Targeted drug delivery

1. TARGETED DRUG DELIVERY
 Concepts,
 Approaches,
 Advantages and disadvantages,
Introduction to
o Liposomes,
o Niosomes,
o Nanoparticles,
o Monoclonal antibodies and their applications.
INTRODUCTION:
Target drug delivery system may also be referred to as smart drug delivery system is the
currently used form of drug delivery system where the pharmacologically active drug (or
pro-drug in some cases) is targeted or is delivered specifically to the site of action.
Targeted drug delivery extensively used for selective and effective localization of
pharmacologically active moiety at pre-determinedtarget in therapeutic concentration,
while restricting its access to non-target normal cellular linings, thus minimizing toxic
effects and maximizing therapeutic index. Targeting of drugs also help us to bypass first
pass metabolism so a drug can be administered in a form such that it reaches the receptor
sites in sufficient concentration without disturbing in extraneous tissue cells.
Targeted drug delivery system is a special form of drug delivery system where the
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.’
It 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.
Targeted drug delivery seeks to concentrate the medication in the tissues of interest
while reducing the relative concentration of the medication in the remaining tissues.
This improves efficacy and reduce side effects.
Targeted drug delivery may be adapted:
 To the capillary bed of the active sites.
 To the specific type of cell (or) even an intracellular region. Ex: Tumour cells but
not to normal cells.
 To a specific organ (or) tissues by complexion with the carrier that recognizes the
target.

2. Objectives of Targetted DDS:
 To achieve a desired pharmacological response at a selected site without
undesirable interaction at other sites, there by the drug have a specific action with
minimum side effects & better therapeutic index.
 Ex- in cancer chemotherapy and enzyme replacement therapy.
Reasons for targeting:
 In the treatment or prevention or diseases.
 Pharmaceutical drug instability in conventional dosage form solubility,
biopharmaceutical low absorption, high-membrane bounding, biological
instability, pharmacokinetic / pharmacodynamic short half-life, large volume of
distribution, low specificity, clinical, low therapeutic index.
Products based on such a delivery system are being prepared by considering the Specific
properties of target cells, Nature of markers or transport carriers or vehicles, which
convey drug to specific receptors. and Ligands and physically modulated components.
Ideally targeted drug delivery system should have following characteristics:
 Should be biochemically inert (non-toxic)
 Should be non-immunogenic.
 Should be physically and chemically stable in vivo and in vitro conditions.
 Should have restricted drug distribution to target cells or tissues or organs and
should have uniform capillary distribution.
 Should have Controllable and predictable rate of drug release and also Drug
release should not affect the drug action.
 Should have therapeutic amount of drug release.
 Should have minimal drug leakage during transit.
 Carriers used should be bio-degradable or readily eliminated from the body
without any problem.
 The preparation of the delivery system should be easy or reasonably simple,
reproductive and cost effective.
Advantages:
 Drug administration protocols may be simplified.
 Toxicity is reduced by delivering a drug to its target site, thereby reducing harmful
systemic effects.
 Drug can be administered in a smaller dose to produce the desire effect.

3.  Avoidance of hepatic first pass metabolism.
 Enhancement of the absorption of target molecules such as peptides and
particulates.
 Dose is less compared to conventional drug delivery system.
 No peak and valley plasma concentration.
 Selective targeting to infections cells that compare to normal cells.
Disadvantages:
 Rapid clearance of targeted systems.
 Immune reactions against intravenous administered carrier systems.
 Insufficient localization of targeted systems into tumour cells.
 Diffusion and redistribution of released drugs.
 Requires highly sophisticated technology for the formulation.
 Requires skill for manufacturing storage, administration.
 Drug deposition at the target site may produce toxicity symptoms.
 Difficult to maintain stability of dosage form. E.g.: Resealed erythrocytes have to
be stored at 40 C.
 Drug loading is usually law. E.g. As in micelles. Therefore, it is difficult to predict
/fix the dosage regimen.
Inspite of many complications and failures in the development of such a system like Rapid
clearance of targeted systems, Immune reactions against intravenous administered
carrier systems, Insufficient localization of targeted systems into tumour cells and
Diffusion and redistribution of released drugs to name a few the advantages of drug
targeting is the simplified protocols of Drug administration, reduced Drug quantity hence
it affects the cost of therapy and also Drug concentration in the required sites can be
sharply increased without negative effects on non-target compartments.
Different types of drug targeting
As discussed, targeting drug to a specific area not only increases the therapeutic efficacy
of drugs also it aims to decreases the toxicity associated with drug to allow lower doses
of the drug to be used in therapy. For the fulfillment of such conditions, two approaches
are used extensively (also known as classification of drug targeting)
 passive targeting
 active targeting

