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What is drug targeting
The therapeutic response of a drug depends upon the interaction of drug
molecules with cell on cell membrane related biological events at receptor
sites in concentration dependent manner.
Selective and effective localization of the pharmacologically-active
moiety at preidentified target(s) in therapeutic concentration, while
restricting its access to non-target(s) normal cellular linings, thus
minimizing toxic effects and maximizing the therapeutic index.
Reasons for Drug Targeting
Large volume of distribution
Low therapeutic index
Common Approaches of Targeted Drug
Controlling the distribution of drug by incorporating it in a carrier system
Altering the structure of the drug at molecular level
Controlling the input of the drug into bioenvironment to ensure a programmed
and desirable biodistribution
Properties of Ideal Targeted Drug Deliver
Nontoxic, biocompatible and physicochemical stable in vivo and invitro.
Restrict drug distribution to target cells or tissue or organ or should have
uniform capillary distribution.
Controllable and predictable rate of drug release.
Minimal drug leakage during transit.
Carrier used must be biodegradable or readily eliminated from the body
without any problem.
Its preparation should be easy or reasonably simple, reproductive and
Important Properties Influencing
Drug Concentration, Particulate location and Distribution
Molecular Weight, Physiochemical properties
Drug Carrier Interaction
Carrier Type, Amount of Excipients, Surface Characteristics, size,
PH, Polarity, Ionic Strength, Surface Tension, Viscosity,
Temperature, Enzyme, Electric Field
It utilizes the natural course of biodistribution of the carrier.
The colloids which are taken up by the reticulo-endothelial system
(RES) can be ideal vectors for passive targeting of drugs to RES
Passive capture of colloidal carriers by macrophages offers
therapeutic opportunities for the delivery of anti-infective agents.
It is a result of the avoidance of passive uptake of colloidal carriers
by the RES.
It can be achieved by suppressing the function of RES by pre-
junction of a large amount of blank colloidal carriers or
macromolecules like dextran sulphate.
Other strategies include modification and defined manipulation of
the size, surface charge, composition, surface rigidity &
hydrophilicity characteristics of carriers for desirable biofate.
It involves the modification or functionalization of the drug carriers
so that the contents are delivered exclusively to the site
corresponding to which the carrier is architected.
Active targeting can be affected at different levels –
1. First order targeting (organ compartmentalization)
2. Second order targeting (cellular targeting)
3. Third order targeting (intercellular organelles targeting)
Restricted distribution of the drug
carrier system to the capillary bed
of a pre-determined target site,
organ or tissue.
The selective drug delivery to a
specific cell type such as tumor
cells (& not to the normal cells)
Drug delivery specifically to the
intracellular organelles of the target
Ligands are carrier surface group(s), which can selectively direct the
carrier to the pre-specified site(s) housing the appropriate receptor
units to serve as ‘homimg device’ to the carrier/drug.
Most of the carrier systems are colloidal in nature & can be specifically
functionalized using various biologically-relevant molecular ligands
including antibodies, polypeptides, oligosaccharides, viral proteins &
The ligands confer recognition & specificity upon drug carrier & endow
them with an ability to approach the respective target selectivity &
deliver the drug
Examples of Ligands
Ligands Target Tumor target
Folate Folate receptor Overexpression of folate
Transferrin Transferrin receptor Overexpression of transferrin
Galactosamine Galactosamine receptors
Characteristics of environment changes like pH,
temperature, light intensity, electric field, and
This approach was found exceptional for tumor
targeting as well as cytosolic delivery of
entrapped drug or genetic material.
Physical Targeting Formulation System Mechanism for Drug
Heat Liposome Change in Permeability
Magnetic Field can retard
fluid Flow of particles.
Ultrasound Polymers Change in Permeability
Electrical Pulse Gels Change in Permeability
Light Photo responsive Hydro
gels Containing Azo-
Change in Diffusion
Channels, Activated by
In this targeting approach, carrier molecule,
itself have their own therapeutic activity and
thus increase the therapeutic effect of drug.
A carrier molecule having its own antiviral
activity can be loaded with antiviral drug
and for the synergistic effect of drug
Targeting drugs to specific
organs, tissues, cells or even
sub cellular compartment
Controlling the rate of drug
delivery to target site
These targeting systems are equipped with
carriers, polymers and homing devices of
molecular specificity that could provide a direct
approach to target site.
