release of Drug
Drug
Targeting

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e.g.
PEG coated liposomes (for selective release of drug in
low pH medium) attached with MAb (for targeting specific
target like tumor)
Combination Targeting
These targeting systems are equipped with carriers,
polymers & homing devices of molecular specificity that could
provide a direct approach to the target site.

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Factors affecting the Drug TargetingFactors affecting the Drug Targeting
Cellular Uptake & ProcessingCellular Uptake & Processing
OpsonizationOpsonization
Phagocytosis carried out specialized cells of mononuclearPhagocytosis carried out specialized cells of mononuclear
phagocyte system mediated by absorption of specific bloodphagocyte system mediated by absorption of specific blood
components (opsonins) is called as opsonization.components (opsonins) is called as opsonization.
Affected ByAffected By: Hydrophilic property of carrier system,: Hydrophilic property of carrier system,
Its molecular weight, size & conc. in extra-vascularIts molecular weight, size & conc. in extra-vascular
fluidfluid
Transport Across the Epithelial BarrierTransport Across the Epithelial Barrier
Affected ByAffected By: pH of the site, enzymes present, surface area of target,: pH of the site, enzymes present, surface area of target,
segment length, microbial flora, transit timesegment length, microbial flora, transit time

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Extravasation
In many diseases drugs have to egress from the central
circulation & interact with its extra vascular-extracellular or extra
vascular-intracellular targets .This process of transvascular exchange
is called as extravasation.
Affected By: permeability of the blood capillary walls, rate & flow of
blood supply, physiochemical factors of the compound,
presences of the anionic sites on the endothelium etc.
Lymphatic Uptake
Following extravasation, drug molecules either reabsorbed
into the blood circulation or into lymphatic system & then return with
lymph into blood circulation. This process is known as Lymphatic
Uptake.
Affected By: size & surface characteristics of the particles,
formulation medium, composition & pH of the
interstitial medium04/28/1604/28/16 Sagar SavaleSagar Savale

1616
Targeted Drug Delivery
System
Prodrugs Drug-Carrier Delivery
System
Liposomes
Niosomes
Nanoparticles
Microparticles
Erythrocytes
Neutrophills
Specialized Emulsions
Virosomes
ADPET
Polymeric Prodrugs

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ProdrugsProdrugs
ConceptConcept ::
Chemically modification of the drug, which followingChemically modification of the drug, which following
administration in side the body under go suitable changes yieldingadministration in side the body under go suitable changes yielding
active principles at the target site in the body compartmentactive principles at the target site in the body compartment
avoiding unnecessary exposure of drugs to the other parts of theavoiding unnecessary exposure of drugs to the other parts of the
body.body.
e.g.e.g.
Delivery of L-Dopa (precursor of dopamine) to brain, inDelivery of L-Dopa (precursor of dopamine) to brain, in
the corpus striatum converted to dopamine by an enzyme aromaticthe corpus striatum converted to dopamine by an enzyme aromatic
amino acid decarboxylaseamino acid decarboxylase
A prodrug is pharmacologically inertA prodrug is pharmacologically inert
form of an active drug that undergoform of an active drug that undergo
transformation to the parent compound intransformation to the parent compound in
vivo either by a chemical or an enzymaticvivo either by a chemical or an enzymatic
reaction to exert its therapeutic effects.reaction to exert its therapeutic effects.

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Prodrug
ADPET Polymeric Prodrugs
ADPET (Antibody Directed Enzyme Prodrug Therapy)
Polymeric Prodrugs
Prodrug
Prodrug
POLYMER
POLYMER

1919
Drug-Carrier Delivery
Systems
Drug Carriers
Carrier is the one of the most important entities
essentially required for the successful transport of the
loaded drug(s). These are the drug vectors which
sequester, transport and retain drug en route, while elute or
delivery it within or in the vicinity of target.
Ideal Features of Drug Carrier
Must be specific & selective for target cells
Must maintain avidity & identity of the surface ligands.
It must be able to cross the anatomical barriers & in case
of tumor, tumor vasculature.
Should be stable in plasma, interstitial & other biofluids04/28/1604/28/16 Sagar SavaleSagar Savale

2020
It should be non-toxic, non-immunogenic & biodegradable, & after
recognition, & internalization the carrier system should release the drug
moiety inside the target
The biomolecules used for carrier navigation & site recognition should
not be ubiquitous otherwise it may cross over the sites, defeating the
concept of targeting

2121
Liposomes are microscopic
vesicles composed of one or more lipid
bilayers, separated by water or
aqueous buffer compartments with a
diameter ranging from 80nm-10µm.
Liposomes
As a Carrier for Targeted Drug Delivery
Mainly used to target the organs like liver & spleen
prolonged circulating time & small size (easy for extravasation)
Magnetic liposomes
pH sensitive cationic liposomes & anionic liposomes
MAb can be easily incorporated on their surface
Ostearlylamylopectin coated liposomes specific for lung targeting

2222
Niosomes
Niosomes are essentially no n-ionic
surfactant based multi-lamellar or uni-
lamellar vesicles in which an aqueous
solution of solute is entirely enclosed by a
membrane resulted from the organization of
the surfactant molecules as a bilayers.
Niosomes are chemically more stable
compare to liposomes
As a Carrier for Targeted Drug Delivery System
 carrier for drug delivery to the sites other than liver &
spleen.
e.g. Niosomes containing muramic acid
Like liposomes selectively taken up by liver & spleen
Immunoglobulin can be easily coated on the lipid surface

2323
Nanoparticles
polyoxyethylene coated nanoparticles
Polysorbate 80 coated nanoparticles for drug delivery to brain
 transferrin coated gelatin nanoparticles
for targeting the lymph nodes
easily cross the vasculature of the tumor cells
Nanoparticles include the
colloidal particles ranging in size
from 10-1000nm.

