Targeted Drug Delivery Systems

Molecular Pharmaceutics (Nano
Technology/ Targeted DDS)
UP23MPU641B
Dr. Saniya Jawed
Department of Pharmaceutics

Dr. Saniya Jawed
MOLECULAR PHARMACEUTICS (NANO TECHNOLOGY/
TARGETED DDS) UP23MPU641B
Targeted drug delivery system

Content
Introduction and rationale of targeted drug delivery system
Biological processes and events involved in drug targeting

Content
Introduction and rationale of targeted drug delivery system
Biological processes and events involved in drug targeting
Pharmacokinetic and pharmacodynamic considerations
Basic concept of drug targeting and drug carrier system
Different types of drug targeting
Drug carrier

Learning Outcome
 After this session, students will be able to
• Delineate objectives and characteristics of targeted drug delivery system (TDDS),
• Describe the advantages and disadvantages of TDDS,
• State rationale for TDDS.
• Explain biological processes and events involved in drug targeting.

• Targeted drug delivery system is a special form of drug delivery system
where the medicament/drug/API 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 enhances efficacy (pharmacological response) and minimizes side effects.
• Also known as smart/selective/specific drug delivery system.
MOLECULAR PHARMACEUTICS UP23MPU641B

• It should be focused/targeted:
To the capillary bed of the active sites.
To the specific type of cell (or) even an intracellular region. Ex: Tumour cells
but not normal cells.
To a specific organ (or) tissues by complexion with the carrier that
recognizes the target

• Targeted drug delivery system
Disease targeted: cancer
Tissue/organ targeted: bone, brain
Receptor/gene/cell targeted: stem cell
• Drug disposition (ADME)

Reasons for site-specific drug delivery
• Pharmaceutical (solubility, drug instability in conventional dosage form)
• Biopharmaceutical (low absorption, high-membrane bounding, and
biological instability)
• Pharmacokinetic and pharmacodynamic (short half-life, large volume of
distribution, low specificity)
• Clinical (low therapeutic index)
• Commercial (drug presentation).

Basic concept/ideal characteristics of drug targeting and drug carrier system
• Biochemically inert (non-toxic)
• Non-immunogenic.
• Both physically and chemically stable in vivo and in vitro.
• Restrict drug distribution to target cells or tissues or organs.
• Should have uniform capillary distribution.
• Controllable and predicate rate of drug release.

Basic concept/ideal characteristics of drug targeting and drug carrier system
• Drug release does not affect the drug action.
• Therapeutic amount of drug release.
• Minimal drug leakage during transit.
• Carriers used must be bio-degradable or readily eliminated from the body
without any problem and no carrier-induced modulation of a diseased
state.
• The preparation of the delivery system should be easy or reasonably
simple, reproductive, and cost-effective.

Advantages of targeted drug delivery system
• Drug administration protocols may be simplified.
• Toxicity is reduced by delivering a drug to its target site and reducing
harmful systemic effects.
• Drug can be administered in a smaller dose to produce the desired
effect.
• Avoidance of hepatic first-pass metabolism.

Advantages of targeted drug delivery system
• Enhancement of the absorption of target molecules such as peptides and
particulates.
• Dose is less compared to conventional drug delivery systems.
• No peak and valley plasma concentration.
• Selective targeting to infectious cells that compare to normal cells.

Disadvantages of targeted drug delivery system
• Rapid clearance of targeted systems.
• Immune reactions against intravenously administered carrier systems.
• Insufficient localization of targeted systems into tumor cells.
• Diffusion and redistribution of released drugs.
• Requires highly sophisticated technology for the formulation.

Disadvantages of targeted drug delivery system
• Requires skill in manufacturing storage, and administration.
• Drug deposition at the target site may produce toxicity symptoms.
• Difficult to maintain the stability of dosage form. eg: Resealed
erythrocytes have to be stored at 40 C.
• It is difficult to predict /fix the dosage regimen eg: in micelles, Drug
loading is usually low.