4. Passive targeting: it refers to the accumulation of drug or drug-carrier system at a
particular (like in case of anti-cancerous drug) site whose explanation may be attributed
to physicochemical or pharmacological factors of the disease. Hence in case of cancer
treatment the size and surface properties of drug delivery nano-particles must be
controlled specifically to avoid uptake by the reticuloendothelial system (RES), to
maximize circulation times and targeting ability. For attaining such conditions, the
optimal size should be less than 100 nm in diameter and the surface should be
hydrophilic to circumvent clearance by macrophages (large phagocytic cells of the RES).
Other examples include targeting of anti- malarial drugs for treatment of leishmiansis,
brucellosis, candiadsis.
Active targeting : Active targeting includes specific modification of a 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 .in case of cancer, it is achieved by
conjugating the nanoparticle to a targeting component that provides preferential
accumulation of nanoparticles in the tumor-bearing organ, to tumor, individual cancer
cells, intracellular organelles, or specific molecules in cancer cells. Such an approach is
based on specific interactions such as lectin-carbohydrate, ligand-receptor, and antibody-
antigen.
This active targeting approach can be further classified into three different levels of
targeting.
First order targeting: 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: it refers to selective delivery of drugs to specific cell types such
as tumourcells and not to the normal cells. E.g. include selective drug delivery to kupffer
cells in the liver.
Third order targeting: it is defined as drug delivery specifically to the intracellular site
oftargeted cells. E.g. receptor based ligand mediated entry of a drug complex into a cell
by endocytosis.
Drug Carrier:
Drug carrier or sometimes also referred to as drug vectors are the most important entity
required for successful transportation of the loaded drug. Drug vectors transports and

5. retains the drug and aims deliver it within or in the vicinity of target. They are made
capable of performing such specific functions which can be attributed by slight structural
modification.
Characteristics of an ideal drug carrier
An ideal drug carrier should be able to cross blood brain barriers and in case of tumour
chemotherapy tumour vasculature. It must be recognized by the target cells specifically
and selectively and must maintain the specificity of the surface ligands. The drug ligand
complex should be stable in plasma, interstitial and other biofluids. The carrier used
should be non-toxic, non-immunogenic and biodegradable. After recognition and
internalization, the carrier system should release the drug moiety inside the target
organs, tissues or cells. The biomodules used as carrier should not be ubiquitous (existing
or being everywhere at the same time).
Different Type of drug carrier: drug carrier can be Liposomes, Monoclonal Antibodies and
Fragments, modified (Plasma) Proteins, Soluble Polymers, Lipoproteins, Microspheres
and Nanoparticles, Polymeric Micelles, Cellular Carriers etc. selection and type of drug
carrier depends mainly on the type of drug, targeted area to which the drug action is
desired and type of disease in which the system is being used. Targeting Moieties includes
antibodies, lectins and other proteins, Lipoproteins, Hormones, Charged molecules,
Polysaccharides and Low-molecular-weight ligands
LIPOSOMES:
Liposomes are simple microscopic vesicles in which an aqueous volume is entirely
composed by membrane of lipid molecule various amphiphilic molecules have been used
to form liposomes. The drug molecules can either be encapsulated in aqueous space or
intercalated into the lipid bilayers The extent of location of drug will depend upon its
physico-chemical characteristics and composition of lipids.
Liposomes are small artificially designed vesiclescomposed of phospholipid bilayers
surrounding one or several aqueous compartments. Liposomes are of different types
like:
 Multilamellar vesicle (MLV)
 Small unilamellarvesicle (SUV)
 Large unilamellar vesicle (LUV)
 Cochleate vesicle

6. Charge on the liposomes, lipid composition and size (ranging from 20 to 10 000 nm) can
be varied and these variations strongly affect their behaviour in vivo. Many liposome
formulations are rapidly taken up by macrophages and this can be 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 researched for their application in non-
viral vector mediated gene therapy.
A new variety of liposomes known as ‘stealth’ liposomes has recently been developed by
incorporating polyethylene glycol (PEG) which was considered to prevent liposome
recognition by phagocytic cells. Such liposomes have 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.

