TARGETED DRUG DELIVERY
SYSTEMS

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CONTENTS

 DEFINITION

 REASONS FOR DRUG TARGETING

 BASIC CONCEPTS OF DRUG TARGETING

 BIOLOGICAL PROCESSES AND EVENTS INVOLVED IN
DRUG TARGETING

 BRAIN TARGETED DRUG DELIVERY SYSTEM

 TUMOUR TARGETED DRUG DELIVERY SYSTEM

 REFERENCES

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TARGETED DRUG DELIVERY SYSTEMS

 DEFINITION

Selective and effective localization of a pharmacologically
active moiety at predefined targets in the therapeutic
concentration, while restricting its access to non–targets is called
drug targeting.

It minimizes toxic effects and maximizes the therapeutic
index.

TDDS concentrates the medication in the tissue of interest
or the targeted tissue and reduces the relative concentration of the
medication in the remaining tissues.

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Short Half Large Volume of
life Distribution

Low Low
absorption specificity

REASONS FOR Low
Drug DRUG Therapeutic

instability TARGETING index

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BASIC CONCEPTS OF DRUG TARGETING

LOAD

EVADE
PRINCIPAL

RETAIN
REQUIREMENTS

TARGET

RELEASE

Proper loading of drug into appropriate drug delivery vehicle

The system should escape body’s secretion that degrades it

Leading to longer residence time in circulation

Reaching the specific site or target

www.DuloMix.com Release of drug at specific sites
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 Selective drug delivery improves the benefit/risk ratio associated
with drugs.

 Ideally a drug should possess high therapeutic index, high
efficacy and reduced toxicity. But many chemotherapeutic
agents have narrow therapeutic index. This can be overcome by
three approaches

COMMON APPROACHES TO TDDS

 To control the distribution of the drug by incorporating into a
carrier.

 Altering the structure of drug at molecular level.

 Controlling the input of drug into bio environment to ensure
programmed bio distribution.

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Carriers

 Carriers play an immense role in drug targeting.

 They act as the drug vectors which transport, retain, interact and
deliver the drugs to the target.

Ideal features of a carrier

 Able to cross the anatomical barriers and tumour vasculature in
case of tumour therapy.

 Should be recognized specifically and selectively by the target
cells.

 Should be non-toxic, non-immunogenic and biodegradable.

 After recognition and internalization, the carrier should release the
drug moiety inside the target organs.

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 Types of carriers used in TDDS

 Colloidal carriers

❑ Vesicular systems

Eg: liposomes, niosomes, pharmacosomes etc.

❑ Microparticulate systems

Eg: Nanoparticles, magnetic microspheres, albumin microspheres etc.

 Cellular carriers

Eg: Resealed erythrocytes, serum albumin, antibodies etc.

 Macromolecular carriers

Eg: Proteins, glycoproteins, toxins, immunotoxins etc.

 Polymer based systems

www.DuEloMgix.:co mPolyacrylates, Polyglycolic acid, Polyvinylpyrrolidone etc. 8

Controlled bio distribution
by incorporating the drug

into a carrier

Increased specific Modulated
localization pharmacokinetics

ADVANTAGES

Improved patient Reduced dose
compliance

Increased treatment Decreased side
efficacy effects

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DISADVANTAGES

 Immune reactions against intravenous administered carrier
systems.

 Diffusion and redistribution of the released drugs

DRUG TARGETING
CLASSIFICATION

ORGAN TARGETING

Delivery to individual organs or
tissues

CELLULAR TARGETING

Delivery to specific types of cells within
the organ or tissue

INTRACELLULAR TARGETING

Delivery to different intracellular compartments in
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the target cells via specific transport pathways

Passive Targeting

Combination Inverse Targeting
Targeting

LEVELS OF
TARGETING

Double Targeting Active Targeting

Dual Targeting

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PASSIVE TARGETING

 Targeting occurs because of the body’s natural response to
the physicochemical characters of drug-carrier system.

 It utilizes the natural distribution of the carrier through
which it accumulates in the organ compartments.