Events and biological process involved in drug targeting
• Cellular uptake & processing: pinocytosis, phagocytosis
• Transport across the epithelial barrier
• Extravasation: moving out of central circulation
• Lymphatic uptake

• Cellular uptake & processing:
After administration a drug passed through various cell membranes
and reached the target site.
Low molecular weight drugs enter through simple diffusion but
macromolecules of TDDS cannot take an active transport path such as
endocytosis.

Endocytosis: A cell absorbs extracellular material by engulfing it with
its cell membrane to form a vesicle which is then pinched off
intracellularly.
These processes require energy as large particles are transported
across the membrane in membrane-bound vesicles.
In this process the particles do not pass through the membrane.

 Exocytosis: In this process, materials are expelled or secreted from a
cell.
It is used to rid wastes and secreted substances (hormones) produced
by the cell.
Endocytosis comprises phagocytosis and pinocytosis.
Phagocytosis: It is also known as cell eating.

Phagocytosis is carried by specialized cells of the mononuclear
phagocyte system called phagocytes by absorption of a specific blood
component called ‘opsonins’.
Phagocytic vacuole fuses with one or more lysosomes to form
phagolysosomes.
Digestion of particles occurs by lysosomal acid hydrolysis, making drug
available to exert its effect.

Pinocytosis: It allows a cell to engulf large molecules and fluid that may
be present in the extracellular region.
The cell membrane folds inwards, encloses the fluid or particle to be
transported, and then fuses to form a vesicle.
The vesicle detaches from the membrane and moves to the interior of
the cell.

It is of two types: Fluid phase pinocytosis and Receptor-mediated
pinocytosis.
Fluid phase pinocytosis is a non-specific & continuous process where
macromolecules adhere to the general cell surface site.
Adsorptive pinocytosis or Receptor-mediated pinocytosis is a specific
process where the macromolecules bind to a specific cell receptor site.

Receptor-mediated pinocytosis is a particularly efficient form of
pinocytosis.
A receptor on the surface of the cell binds to a molecule in the tissue
fluid and the complex of binding molecule (ligand) and receptor is
ingested.
For example, iron is absorbed in human cells through the transferrin
protein which is present in the tissue fluid.

• Transport across the epithelial barrier:
Oral, buccal, nasal, vaginal, and rectal cavities are internally lined with
one or more layers of epithelial cells.
Depending on position and function in the body, these cells vary
(squamous, cuboidal, columnar).
These cells are extremely cohesive and low molecular weight drugs'
absorption from these routes is well established.

To cross the epithelial barrier lining these cavities drug used passive
diffusion, carrier-mediated transfer systems, and selective and
nonselective endocytosis.
Additionally, polar materials also can diffuse through the tight junctions
of epithelial cells (the paracellular route).
Both passive and active transport pathways are energy-dependent
processes, and they may occur simultaneously.

Passive transport is usually higher in damaged mucosa, whereas active
transport depends on the structural integrity of epithelial cells.
Macromolecules with a molecular weight of less than 10,000 can be
absorbed from the nasal epithelium into the systemic circulation in
sufficient amounts without the need for added materials except for
bioadhesives.

Larger molecules, such as proteins [e.g., interferon, granulocyte colony-
stimulating factor (G-CSF), human growth hormone], however, require
both a penetration enhancer (e.g., bile salts and surfactants) and
bioadhesives.
The transport of macromolecules across intestinal epithelium may occur
by cellular vesicular processes involving either fluid-phase pinocytosis or
specialized (receptor-mediated) endocytic processes.

The different region of GIT shows different sensitivity to penetration
enhancers.
The following order of sensitivity is suggested: Rectum> colon> small
intestine> stomach.
Factors influencing the absorption of drugs from the gastrointestinal
tract are pH, enzymes, surface area, microflora, and transit time.

• Extravasation:
For a drug to exert its therapeutic effects, it must move from the central
circulation and interact with its extra vascular-extracellular or extra
vascular-intracellular target.
This process of transvascular exchange is called “extravasation” and
governed by the permeability of blood structure of the capillary wall.

The main biological features that control the permeability of capillaries
include the (patho) physiological conditions, and the rate of blood and
lymph supply.
Physicochemical factors of compounds that are of profound importance
in extravasation are molecular size, shape, charge, and hydrophilic-
lipophilic balance (HLB) characteristics.

