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Site agent or medicament is selectively targeted or delivered

Site specific drug delivery system is a
special form of drug delivery system where the pharmacologically active agent
or medicament is selectively targeted or delivered only to its site of action
or absorption and not to the non-target organs or tissues or cells. The ability
of a drug molecule to accumulate in the target organ or tissue selectively such
that the concentration of the drug at the disease site is high, while its
concentration in non-target organs and tissues is low, preferably, below
certain minimal level so as to prevent any toxic effect dictates the efficiency
of drug targeting. Thus, drug targeting can overcome the non-specific toxic
effect of conventional drug delivery. This may also reduce the amount of drug
required to dose. Targeting of drugs to special cells and tissues of the body
without their becoming a part of systemic circulation is a very novel concept.
If a drug can be administered in a form such that it reaches the receptor sites
in sufficient concentration without disturbing in extraneous tissue cells. Such
products are prepared by considering-Specific properties of target cells, Nature
of markers or transport carriers or vehicles, which convey drug to specific
receptors, Ligands and physically modulated components 1. The concept of drug
targeting is not new. It was first mentioned by Paul Ehrlich when he suggested
the hypothetical “magic bullet” as an entity consisting of two components — the
first one should recognize and bind the target, while the second should provide
a therapeutic action in this target. Drug targeting, thus, includes a
coordinated behavior of three components – drug, targeting moiety and
pharmaceutical carrier 2. Drug
instability, low absorption, short half-life, large volume of distribution, low
specificity, low therapeutic index are some of the parameters that specifies
the need for drug targeting.




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·   It
should be nontoxic, biodegradable, biocompatible and physicochemical stable invivo
and invitro

Confine drug delivery to target cells or
tissue or organ or should have uniform capillary distribution.

Predictable and Controllable and rate of
drug release.

Drug release should not influence the
drug delivery.

Therapeutic amount of drug release.

Minimal drug leakage during transit

Carrier used should be biodegradable or
readily eliminated from the body without any problem and no carrier should
induce modulation of diseased state.

Its preparation should be easy or
reasonably simple, reproductive and cost effective.


approaches for targeted drug delivery systems involve 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 bioenvironmental zone to ensure a programmed and desirable biodistribution.
Passive Targeting, Inverse Targeting, Active Targeting, Ligand- mediated
Targeting, Physical Targeting, Dual Targeting, Double Targeting, Combination
Targeting are some of the newer aspects used to maximize the benefits of
targeted drug delivery systems.

Targeting by route of administration:
selection of the route of administration for nanoparticles can be critical for
successful targeting. One important distinction is the direct administration to
a physically local region of tissue versus indirect delivery via the systemic circulation.
For example, the oral administration of particles is an attractive approach for
direct targeting of intestinal mucosal sites, such as gut-associated lymphoid
tissue (GALT) for the delivery of protein antigens for vaccination. At the same
time, oral administration has the potential for sustained noninvasive drug
delivery via the systemic circulation.

Passive Targeting: Passive
targeting refers to the accumulation of drug or drug-carrier system at a
particular site due to physicochemical or pharmacological factors. It utilizes
the natural course of biodistribution of the carrier. Drug or drug carrier
nanosystems can be passively targeted making use of the patho-physiological and
anatomical opportunities.eg includes targeting of anti-malarial drugs for
treatment of leishmiansis, brucellosis, candiadsis. The colloids which are
taken up by the reticulo-endothelial system (RES) can be ideal vectors for
passive targeting of drugs to RES predominant compartments. Passive capture of
colloidal carriers by macrophages offers therapeutic opportunities for the
delivery of anti-infective agents.

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. This approach leads to saturation of RES and suppression of defense
mechanism. This type of targeting is a effective approach to target drug(s) to
non-RES organs. Other strategies include modification and defined manipulation
of the size, surface charge, composition, surface rigidity & hydrophilicity
characteristics of carriers for desirable biofate.

Active Targeting:  Active targeting
employs specific modification of drug/drug carrier nano systems with active
agents having selective affinity for recognizing and interacting with a
specific cell, tissue or organ in the body. Direct coupling of drugs to
targeting ligand, restricts the coupling capacity to a few drug molecules. In
contrast, coupling of drug carrier nanosystems to ligands allows import of
thousands of drug molecules by means of one receptor targeted ligand. Example
of active targeting is use of monoclonal antibody the treatment of cancer. 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 approach can be further classified into three different levels
of targeting.

First order targeting it refers to restricted distribution of the drug
carrier systems to the capillary bed of a predetermined target site, organ or
tissue. Example includes compartmental targeting in lymphatics, peritoneal
cavity, plural cavity, cerebral ventricles, eyes, joints, etc.

Second order targeting selective delivery of drugs to specific cell
types such as tumour cells and not to the normal cells is referred as second
order targeting .Eg include selective drug delivery to kupffer cells in the

Third order targeting defined as drug delivery specifically to the
intracellular site of targeted cells.eg include receptor based ligand mediated
entry of a drug complex into a cell by endocytosis.

