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Targeted drug delivery is a method of delivering medication to a patient in a
manner that increases the concentration of the medication in some parts of the
body relative to others.
• Provide therapeutic concentration of drugs at the site of action
• Reduce systemic toxicity
• Increase patient compliance
• This improves efficacy of the drug while reducing side effects.
Classification of Drug Targeting
Drug targeting has been classified into three types:
It refers to restricted distribution of the drug-carrier system to the capillary bed of a
predetermined target site, organ or tissue. Compartmental targeting in lymphatics*,
peritoneal cavity, cerebral ventricles, lungs, joints, eyes, etc.
The selective delivery of drugs to a specific cell type such as tumor cells and not to the
normal cells is referred as second order drug targeting. The selective drug delivery to
the Kupffer cells in the liver** exemplifies this approach.
The third order targeting is defined as drug delivery specifically to the intracellular site
of target cells. The receptor based ligand-mediated entry of drug complex into a cell by
endocytosis, lysosomal degradation of carrier followed by release of drug intra-
cellularly or gene delivery to nucleolus is an example for this approach.
Principal schemes of drug targeting currently investigated in various experimental and
clinical settings include:
• Direct application of the drug into the affected zone (organ, tissue)
• Passive accumulation of the drug through leaky vasculature (tumors, infarcts,
• ‘physical’ targeting based on abnormal pH and / or temperature in the target
zone, such as tumor or inﬂammation (pH- and temperature-sensitive drug
• Magnetic targeting of drugs attached to paramagnetic carriers under the action
of external magnetic field
• Use of vector molecules possessing high speciﬁc affinity toward the affected zone
The parameters determining the efficacy of drug targeting:
• Size of the target
• Blood flow through the target
• Number of binding sites for the targeted drug/ drug carrier within the
• Number and affinity of targeting moieties
Passive targeting approaches:
Pathophysiological factors – Inflammation, Infection, EPR effect
Physicochemical factors – Size, Molecular weight
Anatomical opportunities – Catheterization, Direct injection
Chemical approaches – Prodrugs, Chemical delivery systems
Active targeting approaches:
Carrier specificity can be enhanced, through surface functionalization with site-
directed ligands which bind or interact with specific tissues
Biochemical targets – Organs, Cellular, Organelles, Intracellular
Physical/External Stimuli – Ultrasound, Magnetic field
Main Approaches to Targeting:
Individual drug molecules chemically modified to target
particularly to the disease site.
Carrier – Based Systems:
Drug is first packaged non-covalently into a synthetic Carrier that
is then targeted to the disease site.
Drug Targeting: Prodrugs
Compounds that undergo biotransformation prior to exhibiting pharmacological
Chemically linking pro-moiety to form prodrug
Release of parent drug
Barrier is circumvented
6-Monoacetylmorphine (6-MAM) is a heroin metabolite which converts into active morphine
Prednisone, a synthetic cortico-steroid drug, is bioactivated by the liver into the active drug
Drug Targeting: Magnetic Drug Targeting
• Using magnetic nanoparticles (ferrofluids)
• Enhancing efficacy
• Minimum side effects
• Ferromagnetic element (e.g. an implant) is placed in a magnetic field, it becomes
Magnetic drug targeting is used to treat malignant tumors loco-regionally
without systemic toxicity.
Magnetic particles used as “carrier system” for a variety of anticancer agents,
e.g. radionuclides, cancer – specific antibodies, and genes
Drug Targeting: LIPOSOMES
These are vesicular concentric structures, range in size from a nanometer to several
micrometers, containing a phospholipids bilayer and are biocompatible, biodegradable and
Liposomes have generated a great interest because of their versatility and have played a
significant role in formulation of potent drugs to improve therapeutics. Enhanced safety and
efficacy have been achieved for a wide range of drug classes, including antitumor agents,
antiviral, antimicrobials, vaccines, gene therapeutics etc.
Transdermal drug delivery system is topically administered medicaments in the
form of patches that deliver drugs for systemic effects at a predetermined and
A transdermal drug delivery device, which may be of an active or a passive
design, is a device which provides an alternative route for administering
medication. These devices allow for pharmaceuticals to be delivered across the
Transdermal Approach Continuing:
In theory, transdermal patches work very simply. A drug is applied in a relatively high
dosage to the inside of a patch, which is worn on the skin for an extended period of time.
Through a diffusion process, the drug enters the bloodstream directly through the skin.
Since there is high concentration on the patch and low concentration in the blood, the
drug will keep diffusing into the blood for a long period of time, maintaining the
constant concentration of drug in the blood flow.