Depending on the morphology and continuity of the endothelial layer
and the basement membrane, blood capillaries are divided into three
types:
continuous,
fenestrated, and
sinusoidal

Continuous capillaries: These are common and widely distributed in the
body. They exhibit tight inter endothelial junctions and an uninterrupted
basement membrane.
Fenestrated capillaries: It shows inter endothelial gaps of 20-80 nm at
irregular intervals. These gaps have a thin membrane, and are derived
from the basal membrane.

Sinusoidal capillaries: It shows 150 nm of inter endothelial gaps. The
basal membrane is absent in sinusoidal capillaries of the liver and is
discontinuous in the spleen and bone marrow.
They are also wider in diameter, have irregular Iumens, and their wall is
very thin. Furthermore, they have hardly any connecting tissues between
the endothelial cells and the cells in which they are located.

This area is occupied by a variety of cells, including highly active
phagocytic cells.
There are also numerous important variations in the microvasculature
bed (i.e., arterioles, capillaries, and venules) that affect permeability.

Lymphatic uptake:
• Following extravasation, the drug molecules can either reabsorb into the
bloodstream directly by the enlarged post-capillary inter endothelial cell
pores found in most tissues or enter into the lymphatic system and then
return with the lymph to the blood circulation.
• Drugs administered through subcutaneous, intramuscular, transdermal, and
peritoneal routes reach the systemic circulation by the lymphatic system

Lymphatic pathway is of minor importance in drug absorption into systemic
circulation:
The lymph vessels are less accessible than the capillaries.
The lymph flow is exceptionally slow.
However, fats, fat-soluble vitamins & highly lipophilic drugs are absorbed
through lymphatic circulation.

Advantage of lymphatic absorption of drugs:
Avoidance of first-pass effect: Compounds of high molecular weight (above
16,000) can be absorbed by lymphatic transport.
Targeted delivery of drugs to the lymphatic system as in certain cases of
cancer is possible.

• Factors like size and surface characteristics of particles, formulation
medium, the composition and pH of the interstitial fluid, and disease within
the interstitium are known to influence the clearance of drugs from
interstitial sites, following extravasation or parenteral interstitial or
transepithelial administration.
• Soluble macromolecules smaller than 30 nm can enter the lymphatic
system, whereas particulate materials larger than 50 nm are retained in the
interstitial sites and serve as a sustained-release depot.

• The use of lipids or oil in a formulation and the presence of a negative
surface charge all appear to facilitate the absorption of particles into the
lymphatic system.
• Solid tumors, in general, lack lymphatic drainage; therefore,
macromolecular drugs that enter tumor interstitium, by extravasation
remain there. This mechanism is commonly referred to as the tumor-
enhanced permeability and retention (EPR) effect.

Pharmacokinetic and pharmacodynamic considerations
• When a drug is administered; it is readily distributed to various
compartments by blood.
• The relative amounts of drug available at the target (response
compartment) and non-target (toxicity compartment) sites determine the
therapeutic effect and toxicities relative to that effect.

• Targeted drug-delivery systems are designed to maximize therapeutic
response by delivering drugs selectively to their pharmacological site.
• Following factors determine the availability of drugs at the target site.
input of targeted drug into the body plasma.
Distribution of targeted drug to the active site.
Release of active drug from the targeted drug at the site of action.

Removal (elimination) of targeted drug and free drug from the target site.
Diffusion or transport of targeted and free drugs from active sites to
nontarget sites.
Blood and lymph flow to and from the target site. (Boddy et al.)

• On the basis of the assumption that the targeted drug-delivery product will
be transported from the target site to the rest of the body (sink), by
diffusion, convection, or transport processes, Levy concluded:
Drug elimination from the target site will frequently be much more rapid
than drug elimination from the body as a whole.
The duration of action of a targeted bolus dose will be much shorter than
the duration of action of a conventionally administered bolus dose.