7. Some of the approved liposomal drugs which are available in the market are as follows.
Name Trade name Company Indication
Liposomal amphotericin B Abelcet Enzon Fungal infections
Liposomal amphotericin B Ambisome Gilead Sciences Fungal and protozoal
infections
Liposomal cytarabine Depocyt Pacira (formerly
SkyePharma)
Malignant lymphomatous
Meningitis
Liposomal daunorubicin DaunoXome Gilead Sciences HIV-related Kaposi’s
sarcoma
Liposomal doxorubicin Myocet Zeneus
Combination therapy with
cyclophosphamide in
metastatic breast cancer
Liposomal IRIV vaccine Epaxal Berna Biotech Hepatitis A
Liposomal IRIV vaccine Inflexal V Berna Biotech Influenza
Liposomal morphine DepoDur SkyePharma, Endo Postsurgical analgesia
Liposomal verteporfin Visudyne QLT, Novartis
Age-related macular
degeneration, pathologic
myopia, ocular
histoplasmosis
Liposome-PEG doxorubicin Doxil/Caelyx Ortho Biotech, Schering-
Plough
HIV-related Kaposi’s
sarcoma, metastatic breast
cancer,metastatic ovarian
cancer
Micellularestradiol Estrasorb Novavax Menopausal therapy
NIOSOMES:
Niosomes are nonionic surfactant vesicles which can entrap both hydrophilic and
lipophilic drugs either in aqueous phase or in vesicular membrane made up of lipid
materials It is reported to attain better stability than liposome’s. It may prove very useful
for targeting the drugs for treating cancer, parasitic, viral and other microbial disease
more effectively.
Advantages:
 Since the structure of the noisome offers place to accommodate hydrophilic, lipophilic
as well as ampiphilic drug moieties, they can be used for a variety of drugs.
 Niosomes exhibits flexibility in their structural characteristics (composition, fluidity
and size) and can be designed according to the desired situation.
 They improve the therapeutic performance of the drug by protecting it from the
biological environment and restricting effects to target cells, thereby reducing the
clearance of the drug.
 Niosomes can act as a depot to release the drug slowly and offer a controlled release.
 They can increase the oral bioavailability of drugs.

8.  They are osmotically active and stable.
 They increase the stability of the entrapped drug.
 They can enhance the skin penetration of drugs.
 They can be made to reach the site of action by oral, parenteral as well as topical
routes.
 The surfactants are biodegradable, biocompatible, and non-immunogenic.
 The niosomal dispersions in an aqueous phase can be emulsified in a non-aqueous
phase to control the release rate of the drug and administer normal vesicles in
external non-aqueous phase.
 Handling and storage of surfactants do not require any special conditions.
 The vesicle suspension being water based offers greater patient compliance over oily
dosage forms.
Applications of Niosomes:
Niosomes as Drug Carriers: Niosomes have also been used as carriers for iobitridol, a
diagnostic agent used for X-ray imaging. Topical niosomes may serve as solubilization
matrix, as a local depot for sustained release of dermally active compounds, as
penetration enhancers, or as rate-limiting membrane barrier for the modulation of
systemic absorption of drugs.
Drug Targeting: One of the most useful aspects of niosomes is their ability to target
drugs. Niosomes can be used to target drugs to the reticuloendothelial system. The
reticulo-endothelial system (RES) preferentially takes up niosome vesicles. The uptake of
niosomes is controlled by circulating serum factors called opsonins. These opsonins mark
the niosome for clearance. Such localization of drugs is utilized to treat tumors in animals
known to metastasize to the liver and spleen. This localization of drugs can also be used
for treating parasitic infections of the liver. Niosomes can also be utilized for targeting

9. drugs to organs other than the RES. A carrier system (such as antibodies) can be attached
to niosomes (as immunoglobulin’s bind readily to the lipid surface of the niosome) to
target them to specific organs.
Anti-neoplastic Treatment: Most antineoplastic drugs cause severe side effects.
Niosomes can alter the metabolism; prolong circulation and half-life of the drug, thus
decreasing the side effects of the drugs. Niosomes are decreased rate of proliferation of
tumor and higher plasma levels accompanied by slower elimination.
Leishmaniasis: Leishmaniasis is a disease in which a parasite of the genus Leishmania
invades the cells of the liver and spleen. Use of niosomes in tests conducted showed that
it was possible to administer higher levels of the drug without the triggering of the side
effects, and thus allowed greater efficacy in treatment.
Delivery of Peptide Drugs: Oral peptide drug delivery has long been faced with a
challenge of bypassing the enzymes which would breakdown the peptide. Use of
niosomes to successfully protect the peptides from gastrointestinal peptide breakdown
is being investigated. In an in vitro study conducted by oral delivery of a vasopressin
derivative entrapped in niosomes showed that entrapment of the drug significantly
increased the stability of the peptide.
Use in Studying Immune Response: Due to their immunological selectivity, low toxicity
and greater stability; niosomes are being used to study the nature of the immune
response provoked by antigens. Nonionic surfactant vesicles have clearly demonstrated
their ability to function as adjuvant following parenteral administration with a number
of different antigens and peptides.
Niosomes as Carriers for Haemoglobin: Niosomes can be used as carriers for
haemoglobin within the blood. The niosomal vesicle is permeable to oxygen and hence
can act as a carrier for haemoglobin in anaemic patients.
NANOPARTICLES:
Nanoparticle, Ultrafine unit with dimensions measured in nanometers (nm; 1 nm =
10−9 meter). Nanoparticles exist in the natural world and are also created as a result of
human activities. Because of their submicroscopic size, they have unique material
characteristics, and manufactured nanoparticles may find practical applications in a
variety of areas, including medicine, engineering, catalysis, and environmental
remediation.