 Eg: Hepatic targeting and Macrophagial targeting is
possible due to the passive capture of colloidal carriers by the
macrophages of Reticuloendothelial cells in the liver. Treatment
of candidiasis by antimalarial agents.

INVERSE TARGETING

 It leads to reversion of biodistribution of the carrier and so
referred to as inverse targeting. Its main aim was to target the
drugs to non-RES organs.

 It lead to saturation of RES by pre-injection of blank
colloidal carriers which lead to suppression of defense
mechanism.

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 Alternative strategies include modification of size, surface charge,
composition and hydrophilicity of carriers in which imparting
hydrophilicity to the carrier molecules was found as an effective
mode of drug targeting to non-RES organs.

 Eg: Polaxamine 908 is hydrophilic nonionic surfactant which
diverts normal RES uptake of coated nanoparticles and has diverted to
the inflammatory sites.

ACTIVE TARGETING

 Facilitation of binding of drug-carrier to target cells through
the use of ligands to increase the receptor mediated localization of
the drug is called active targeting.

 The ligand-receptor interactions are highly stereospecific.
These ligands and receptors are the key requirements to achieve the
site specific or cell specific delivery of drugs.

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 This technique is mainly used in the treatment of cancer and
tumour where Anti-cancer drugs and Anti-tumour drugs are
designed for site specific delivery without affecting the normal
healthy cells.

Drug

Active
Release targeted drug Drug
trigger delivery carrier

system

Ligand
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 Ligands

 Examples of targeting ligands used for active targeting

• Folate

• Transferrin

• Galactosamine

 Release trigger

 Triggering is made by physical means such as

• pH sensitive release

• Temperature sensitive release

• Photo activated release

• Magnetic release

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CLASSIFICATION BASED ON
SITE OF ACTION

First order targeting Second order targeting Third order targeting

or or or

Organ Cellular Intracellular
compartmentalization compartmentalization compartmentalization

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CLASSIFICATION BASED ON
TECHNIQUES

Ligand mediated Physical targeting

 LIGAND MEDIATED TARGETING

 Here the ligands are anchored on to the drug carrier systems for
specific delivery.

 Antibodies, polypeptides, oligosaccharides and viral proteins acts as
ligands

 Usually these ligands are coated on the drug- carrier complex to
direct them to the receptors that are specific to them.

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 Transferrin is the commonly used cell specific ligand, which
was conjugated with to nanoparticles to target tumour cells
possessing Transferrin receptor mediated endocytosis
mechanism on their membrane.

 This method is also called as the Ligand driven receptor
mediated targeting.

PHYSICAL TARGETING

 Selective drug delivery programmed with the aid of physical
means is called physical targeting.

 In this method, some characteristics of the bioenvironment
such as temperature and pH are used to cause selective release
of the drugs

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 The release of anti-tumour drugs from temperature sensitive
liposomes in the vicinity of the tumour is brought about by
lipoproteins.

 Methotrexate was released from liposomes preferentially at
low pH regions of tumours.

DUAL TARGETING

 This approach employes a carrier that has its own
pharmacological activity thus synergises the pharmacological
effect of the loaded drug.

 Eg: Carriers with anti-viral activities are employed in the
delivery of anti-viral drugs, thus synergistic effect is produced.

 A major advantage is that the viral replication is attacked at
multiple points in this delivery.

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DOUBLE TARGETING

 In this approach, the combination is made between spatial
control and temporal control of the drug delivery.

 Temporal control – Controlled release and stimuli
responsive release

 Spatial targeting – Active targeting and passive targeting

Temporal
control

Improved
Double Therapeutic

targeting
index

Spatial
targeting

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COMBINATION TARGETING

 This approach was designed for targeting proteins and peptides.

 They are equipped with carriers, polymers and homing devices
that could provide direct approach to the target.