The rate of drug administration to maintain a constant pharmacological
effect will need to be much higher for a targeted drug than for a
conventionally administered drug.
Changes in the biotransformation and excretion kinetics or of other
processes (e.g., the liver perfusion rate) that determine the systemic
clearance of a drug by the body will have no effect on the kinetics of
elimination of the targeted drug from the site of action.

• The relationship between concentration and effect of drugs is much more
complex in targeted drug delivery.
• It can vary in different organs or tissues, depending on access, retention
(maintenance of adequate levels of targeted delivery and free drug at the
active site), and timing of the release of drug within that site.
• The overall drug-targeting efficiency was reviewed by Gupta and Hung
which represents the selectivity of a delivery system for the target tissue
(T), compared with n non-target (NT) tissues, which can be calculated by:

• Where (AQU) is the area under the amount of drug (Q) in a tissue versus
time curve.
• Q can be obtained, at any time t, by the relationship Q = CV (or W), where C
is the concentration of the drug at time t and V and W are the volume and
weight, respectively, of that tissue.

Types of drug targeting
• Active targeting (carrier and drug
directly to a specific site)
• Passive targeting (systemic
circulation)
• Dual targeting (drug + carrier)
• Double targeting (temporal +
spatial)
• Inverse targeting (avoid passive
uptake)
• Combination targeting
• Physical targeting (pH, temp)
• Ligand-mediated targeting

Types / strategies of drug targeting
• Passive targeting: It is the accumulation of a drug or drug-carrier system at
a particular site (disease site) to maximize circulation times and targeting
ability.
• In cancer treatment the size (less than 100 nm in diameter) and surface
properties (hydrophilic) of drug delivery nano-particles must be controlled
specifically to avoid uptake by the reticuloendothelial system (RES).
• Targeting of anti-malarial drugs for the treatment of leishmaniasis,
brucellosis, and candidiasis.

• Active targeting: It includes specific modification of drug/drug carriers with
active agents having a selective affinity for recognizing and interacting with a
specific cell, tissue, or organ in the body.
• In cancer, it is achieved by conjugating the nanoparticle to a targeting
component that provides a preferential accumulation of nanoparticles in the
tumor-bearing organ, to the tumor, individual cancer cells, intracellular
organelles, or specific molecules in cancer cells.

• This approach is based on specific interactions such as lectin-carbohydrate,
ligand-receptor, and antibody-antigen.
• Active targeting can be further classified into three different levels of
targeting:
First-order targeting
Second-order targeting
Third-order targeting

• First-order targeting: It refers to the restricted distribution of the drug carrier
systems to the capillary bed of a predetermined target site, organ, or tissue.
• For example compartmental targeting in lymphatics, peritoneal cavity,
cerebral ventricles, eyes, joints, etc.
• Second-order targeting: It refers to the selective delivery of drugs to specific
cell types such as tumor cells and not to normal cells.
• E.g.: selective drug delivery to Kupffer cells in the liver.

• Third-order targeting: It is defined as drug delivery specifically to the
intracellular site of targeted cells.
• E.g. receptor-based ligand-mediated entry of a drug complex into a cell by
endocytosis.

Drug carrier
• They are also referred to as drug vectors and are the most important
entity required for the successful transportation of the loaded drug.
• Drug vectors transport and retains the drug and aim to deliver it within or
in the vicinity of the target.
• They are made capable of performing such specific functions which can be
attributed to slight structural modification.

Drug carrier: Ideal characteristics
• It should be able to cross blood-brain barriers and in case of tumor
chemotherapy tumor 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 molecules used as carriers should not be ubiquitous (existing or being
everywhere at the same time).
• Drug carriers 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 depend 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 include antibodies, lectins and other proteins,
lipoproteins, hormones, Charged molecules, Polysaccharides, and Low-
molecular-weight ligands.