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Microparticles
Microparticles
include particles larger than 1µm
but small enough not to sediment
when suspended in water & larger
enough to scatter the incoming
light.
For targeting inflammatory bowels
To target specific blood cells.
Magnetic microspheres for delivery of radiopharmaceuticals
MAb can be easily attached

2525
Virosomes
Virosomes are
reconstituted influenza virus
envelopes. The membrane of these
vesicles consists of a spherical,
unilamellar lipid bilayer. Purified
influenza envelope glycoproteins are
inserted into the lipid bilayer. The
mean diameter of the vesicles is in
the range of 120 - 180 nm.
Can be easily conjugated to the antibody against
the antigen present on the tumor cells.

2626
Specialized Emulsions
Emulsions are the dispersion of one liquid
inside the other liquid
For liver targeting
 Polyoxyethylene as an emulsifier
Conjugating antibodies to the distal end of
polyoxyethylene

2727
Released RBCs
The membrane of
RBCs can be temporarily broken by
changing tonicity or applying current
to load drug inside them & this can
be repair to gate intact RBCs. These
RBCs can be used as targeted drug
delivery
In liver cancer tumors, in Gaucher’s disease, in case of
iron overload
Magnetic RBCs04/28/1604/28/16 Sagar SavaleSagar Savale

2828
Neutrophills
Neutrophills are one of
the WBCs present inside the
blood.
Mainly in the pyrogenic diseases like acute arthritis,
ulcerative colitis

2929
Problems Associated With Targeted DrugProblems Associated With Targeted Drug
Delivery SystemDelivery System
 Rapid clearance of targeted systemsRapid clearance of targeted systems
 Immune reactions against i.v. administered carrier systemImmune reactions against i.v. administered carrier system
 Target tissue heterogeneityTarget tissue heterogeneity
 Problems of insufficient localization of targeted systems intoProblems of insufficient localization of targeted systems into
tumor cellstumor cells
 Down regulation & slugging of surface epitopesDown regulation & slugging of surface epitopes
 Diffusion & redistribution of released drug leading to non-Diffusion & redistribution of released drug leading to non-
specific accumulationspecific accumulation

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REFERENCESREFERENCES
 Banker G S, Rhodes T R, Modern Pharmaceutics, MarcelBanker G S, Rhodes T R, Modern Pharmaceutics, Marcel
Dekker, 4Dekker, 4thth
ed, 529-586ed, 529-586
 Shargel L, Wu-pong S, Andrew B, Applied BiopharmaceuticsShargel L, Wu-pong S, Andrew B, Applied Biopharmaceutics
& Pharmacokinetics, Mc Garw Hill, 567-573& Pharmacokinetics, Mc Garw Hill, 567-573
 Kulkarni J S, Pawar A P, Shedbalkar V P, BiopharmaceuticsKulkarni J S, Pawar A P, Shedbalkar V P, Biopharmaceutics
& Pharmacokinetics, 1& Pharmacokinetics, 1stst
ed, CBS publishers, 159-164ed, CBS publishers, 159-164
 Ali J, Khar R, Ahuja A, Textbook of Biopharmaceutics &Ali J, Khar R, Ahuja A, Textbook of Biopharmaceutics &
Pharmacokinetics,1Pharmacokinetics,1stst
ed, Birla Publication, 226-234ed, Birla Publication, 226-234

3131
 Vyas S P, Khar R K, Targeted & controlled Drug DeliveryVyas S P, Khar R K, Targeted & controlled Drug Delivery
Novel Carrier Systems, CBS Publishers, 1Novel Carrier Systems, CBS Publishers, 1stst
ed;2004, 38-80ed;2004, 38-80
 Brahmankar D M, Jaiswal S B, Biopharmaceutics &Brahmankar D M, Jaiswal S B, Biopharmaceutics &
Pharmacokinetics A Treatise, Vallabh Prakashan, 1Pharmacokinetics A Treatise, Vallabh Prakashan, 1stst
ed;2006,336-340ed;2006,336-340
 Shaji J, Chhatwani D, Liposomes: Biomedicines of TheShaji J, Chhatwani D, Liposomes: Biomedicines of The
Future, ijper, Vol 41 (3), Jul-sep-2007,180-194Future, ijper, Vol 41 (3), Jul-sep-2007,180-194
 http://www.pharmainfo.net/reviews/niosome-unique-drug-http://www.pharmainfo.net/reviews/niosome-unique-drug-
delivery-systemdelivery-system
 www.pathology.unibe.ch/.../virosomes/drug_tg.htmwww.pathology.unibe.ch/.../virosomes/drug_tg.htm

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