Drug Targeting: Brain targeted drug delivery system
The brain is a delicate organ, and evolution built very efficient ways to protect it. The
delivery of drugs to central nervous system (CNS) is a challenge in the treatment of
Drugs may be administered directly into the CNS or administered systematically (e.g.,
by intravenous injection) for targeted action in the CNS. The major challenge to CNS
drug delivery is the blood-brain barrier (BBB), which limits the access of drugs to the
Research related to the development of targeted drug delivery system is now a
day is highly preferred and facilitating field of pharmaceutical world. It has
crossed the infancy period and now touching height of growths from the
pharmacy point of view.
Targeted delivery of drugs, as the name suggests, is to assist the drug molecule to
reach preferably to the desired site. The inherent advantage of this technique has
been the reduction in dose & side effect of the drug.
Overall it may be concluded with the vast database of different studies, the
science of site specific or targeted delivery of these drugs has become wiser.
Manifestation of these strategies in clinical now seems possible in near future.
Transporters are those proteins that carry either endogenous compounds or
xenobiotics across biological membranes.
They can be classified into either efflux or uptake proteins, depending on the
direction of transport.
The extent of expression of genes coding for transport proteins can have a
profound effect on the bioavailability and pharmacokinetics of various drugs.
Additionally, genetic variation such as single-nucleotide polymorphisms (SNPs)
of the transport proteins can cause differences in the uptake or efflux of drugs.
In terms of cancer chemotherapy, tumor cells expressing these proteins can have
either enhanced sensitivity or resistance to various anticancer drugs.
Transporters that serve as efflux pumps on a cell membrane can remove drugs
from the cell before they can act.
Transport proteins that are responsible for the vital influx of ions and nutrients
such as glucose can promote growth of tumor cells if overexpressed, or lead to
increased susceptibility for a drug if the transporter carries that drug into the
Importance of Drug Transporter
Role in overall disposition of drugs to the target organs
Significant determinant of drug-drug interaction
Variability in drug response
Types of drug transporter
Two types of transporter :
ATP binding Cassette (ABC) – Found in ABCB, ABCD and ABCG family.
Associated with multidrug resistance (MDR) of tumor cells causing treatment
failure in cancer.
Solute Carrier (SLC) – Transport varieties of solute include both charged or
ATP Binding Cassette Solute Carrier
Efflux transporter Influx / bidirectional transporter
Utilize energy from ATP Electrochemical gradient / facilitated diffusion
Primary active Secondary active
Subfamilies : ABCA, ABCB, ABCD, ABCE, ABCDF,
Subfamilies ; SLC15, SLC22, SLCO
• ATP binding cassette sub family B member-1 (ABCB 1)
• Multidrug resistance protein 1 (MDR1)
• Transport various molecules, including xenobiotic, across cell membrane
• Extensively distributed and expressed throughout the body
Function of P-glycoprotein
Site of transportation Function
Liver – Bile Elimination
Kidney - Urine Excretion
Placenta – Maternal blood Protect fetal from drug exposure
Intestine – Intestinal lumen Reduce drug absorption into the blood
Brain – Blood Monitor drug access to the brain
Mechanism of P-glycoprotein
① Substrate bind to P-gp form the inner leaflet of the membrane
② ATP binds at the inner side of the protein
③ ATP is hydrolyzed to produce ADP and energy
④ Substrate is excreted outside the cell
P-gp is a multidrug resistant protein (MDR)
Role of P-gp is significant in tumor cells. Expression of P-gp in tumor cells reduces
the accessibility of cytotoxic drugs by eliminating them in various pathways. Hence,
P-gp may act as a major barrier to effective drug treatments.
Over expression of P-gp in limit the treatment for cancer, AIDS, Alzheimer’s and
Dean M, Hamon Y, Chimini G (July 2001). "The human ATP-binding cassette
(ABC) transporter superfamily”
Hediger MA, Romero MF, Peng JB, Rolfs A, Takanaga H, Bruford EA (2004).
"The ABCs of solute carriers: physiological, pathological and therapeutic
implications of human membrane transport proteins: Introduction”
Dean, Michael (2002-11-01). "The Human ATP-Binding Cassette (ABC)
Peter N Bennett, Morris J Brown, Pankaj Sharma, 11th Edition (2012). “Clinical
Department of Drug Metabolism, Merck Research Laboratories (Nov 2003).
“Clinical relevance of P-glycoprotein in drug therapy”