Drug carrier: Examples
• Liposomes
• Monoclonal Antibodies and Fragments
• Soluble Polymers
• Lipoproteins
• Microspheres and Nanoparticles
• Polymeric Micelles

Liposomes
• These are small artificially designed vesicles composed of phospholipid
bilayers surrounding one or several aqueous compartments.
• They are of different types like
Multilamellar vesicle (MLV)
Small unilamellar vesicle (SUV)
Large unilamellar vesicle (LUV)
Cochleate vesicle

Liposomes
• Charge on the liposomes, lipid composition, and size (ranging from 20 to
10000 nm) can be varied and affect their behavior 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 (lipoplexes) have been extensively researched for their
application in non-viral vector-mediated gene therapy.

Liposomes
• A new variety of liposomes known as 'stealth' liposomes has recently been
developed by incorporating polyethylene glycol (PEG).
• It was considered to prevent liposome recognition by phagocytic cells.
• Such liposomes have longer circulation times and increased distribution to
peripheral tissues in the body.

Liposome for drug delivery
• Liposomes do not easily extravasate from the systemic circulation into the
tissues, but enhanced vascular permeability during an inflammatory
response or pro-angiogenic conditions in tumors can favor 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.

Liposome for drug delivery
• Charged liposome as drug delivery system:

Approved liposomal drugs available in the market

Monoclonal Antibodies and Fragments
• It was developed by Kohler and Milstein in 1975.
• The majority of strategies for cancer therapy, are based on antigen
recognition by antibodies.
• These strategies are mostly aimed at tumor-associated antigens being
present or in more specific terms 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.
• The high selectivity of ADC greatly reduces the toxic side effects of
traditional chemotherapy and also makes possible the use of newer
actives with a high toxicity profile.
• Antibodies against other diseases have been developed for clinical
application.

• Anti-TNFa antibodies for the treatment of chronic inflammatory diseases
and anti-VEGF (vascular endothelial growth factor), inhibits new blood
vessel formation or angiogenesis.
• The advancement of recombinant DNA technology had also led to the
development of antibodies and fragments that can be synthesized and
tailored for optimal behavior in vivo.
• Target cell-specific ligands like EGF and RGD peptides can provide a
solution for selective and targeted chemotherapy.

• Modified plasma proteins can be intelligent carriers for drug targeting as
they are soluble molecules with a relatively small molecular weight.
• They can easily be modified by the attachment of different molecules like
peptides, sugars, other ligands, and drugs.
• In the case of liver cell targeting, extensive modifications of protein
backbones such as albumins have been carried out for effective delivery of
the drug.

Soluble polymers
• Soluble synthetic polymers have been extensively researched as versatile
drug carrier systems.
• Polymer chemistry allows the development of tailor-made conjugates in
which target moieties as well as drugs can be entrapped into the carrier
molecule.
• In such cases enhanced bioavailability is seen.

Soluble polymers
• In the design of polymeric carriers excessive charge or hydrophobicity
should be avoided.
• For cancer therapy, the N (-2- hydroxypropyl)nethacrylamide (HMPA)
polymers have been extensively studied which provides a solution for
selective and targeted chemotherapy.
• A thin film of polymers from natural resources like cellulose has also been
studied and is in use for applications in pharmaceutics, medical devices,
packaging, and food products.

Lipoproteins
• Lipid particles such as LDL and HDL containing lipid and an apoprotein
moiety are termed as 'natural targeted liposomes’.
• The lipid core can be used to incorporate lipophilic drugs or lipophilic Pro-
drugs without the formation of any covalent bond.
• The apolipoprotein moiety of these particles can be glycosylated or
modified with other (receptor) targeting ligands.
• Modifications at the level of glycolipid incorporation can be used to
introduce new targeting moieties.

Microspheres and Nanoparticles
• It consists of biocompatible polymers and belongs either to the soluble or
the particle type carriers.
• Nanoparticles are smaller (0.2-0.5 nm) than microspheres (30-200 µm)
and have a smaller 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.

Microspheres and Nanoparticles
• 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.
• Besides the parenteral application of microspheres and nanoparticles for
cell-selective delivery of drugs, they have been studied for their
application in the oral delivery of peptides and peptidomimetics.