10. Applications of nanoparticles:
 Commercial applications have adapted gold nanoparticles as probes for the detection
of targeted sequences of nucleic acids, and gold nanoparticles are also being clinically
investigated as potential treatments for cancer and other diseases.
 Better imaging and diagnostic tools enabled by nanotechnology are paving the way
for earlier diagnosis, more individualized treatment options, and better therapeutic
success rates.
 Nanotechnology is being studied for both the diagnosis and treatment of
atherosclerosis, or the buildup of plaque in arteries. In one technique, researchers
created a nanoparticle that mimics the body’s “good” cholesterol, known as HDL
(high-density lipoprotein), which helps to shrink plaque.
 The design and engineering of advanced solid-state nanopore materials could allow
for the development of novel gene sequencing technologies that enable single-
molecule detection at low cost and high speed with minimal sample preparation and
instrumentation.
 Nanotechnology researchers are working on a number of different therapeutics
where a nanoparticle can encapsulate or otherwise help to deliver medication directly
to cancer cells and minimize the risk of damage to healthy tissue. This has the
potential to change the way doctors treat cancer and dramatically reduce the toxic
effects of chemotherapy.
 Research in the use of nanotechnology for regenerative medicine spans several
application areas, including bone and neural tissue engineering. For instance, novel
materials can be engineered to mimic the crystal mineral structure of human bone or
used as a restorative resin for dental applications. Researchers are looking for ways
to grow complex tissues with the goal of one day growing human organs for
transplant. Researchers are also studying ways to use graphene nanoribbons to help
repair spinal cord injuries; preliminary research shows that neurons grow well on the
conductive graphene surface.
 Nanomedicine researchers are looking at ways that nanotechnology can improve
vaccines, including vaccine delivery without the use of needles. Researchers also are
working to create a universal vaccine scaffold for the annual flu vaccine that would
cover more strains and require fewer resources to develop each year.

11. MONOCLONAL ANTIBODIES AND FRAGMENTS
 Since the development of monoclonal antibodies by Köhler and Milstein in 1975,
the monoclonal antibodies have proven its edge over the others in antibody
therapy for disease. From the last 2 decades, the number of pre-clinical and clinical
studies associated with monoclonal antibodies and derivatives have seen a
tremendous growth. The majority of strategies based on antigen recognition by
antibodies have been developed for more specifically for cancer therapy. These
strategies are mostly aimed at tumor associated antigens being present or in more
specific term expressed by tumor cells. Antibody- drug conjugates (ADC) combine
a drug with a monoclonal antibody which provides selective targeting for tumoral
cell masses or lymphomas. The drug is released by enzymatic cleavage of the
linker under physiological conditions. One such example of ADC is Mylotarg
(gemtuzamabozogamicin), was approved by the FDA, but later voluntarily
withdrawn from the US market. Another ADC has been submitted for approval and
at least 15 antibody conjugates are currently being investigated in clinical trials.
The high selectivity greatly reduces the toxic side effects of traditional
chemotherapy, and also makes possible the use of newer actives with a high
toxicity profile. Also antibodies against other diseases have been developed for
clinical application. Examples are anti-TNFα antibodies for treatment of chronic
inflammatory diseases and anti-VEGF (vascular endothelial growth factor), such
antibodies inhibit new blood vessel formation or angiogenesis. The advent of
recombinant DNA technology had also led to the development of antibodies and
fragments that can be synthesized and tailored for optimal behaviour in vivo.
Equipping polymer-drug conjugates with target cell specific ligands like EGF and
RGD peptides can provide a solution for selective and targeted chemotherapy.