Ligand-mediated Targeting:

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
for example, Folate receptor; over expression of folate receptor. Transferrin
receptor; Over expression of transferrin receptor, Galactosamine receptors; on
hepatocytes Hepatoma.

Physical Targeting:

the characteristics of environmental changes like pH, temperature, light
intensity, electric field, and ionic strength the drug targeting can be
achieved. This approach is found exceptional for tumor targeting as well as
cytosolic delivery of entrapped drug or genetic material.

Dual Targeting:

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:
(Spatial Control, Temporal Control, Double Targeting)

temporal and spatial methodologies are combined to target a carrier system,
then targeting may be called double targeting. Spatial placement relates to targeting
drugs to specific organs tissues, cells or even subs cellular compartment, whereas
temporal delivery refers to controlling the rate of drug delivery at the target

Combination Targeting:

targeting systems are equipped with carriers, polymers and homing devices of
molecular specificity that could provide a direct approach to target site.


important entity required for successful transportation of the loaded drug.

Drug vectors which, transport and retain drug; deliver it within or in the
vicinity of target.

Do so through an inherent characteristic or acquired through structural

of ideal drug carriers:

It must be able to cross anatomical barriers and in case of tumour chemotherapy
tumour vasculature.

It must be recognized specifically and selectively by the target cells and must
maintain the specificity of the surface ligands.

linkage of the drug and the directing unit (ligand) should be stable in plasma,
interstitial and other bio-fluids.

Carrier should be non-toxic, non-immunogenic and biodegradable particulate or

After recognition and internalization, the carrier system should release the
drug moiety inside the target organs, tissues or cells.


can be categorized into local targeting and systemic targeting. In locally
targeted systems, such systems are non-invasive in nature and the prime goal of
the locally targeted therapies are to deliver the drug at the local site for
the management of local pathologies (such as IBD, inflammation, ulceritis,
colon cancer, gastritis, stomach cancer etc.). Local targeted systems encompass
colon specific targeted systems (pH sensitive, time dependent, combined pH and
time dependent, microbially triggered systems, coated systems, prodrug
approaches), Gastroretentive systems, buccal adhesive systems etc. However, In
case of systemic targeting, delivery of such therapeutic systems occurs through
the invasive route such as intravenous administration of nanotechnological
systems (liposomes, niosomes, solid lipid nanoparticles (SLN’s), nanocrystals,
dendrimers). Such systems deliver the drug via systemic circulation after the distribution
in the body. The major limitations of such systems are due to the adverse
effects of the drugs in the non-specific tissues. Some of the carriers that are
used to achieve these targeting are liposomes, monoclonal antibodies and fragments,
modified (Plasma) proteins, soluble polymers, lipoproteins, microspheres and nanoparticles,
polymeric micelles, cellular carriers are introduced here.


are small vesicles composed of unilamellar or multilamellar phospholipid
bilayers surrounding one or several aqueous compartments. Charge, lipid
composition and size (ranging from 20 to 10 000 nm) of liposomes can be varied
and these variations strongly affect their behaviour in vivo. Many liposome
formulations are rapidly taken up by macrophages.They are exploited either for
macrophage-specific delivery of drugs or for passive drug targeting, allowing
slow release of the drug over time from these cells into the general
circulation. Cationic liposomes and lipoplexes have been extensively
investigated for their application in non-viral vector mediated gene therapy.
The use of molecules such as polyethylene glycol (PEG) to prevent liposome
recognition by phagocytic cells led to the development of so called ‘stealth’
liposomes with longer circulation times and increased distribution to
peripheral tissues in the body. Although liposomes do not easily extravasate
from the systemic circulation into the tissues, enhanced vascular permeability
during an inflammatory response or pro-angiogenic conditions in tumours can
favour local accumulation. Another approach is the design of target sensitive
liposomes or fusogenic liposomes that become destabilized after binding and/or
internalization to/into the target cells.


are synthetic, unimolecular, branched nanostructures (approx. 20 nm in size) comprising
a core or focal point, multiple branched layers of repeated units and high
density  function terminal group. The
functional group regulates the biocompatibility and physical, chemical
properties of dendrimers. The molecular structure of dendrimers makes it
possible for them to carry different drugs. The drugs may either be
encapsulated in the core via hydrogen bonding, hydrophobic interaction or
chemical bonding or these can be adsorbed via covalent bonding on the terminal

Monoclonal Antibodies and

development of monoclonal antibodies by Köhler and Milstein in 1975 passed the
way to antibody therapy for disease. In the last 25 years, the number of
pre-clinical and clinical studies with monoclonal antibodies and derivatives
thereof have greatly increased. The majority of strategies based on antigen
recognition by antibodies have been developed for cancer therapy. These
strategies are mostly aimed at tumour associated antigens being present on
normal cells but over- expressed by tumour cells. More recently, antibodies
against other molecules have been developed for clinical application. Examples
are anti-TNF? antibodies for treatment of chronic inflammatory diseases and
anti-VEGF (vascular endothelial growth factor) antibodies which inhibit new
blood vessel formation or angiogenesis. The advent of recombinant DNA
technology led to the development of antibodies and fragments that are tailored
for optimal behaviour in vivo. Humanized and chimeric antibodies can be
constructed to circumvent the human anti-mouse antibody response elicited by
mouse antibody treatment of patients, which severely hampers the application of
these powerful molecules 4-6.