Polymeric Micelles
• These are small (10-100 nm) in size and drugs can be incorporated by
chemical conjugation or physical entrapment.
• They have a characteristic core-shell (hydrophobic-hydrophilic) structure.
• The hydrophobic core consists of a biodegradable polymer that serves as a
reservoir for an insoluble drug.
• Non or poorly biodegradable polymers can be used if they are not toxic to
cells and can be secreted through urine or feces.

Polymeric Micelles
• If a water-soluble polymeric core has to be used, it should be hydrophilic
and should have chemical conjugation with a hydrophobic drug.
• The viscosity of the formulation influences the physical stability of the
micelles as well as drug release.
• The bio-distribution of the micelle mainly depends on the nature of the
shell and also on micelle stabilization and interactions with plasma
proteins and cell membranes.

Polymeric Micelles
• The micelles may contain functional groups at their surface for conjugation
with a targeting moiety.
• For efficient delivery of the desired drug, integrity should be maintained
for a sufficient time after injection into the body.
• It has been widely utilized for targeting anticancer drugs to tumors.

Cellular carriers
• They have the advantage of their natural biocompatibility.
• They may pass through endothelial barriers and can invoke an
immunological response.
• Most of the research on cellular carriers has 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.

Various approaches for drug targeting
• Tumor targeting and
• Brain-specific delivery

Tumor targeting
• Tumor is the result of abnormal growth of normal cells raised from a faster
rate of cell division than normal.
• It appears as soft tissues that feel like painful bumps or hard masses.
• Most common types of tumors are benign tumors (non-cancerous) and
malignant tumors (cancerous).
• These are treated by chemotherapy, radiotherapy, and conventional
surgery but these practices couldn’t control the metastasis steps of the
tumor.

Tumor targeting techniques
• Development of Multifunctional polymeric micelles with cancer-targeting
capability through αvβ3 integrins was found to be an effective way to
target tumors.
• In this approach Doxorubicin and a cluster of superparamagnetic iron
oxide nanoparticles loaded micelle core was used to target tumorous cells.
• The presence of cRGD on the micelle surface resulted in the cancer-
targeted delivery to αvβ3-expressing tumor cells (Norased Nasongkla et al.
2006).

• Development of A novel single-walled carbon nanotube-based tumor-
targeted drug delivery system.
• This approach was conjugated with a prodrug of an anticancer agent
taxoid with a cleavable linker and this was attached to tumor-recognition
modules biotin and a spacer to the nanotube surface.
• This showed higher potency towards tumor cells (Jingyi Chen et al. 2008).

• Nanocarrier-loaded molecules as a targeting approach have been
developed.
• These molecules are peptides, antibodies, ligands, and nucleic acids that
enhance their recognition and internalization by the target.
• These have enhanced permeability and retention effects (Emily Gullotti
and Yoon Y. 2009).

• Development of bortezomib pH-sensitive polymeric carrier to target the
cancer cells through cell surface receptor-mediated mechanisms to
increase cellular uptake (Jing Su et al. 2011).
• Development of multifunctional envelope-type mesoporous silica
nanoparticles for tumor targeting (Jing Zhang et al. 2013).
• Development of rod-shaped gold nanocrystals with ligands for tumor
targeting (Xiaohua Huang et al. 2010).

• Development of ligand directive polymeric nanoparticles for targeted
approach to tumor tissues.
• Specific tumor-homing ligands are antibodies, antibody fragments,
peptides, aptamers, polysaccharides, and folic acid worked on the surface
stealth of nanoparticles, which leads to an increase in the retention time
and accumulation of nanoparticles in the tumor vasculature.
• It helps in selective and effective internalization by target tumor cells
(Yinan Zhong et al. 2014).

• Different mechanisms and approaches have been used to treat cancer
cells or tissues.
• These are involved in tumor therapy.
• Targeting the cell membrane, endoplasmic reticulum system, lysosomes,
mitochondria, cell nucleus, and change in the tumor cell environment, etc.
are effective approaches used in tumor targeting.

Brain targeting
• Most common brain diseases are CNS malignancy, brain tumor, multiple
sclerosis, mania, schizophrenia, abscess, etc.
• The efficacy and safety of conventional drugs in brain delivery to treat
these disorders or diseases were found to be less by researchers as
compared to targeted drug delivery systems.
• Targeted brain drug delivery system was designed and developed to
overcome difficulties to cross blood-brain barriers (BBB) by drugs.

