TARGETED DRUG DELIVERY

With the advancement of the pharmaceutical sciences, the industry has certainly observed discovery of
several new drug molecules ranging from small molecule drugs to macromolecules like proteins and
peptides; but the ultimate goal of achieving disease- free conditions in the patients is often left hanging
due to several hurdles relating to physicochemical and molecular intricacies of the “free” drugs and
unapproachability and under-dosing of most of the biological/pathological targets.

To improve on these situations drug delivery systems (DDS) are employed which could either be a
formulation or a device that facilitate the administration of a drug to the body whilst improving its
pharmacokinetic and biodistribution profiles and the efficacy and safety of the whole treatment. Targeting
the drugs (and DDS) involves the improvement of the specificity of the system towards the
pharmacologically relevant target in the body
 FUNCTIONS OF TDDS
A TDDS can be broadly understood as a system that carries out the
following functions:
• Facilitate the therapeutic substance to reach the site of action from the site of
administration where the target site can be organ, tissue, cell or even specific
cell organelles.
• Release the therapeutic payload in its active form in/around the target site
presenting effective therapeutic levels at the site of action.
• Protect the drug/gene from the detrimental effects of environmental factors
such as pH, enzymes, etc.
• Avoid toxicity or adverse reactions of the drug/gene on nonspecific normal
cells and facilitating administration of lower doses to achieve
therapeutic/diagnostic benefits.
Research in the field of targeted drug delivery has given several options of
carrying out the above functions:

• Direct targeting to site of action, e.g., topical applications for skin diseases.
• Use of external stimuli, e.g., ultrasound .
• Chemical modification of the drug to make its physicochemical properties ideal for
the delivery which includes prodrug approach of attaching a promoiety to the drug.
• Use of nanocarriers like liposomes, polymeric micelles, polymeric nanoparticles,
solid lipid nanoparticles which can be functionalized further with attachment of
targeting ligands, antibodies.
 PROPERTIES OF AN IDEAL TDDS
An efficient TDDS ideally should possess the following properties:
• The drug-conjugate/drug-carrier should reach the intended site of action (organ/
tissue/cell/cell organelles) with minimal nonspecific accumulations.
• The chemical conjugation or physical encapsulation of the drug/gene with the
targeting ligands or carriers should not inactivate or alter the drug/gene action on the
intended site of action; the TDDS should be able to protect the drug from
environmental factors such as enzymatic degradation till they reach the target.
• The chemical conjugation or physical encapsulation of the drug/gene with the
targeting ligands or carriers should not inactivate or alter the ligand or carrier activity
and function to reach the intended site of action.
TARGETED DRUG DELIVERY: GENERAL CONCEPTS
• Targeted drug delivery at the site of action can be carried out by direct techniques usually involving
invasiveness:
• Direct injection,
• Catheter,
• Gene-gun
• Though these systems show direct delivery, invasiveness is not patient convenient and expensive to carry out
in many cases. As a result, efforts are put into developing TDDS which involve chemical, physical and
biological modifications with or without the use of carriers
• Changes done to improve targeting the drug include study of structure activity relationships to improve the
physicochemical properties for targeting.
• Small- molecule drugs intended for brain delivery unable to penetrate the blood–brain barrier (BBB) may be
made more lipophilic to aid penetration through the BBB, provided they have small size.
• Prodrugs can be made to improve the pharmacokinetics of the drugs.
• Small molecule drugs are chemically modified by attaching “promoeities” rendered pharmacologically
inactive and are metabolically activated in vivo into active drugs only after reaching their intended target
• Drugs may be conjugated with antibodies, peptides, aptamers, folic acid, etc. to generate targeted prodrugs
• On the other hand, the drugs can be incorporated into nanocarriers or nanosystems.
• These include drug carrier systems like
• Liposomes,
• Polymeric micelles,
• Polymeric nanoparticles,
• Polymer–drug conjugates,
• Nanogels,
• Carbon nanotubes, etc.
• The nanosystems are a very efficient way to deliver the drugs or genes.
• The major advantage of using such systems is that the pharmacokinetic behavior of the drug-
loaded nanocarriers depends on the nanosystems rather than the drugs or genes, which makes it
easy to control with the help of further targeting
• Such drugs/drug carrier systems depend on a few modes of targeting which are broadly classified
into passive and active targeting.
 PASSIVE (PHYSIOLOGY-BASED) TARGETING
Passive targeting is present naturally in the
human body
Hormones, neurotransmitters, growth factors, etc.
have a natural tendency to go and target the receptors
at their sites of action, e.g., insulin and insulin
receptors. This concept can be applied to the drugs
too.
The accrual of drugs/drug-carrier systems at the
intended site of action by the action of
physicochemical and physiological factors is
passive targeting
• Certain tissues under diseased conditions present opportunities in terms of
modified physiologies which can be exploited by passively targeting
nanocarriers. A presence of leaky vasculature with large gaps in the blood
vessel’s epithelial layers has been observed in cases of inflamed tissues in
inflammatory bowel disease and inflammatory rheumatoid arthritis and in
tumor tissues which make it possible to passively target the administered
nanocarriers of appropriate sizes to extravasate into the target tissue.
• Although the tumor tissue has limited lymphatic drainage and the
inflammatory tissues have a functioning lymphatic drainage, the passive
targeting can still benefit the inflammatory diseases.
• Accumulation of nanocarriers is also observed in the liver due to large
fenestrations in it and this can be used for liver targeting in liver diseases.
• This phenomenon wherein the nanocarriers accumulate into the diseased
tissues because of loose fenestrations and/or poorly formed lymphatic drainage
is termed as enhanced permeability and retention (EPR) effect
• The nanocarriers are largely affected to clearance by the reticulo-endothelial system (RES)
comprising of macrophages and mononuclear phagocytes.
• This fact can be used to passively target the macrophages and even lymph nodes and spleen
to treat infections that affect the RES (e.g., leishmaniasis and malaria).
• Often modifications (e.g., attachment of polyethylene glycol; PEG) are made on
nanocarriers to make them long-circulating, avoiding the RES and granting them time to
accumulate at target sites in high amounts (long-circulating nanocarriers).
• Passive targeting also benefits from the presence of internal stimuli, such as pH difference
(e.g., low pH in tumor microenvironment, redox systems (e.g., exploiting high glutathione
in cancer, etc. in the diseased tissues.
• Stimuli- sensitive drug targeting systems will be spurred by such stimuli to release the drug
only at the target site and spare the normal tissues. Such stimuli-responsive systems have
been extensively studied
 INVERSE TARGETING
• 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.
 ACTIVE TARGETING
• Appropriate modifications and functionalization on the drugs or drug carriers afford them
affinity towards specific receptors/markers on cells, tissues or organs
• Factors such as the disease, the intended target organ, and a larger presence of targetable
components on the target organ/cell (e.g., transferrin receptors in tumor) than in normal
cells are taken into consideration while deciding on the targeting moiety to be attached to
the therapeutic substances
• Modifications on the drugs or drug carriers can involve the use of ligands such as
peptides, antibodies, sugars, lectins, etc.
• Thus, on administration to the body, the targeting moieties will enable the drug/drug-
carriers to efficiently reach only the intended sites of action and avoid nonspecific
accumulations and related side effects
 ACTIVE TARGETING
 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)