Modified (Plasma) Proteins:

plasma proteins are attractive carriers for drug targeting as they are soluble
molecules  with a relatively small
molecular weight. They can easily be modified by covalent attachment of
peptides , sugars , and other ligands, as well as drugs of interest.
Particularly in the case of liver cell targeting, quite extensive modifications
of protein backbones such as albumins have been carried out.

Soluble Polymers:

synthetic polymers have been widely employed as versatile drug carrier systems.
Polymer chemistry allows the development of tailor made conjugates in which
target moieties as well as drugs are introduced into the carrier molecule. In
the case of enhanced permeability retention in e.g. tumour vasculature, the
introduction of drugs into the polymer may suffice.As non-specific  adherence to cells is an undesirable
property, excessive charge or hydrophobicity should be avoided in the design of
polymeric carriers. For cancer therapy, the well established
N(-2-hydroxypropyl)methacrylamide (HMPA) polymers have been extensively


lipid particles such as LDL and HDL containing a lipid and apoprotein moiety
can be seen as ‘natural targeted liposomes’. The lipid core can be used to
incorporate lipophilic drugs or lipophilic pro-drugs, covalent binding of the
drug to the carrier is not necessary here. The apolipoprotein moiety of these
particles can be glycosylated or modified with other (receptor) targeting
ligands. Furthermore, modifications at the level of glycolipid incorporation
can be employed to introduce targeting moieties. As with the liposomes, the
size and charge of the particles determine their behaviour in vivo. Large particles
will not easily pass the endothelial barrier of organs containing blood vessels
with a continuous endothelial cell lining. The majority of the research on the
use of LDL and HDL particles has been devoted to the targeting of drugs to the

Microspheres and Nanoparticles:

and nanoparticles often consist of biocompatible polymers and belong either to
the soluble or the particle type carriers. Besides the aforementioned HPMA
polymeric backbone, carriers have also been prepared using dextrans, sepharose
or poly-L-lysine as the main carrier body. More recently alginate nanoparticles
have been described for the targeting of antisense oligonucleotides . As with
other polymeric carrier systems, the backbone can be modified with e.g. sugar
molecules or antibody fragments to introduce cellular specificity.
Nanoparticles are smaller (0.2–0.5 ?m) than microspheres (30–200 ?m) and may
have a maller drug loading capacity than the soluble polymers. Formulation of
drugs into the nanoparticles can occur at the surface of the particles and at
the inner core, depending on the physicochemical characteristics of the drug.
The site of drug incorporation significantly affects its release rate from the
particle. After systemic administration they quickly distribute to and
subsequently become internalized by the cells of the phagocytic system. Even
coating of these carriers with PEG does not completely divert them from
distribution to the phagocytes in liver and spleen. Consequently, intracellular
infections in Kupffer cells and other macrophages are considered a useful
target for these systems. Besides parenteral application of microspheres and
nanoparticles for cell selective delivery of drugs, they have more recently
been studied for their application in oral delivery of peptides and

Polymeric Micelles:

micelles are characterized by a core-shell structure. They have a di-block
structure with a hydrophilic shell and a hydrophobic core. The hydrophobic core
generally consists of a biodegradable polymer that serves as a reservoir for an
insoluble drug. Non- or poorly biodegradable polymers can be used, as long as
they are not toxic to cells and can be renally secreted. If a water-soluble
polymeric core is used, it is rendered hydrophobic by chemical conjugation with
a hydrophobic drug. The viscosity of the micellar core may influence the
physical stability of the micelles as well as drug release. The
bio-distribution of the micelle is mainly dictated by the nature of the shell
which is also responsible for micelle stabilization and interactions with
plasma proteins and cell membranes. The micelles can contain functional groups
at their surface for conjugation with a targeting moiety. Polymeric micelles
are mostly small (10–100 nm) in size and drugs can be incorporated by chemical
conjugation or physical entrapment. For efficient delivery activity, they
should maintain their integrity for a sufficient amount of time after injection
into the body. Most of the experience with polymeric micelles has been obtained
in the field of passive targeting of anticancer drugs to tumors.

Cellular Carriers:

carriers may have the advantage of their natural biocompatibility. However,
they will encounter endothelial barriers and can rather easily invoke an
immunological response. Most of the approaches on cellular carriers have been
applied to the field of cancer therapy. Antigen specific cytotoxic T
lymphocytes have been studied as vehicles to deliver immunotoxins to cancer
cells in vivo.



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