Brain targeting: Advantages and disadvantages
• Advantages:
Reduction in toxicity, enhancement in bioavailability, dose reduction,
concentration fluctuation, and permeability enhancements.
• Disadvantages:
Stability, targeting particular cells or tissues, skilled people required for
delivery, advanced techniques, equipment, etc.

Brain targeting: Advantages and disadvantages
• The aim of brain targeting is to cross the BBB, blood-tumor barrier, blood-
cerebrospinal fluid barrier, and the tight junction of epithelial cells for
macromolecules, proteins, and carriers.
• The carriers like liposomes, nanoparticles, dendrimers, prodrugs,
niosomes, carbohydrates are found suitable for brain targeting

Brain targeting: Approaches
• Lipophilic approach
• Prodrug approach
• Liposomal loaded drug approach
• Polymeric micelles-loaded drug
approach
• Dendrimer approach
• Miscellaneous Approaches
Invasive techniques
Non-Invasive techniques
Physiological approach
Biological approach
Chemical approach
Colloidal approach
Others

• Lipophilic approach: This approach was developed for increasing the
permeability of low molecular weight substances at physiological pH.
It was observed that the lipophilic drug (heroin) has faster penetration
from BBB than the hydrophilic drug (morphine).
• Prodrug approach: This approach has been designed with a drug that is
covalently attached to an inert chemical moiety.
This moiety activates after cleaving by a hydrolytic enzyme inside the cell
and the lipoidal nature of the drug has been increased.

It helps to cross BBB for low molecular masses by modification of drugs
through amidation, carboxylation, and esterification of chemical groups.
Acetylated morphine, a form of a prodrug, has faster intake through BBB
than morphine.
• Liposomal loaded drug approach: This approach has been developed to
target brain delivery in which drug particles have been loaded inside the
liposomal cavity and delivered to the target site.
It reduces the loss of drugs in the vicinity of target cells.

• Polymeric micelles-loaded drug approach: This is the structure developed
by a combination of amphiphilic co-polymers that have both hydrophilic
and lipophilic characteristics (micelles 1-100 nm) to cross the barriers.
Surfactants are biodegradable and biocompatible molecules.
Drug-loaded micelles, consisting of polyethylene glycol, polypropylene
glycol, poloxamer, etc. were found effective in the brain drug delivery
system.

• Dendrimer approach: These are polymer molecules having complex
branches that have a central core loaded with drug molecules.
• These have a small size range of 1.5-14.5 nm suitable for faster uptake
through epithelial cells of the brain.
• Example; poly- amidoamine (PAMAM) dendrimer.

• Miscellaneous Approaches
Invasive techniques: Intra ventricular infusion, BBB disruption, Intra
cerebral implant, Intra cerebro ventricular infusion, etc.
Non-Invasive techniques:
Physiological approach: Transport-mediated delivery, Receptor-mediated
delivery, Insulin receptor-mediated transcytosis, adsorptive mediated
transcytosis, transferring receptor-mediated transcytosis, etc.

Colloidal approach: It includes the use of vesicular systems, nanocarrier
systems, self-micro emulsifying systems, lipid-based drug delivery systems,
emulsions, nanosuspensions, etc.
Others: It includes Focused ultrasound delivery, Intra nasal delivery, Intra
arterial delivery, Iontophoretic delivery, etc.

• Define TDDS.
• Explain the significance of TDDS.
• Enlist applications of TDDS.
• Write briefly about reasons for TDDS.
• Mention the challenges, advantages, and disadvantages of TDDS.
• Describe the events and biological processes in the drug targeting.
• Enlist different types of drug targeting and classify active targeting.
• Define drug carrier. Mention types of drug carriers with their significance.
• Define tumor targeting and explain approaches used for them.
• Define brain targeting and enlist all the approaches used for brain targeting.
Questions

saniyajawed@pesu.pes.edu
THANK YOU
Dr. Saniya Jawed

Targeted Drug Delivery Systems

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