 ACTIVE TARGETING
Restricted distribution of the drug
First Order carrier system to the capillary bed
Targeting of a pre-determined target site,
organ or tissue.
Second
Order
Targetin The selective drug delivery to a
g specific cell type such as tumor
cells (& not to the normal cells)

Third
Order
Drug delivery specifically to the
Targeting intracellular organelles of the target
cells
Strategies for Drug Targeting
 LIGAND-MEDIATED TARGETING
• 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 & fusogenic residues.

• 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
Ligand Target Tumor target
s Folate receptor Overexpression of
Folate folate receptor
Transferrin receptor Overexpression of
transferrin
Transfe
Galactosamine Galactosamine receptors receptor
rrin
on hepatocytes Hepatoma
 PHYSICAL TARGETING
Characteristics of environment changes like;
• pH,
• temperature,
• light intensity,
• electric field,
• ionic strength
This approach was found exceptional for tumor targeting as well as
cytosolic delivery of entrapped drug or genetic material
 PHYSICAL TARGETING
Physical Targeting Formulation System Mechanism for Drug
Delivery

Heat Liposome Change in Permeability

Magnetic Magnetically Responsive Magnetic Field can retard

Microspheres Containing fluid Flow of particles.
Modulation
Iron oxide
Ultrasound Polymers Change in Permeability

Electrical Pulse Gels Change in Permeability

Light Photo responsive Hydro Change in Diffusion

gels Containing Azo- Channels, Activated by
Derivatives Specific Wavelength
 Dual Targeting
• 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 conjugate.
 DOUBLE TARGETING

Targeting drugs to specific

organs, tissues, cells or even Spatial
sub cellular compartment Control

Double
Targeting
Controlling the rate of drug Temporal
delivery to target site Control
COMPONENTS FOR DRUG TARGETING

• Specific organ or a cell or group of cells,

which in chronic or acute condition
Target need
treatment.