Components for Drug
• Specific organ or a cell or group of cells,
which in chronic or acute condition need
• Special molecules or system essentially
required for effective transportation of
loaded drug up to the pre selected sites
Platform Targeting ligand Drug Stage
PEGylated liposome F(ab ¢ ) 2 fragment of human
Doxorubicin Phase I
NGPE liposome Transferrin Oxaliplatin Phase I/II
Liposome Single-chain antibody fragment p53 gene Phase I
PEGylated PLGA NP Peptide Docetaxel Phase I
Applications of Resealed Erythrocytes
Diseases Name of Drug(s) Purpose
Liver tumors Bleomycin, Adriamycin,
Targeting to hepatic carcinoma
Parasitic diseases Pentamidine loaded, IgG
Macrophage containing leshmania,
liver targeting of primaquine
Other Approaches of Drug
1. Magnetically modulated drug targeting
2. Monoclonal antibody based targeted drug delivery
Magnetically modulated drug targeti
An interesting approach of targeting carrier system has been to
magnetize the carrier so that these particles can be retained at or
guided to the target site by the application of an external magnetic
field of appropriate strength.
Retention of magnetic carrier at the target site will delay
reticuloendothelial clearance, facilitate extravasation & thus prolong
the systemic action of drug.
( liver/spleen/ bone
Principle of Magnetic Drug Targering
Therapeutic responses in target organs at
only 1/10th of the free drug dose.
Controlled drug release within target
tissues for intervals of 30 min to 30 h, as
Avoidance of acute drug toxicity directed
against endothelium & normal
Adaptable to any part of the body.
It is expensive
It needs miniaturized specialized magnet
for targeting, advanced techniques for
monitoring, & trained personnel to
Magnet must have relatively constant
gradients, in order to avoid focal
overdosing with toxic drugs.
A large fraction (40 – 60 %) of the
magnetite, which is entrapped in the
carriers, may be deposited permanently in
Magnetic Drug Targeting
Magnetic resealed erythrocytes
Magnetic delivery systems
Monoclonal antibody based targeted
The recognition site for the monoclonal antibody should be located on the
surface of the cell.
The antibodies should have sufficient tumor tissue specificity.
The extent of localization of the antibody at the target site. Biodistribution of
the drug–antibody conjugate in the body relative to that of the parent
Stability of the drug–antibody conjugates in blood.
The host toxicity of the conjugate. The conjugate must be biodegradable and
non-immunogenic. Drugs should be released upon interaction between the
carrier molecule and the cell.
Approved Monoclonal Antibodies
Antibody Target Indication
Trastuzumab HER2 Breast Cancer
Bevacizumab VEGF Lung Cancer
Cetuximab EGFR Colorectal carcinoma
Panitumumab EGFR Colorectal carcinoma
The possibility of raising monoclonal antibodies against cell surface markers allow
tumor site targeting discretely.
Many cytotoxic drugs have been conjugated with monoclonal antibodies. These
conjugates have been used to study drug localization in tumors and modulation of
drug toxicity. They have been found to be useful in the management of various
types of carcinomas.
The conjugation of antibodies developed against a specific tumor determinant with
another recognition component provides them dual specificity to target the drug or
The approach has been mainly suggested for immunotherapy of
immunological disorders especially those related to lack of MHC restricted
recognition by immune effectors cells.
Bispecific antibodies against tumor endothelium & tissue factors (the
initiator of the intrinsic pathway of blood conjugation) have also been
proposed for synergistic effects.
These are conjugates of antibody (Mab & Fab) fragments & toxins, in which cell
binding moieties of the toxins are replaced with specific binding chain of the
The naturally occurring toxins used have very specific biological pathways in
producing their cytocidal effects.
The cytotoxic activity of the toxin that is conjugated to the antibody does not
involve any other secondary agent(s).
Theoretically, immunotoxins should not bind to non-malignant cells, and even if
they do bind, the internalization of the agent should not be sufficient to neutralize
the therapeutic effect.
Immunotoxins under clinical trials
Immunotoxin Target antigen Target malignancy Stage
LMB-2 CD25 Leukemia Phase II
SSIP Mesothelin Pancreatic cancers Phase I
UCHT1 CD3ε Leukemia Phase II
RFT5-dgA CD25 Melanoma Phase I/II
Prodrug is an inactive pharmacological moiety developed to optimize
pharmacokinetics or site selectivity of a drug.
Since the prodrug has low cytotoxicity prior to its activation, it has very few
chances of its encounter with healthy cells.
In general, selective enzyme expression, hypoxia, & low extracellular pH at tumor
site is utilized for prodrug activation.
ADEPT has been investigated in the treatment of tumors, where an antibody-
enzyme conjugate is administered systemically, where it clears from the circulation
& localizes to its target by virtue of the antibody binding to its specific biomarker
on the tumor.
Enzymes & prodrugs used for ADEPT
Enzymes Prodrug Reactivity
Alkaline Phosphatase Doxorubicin Hydrolysis of Phosphate Group
β lactamase Mitomycin Cleavage of Lactam Ring
Schematic representation of ADEPT
Targeted drug delivery essentially implies for selective and effective
localization of the pharmacologically-active moiety at preidentified
target(s) in therapeutic concentration,
Various strategies such as active targeting, passive targeting etc. can
be applied to achieve efficient drug targeting.
The targeted delivery is of great importance in cancer chemotherapy
which always demands for reduction in adverse effect.
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