• Special molecules or system essentially

required for effective transportation
Carrier of loaded drug up to the pre selected
sites
Targeting Mediated by External Stimuli
External stimulus, such as magnetic fields and ultrasound, acting on nanocarriers, are employed to
perform imaging, to target and release drugs from the nanocarriers at the intended site of action. The
benefits of using this mode of active targeting are:
• Real-time targeting,
• Targeting deep-seated tissues,
• Simultaneous imaging and therapy.
The approach can also combine different external stimuli, for example, ultrasound and magneticfield,
for enhanced targeting and efficiency.
The use of magnetic nanoparticles (MNP) as imaging agents for magnetic resonance imaging,
magnetic drug targeting and hyperthermia treatment is well explored in the field of targeted drug
delivery.
• The MNP can be either metallic or bimetallic or superparamagnetic iron oxide nanoparticles
(SPION); among them SPION are widely studied for biomedical applications because of nontoxic
nature, ability to be functionalized with different targeting coatings and can encapsulate drugs in
reasonable quantity. Optimizing the MNP as well as the external magnet is of prime importance
because on application of magneticfield, they must be able to generate enough magnetic moments
and magnetic gradient that the MNP can overcome the force of the blood-flow (rating from 0.05–
50 cm/s) depending on the target area
• The MNP have found several uses in
• Thrombolytic therapy
• Intravascular imaging and
• Cardiovascular diseases
• Tumor imaging and treatment
• Delivery across the blood–brain barrier
• Ultrasound has been used previously for contrast imaging, and it is
explored at length for use in drug delivery. Ultrasound mediated
targeting can lead to disruption of the drug-loaded carriers
(microbubbles, micelles, etc.) causing drug release; exact
mechanism of release is still under study. Furthermore, ultrasound
focusing has also been found to cause reversible disruptions in
the intravascular endothelial layers creating pores for the drug to
enter the extracellular space of the target tissue. This occurrence
was also observed with blood–brain barrier/blood–tumor barrier
• Another benefit of using the ultrasound-mediated delivery is in targeted
hyperthermia when combined with temperature-sensitive nanocarriers. The
generation of hyperthermia can prove cytotoxic for nearby tissues and in case of
tumor treatment this is highly beneficial; the hyperthermia will kill tumor
periphery cells and open the way for simultaneously administered drugs to enter
the core of tumor tissue for enhanced killing. Studies with ultrasound therapy find
applications in tumor imaging, tumor treatment, thrombosis, cardiovascular
diseases.
• This mode of targeting also gives the opportunity to image and trigger release of
the drug at the same time, and also to combine it with magnetic field
applications for enhanced benefits.
 ANTIBODY-DIRECTED ENZYME PRODRUG THERAPY (ADEPT)
• This approach is a two-step approach:
• An activating enzyme is specifically delivered to intended site of action with a targeting antibody
(e.g., Tumor-specific antibody, anti-tag-72)
• A subsequent administration of substrate prodrug.
The advantage with such a system is a single enzyme at the target site can activate multiple prodrugs
and increase the load at the target site.
A 3-phase ADEPT was performed in human ovarian carcinoma xenografts in mice. First, an
enzyme–antibody complex—AB57-F(ab′) 2- CPG2—was allowed to localize in the tumor
followed by a wash step of removing blood CPG2 by anti-CPG2 antibody administration to
avoid nonspecifi c activation of the prodrug. Lastly, a benzoic acid mustard-derived prodrug
was injected leading to tumor growth delay
A modification of this approach is the gene-directed enzyme prodrug therapy (GDEPT). Here,
instead of antibody-targeted enzyme, a gene is targeted to the intended site where it transcribes and
translates to produce enzyme intracellularly which acts on the subsequently administered prodrug
 TARGETING IN GENE THERAPY
• The viruses have a unique ability to transfer their genes into cells. This
function can be utilized to deliver genes. The bottom line, though, is that
the viral vectors have to be modified to be devoid of virulent pathogenesis
and replicative genes. The commonly used viral vectors include
adenovirus, baculovirus, herpes simplex virus type 1 (HSV-1), etc.
• Utmost care has to be taken when designing these systems because the
viral vectors are notorious for adverse effects such as inflammatory and
immune responses, activation of latent infections, incorporation of
transgenes into the host genomes and permanent expression persistence
• Nonviral methods to target gene transfer are not proficient with
transfection efficiency but they are generally safer than the viral
vectors. Polymeric micelles, liposomes and other nanocarriers have
been studied to deliver the nucleic acids. Thus presented are the
classifications and the strategies of targeted drug/gene delivery
systems. The next few sections feature the benefits of TDDS in various
diseases.
Carriers

Nanoerythrocytes
Microspheres

Resealed Erythrocytes
Liposome
s

Quantum Dots
Nanoparticles
Dendrimers
 TARGETED NANOPARTICLES
Platform Targeting ligand Drug Stage

PEGylated liposome F(ab ¢ ) 2 fragment of Doxorubicin Phase I

human antibody GAH

NGPE liposome Transferrin Oxaliplatin Phase I/II

Liposome Single-chain antibody fragment p53 gene Phase I

PEGylated PLGA Peptide Docetaxel Phase

NP I