Modification of protein by natural polymers or synthetic
polymers

Vectorization into vesicular or microparticulate carriers

Both the polymers and carriers favour targeting to the specific
compartments

Site specific targeting of the encapsulated contents
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BIOLOGICAL PROCESSES AND EVENTS
INVOLVED IN DRUG TARGETING

Cellular Uptake and
Processing

Transport across
BIOLOGICAL Epithelial barrier

PROCESSES AND
EVENTS

Extravasation

Lymphatic uptake
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CELLULAR UPTAKE AND PROCESSING

Micromolecules Simple diffusion

Targeted drug
Macromolecules Endocytosis

delivery

Endocytosis

Pinocytosis or cell Phagocytosis or
drinking cell eating

Fluid phase Adsorptive
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 Endocytosis is divided into two types:

 Phagocytosis – capture of particulate matter

 Pinocytosis – engulfment of fluids

Phagocytosis Pinocytosis

Fluid phase pinocytosis
Carried out by special cells called

phagocytes Involves binding to general cell
surface site

Mediated by adsorption of Adsorptive pinocytosis
opsonins on the receptors located Involves binding to cell

on macrophages receptor site
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TRANSPORT ACROSS THE EPITHELIAL BARRIER

 Oral, buccal, nasal, vaginal and rectal cavities are internally lined
with one or more layers of epithelial cells.

 The lateral membrane of these cells forms intercellular tight
junctions which serves as sites of adhesion and prevent the flow of
materials through intercellular spaces.

 Various transport process to cross epithelial barrier lining are

▪ Passive diffusion

▪ Carrier mediated transport

▪ Endocytosis

 Passive transport is usually higher in damaged mucosa where as
active transport depends on structural integrity of epithelial cells.

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 Positively charged particles showed increased uptake than
negatively charged counterparts.

 Absorption of drugs from buccal can occur via transcellular and
paracellular, while paracellular being dominant.

 Larger molecules such as proteins require both penetration
enhancers and bio adhesives.

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 EXTRAVASATION

 Extravasation is the process by which any liquid or drug
accidentally leaks into the surrounding tissue.

 For a chemotherapeutic drug to exert its therapeutic effects it must
exit from the central circulation and interact with extravascular –
extracellular or extravascular -intracellular target.

Transcapillary
pinocytosis

Extravasate across Passage across
Macromolecules the normal Inter endothelial

endothelium by cell junctions

Passage across
fenestrated

endothelium
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 Factors that control permeability of capillaries

• Structure of the capillary wall

• Pathological condition

• Rate of blood and lymph supply

• Physicochemical factors of drug – Molecular size, shape and
charge

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LYMPHATIC UPTAKE

 Following extravasation drug molecules can either reabsorb into the
blood stream directly by the post capillary interendothelial cell
pores or enter into the lymphatic system and return with the lymph
to the blood circulation.

 Also drugs administered by subcutaneous, transdermal and
peritoneal routes can reach the systemic circulation by lymphatic
system.

 Soluble macromolecules smaller than 30 nm can enter the
lymphatic system, whereas particulate materials larger than 50 nm
are retained in interstitial sites and serve as sustained release depot.

 The direct delivery of drugs into lymphatics has been proposed as a
potential approach to kill malignant lymphoid cells located in
lymph nodes.

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BRAIN TARGETED DRUG DELIVERY SYSTEM

BARRIERS

BLOOD BRAIN BLOOD CSF
BARRIER(BBB) BARRIER (BCSFB)

 BBB and BCF

control the entry of compounds into the brain and regulate brain
homeostasis.

restricts access to brain cells of blood–borne compounds and
facilitates nutrients essential for normal metabolism to reach brain

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BLOOD BRAIN BARRIER

 The brain capillaries consists of

 Non fenestrated (without pores) endothelial cells which are
joined together by intercellular tight junctions.

 Pericytes and astrocytes as the supporting tissues at the base of
the endothelial membrane, which forms a solid envelope.

 This composition is called as the Blood Brain Barrier.

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 Intercellular passage is completely blocked due to the presence of
tight junctions.

 Only intracellular passage is possible that to only to lipophilic
substances.

 A solute can gain access into BBB by:

❑ Passive diffusion through lipoidal barrier

Restricted to lipophilic substances of molecular weight of
approximately 700 Daltons

❑ Active transport of essential nutrients

These includes sugars, aminoacids, choloins etc, which are
transported via carrier mediated transport.

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BRAIN TARGETED DRUG DELIVERY SYSTEM

BTDDS

Invasive Non-Invasive
approach approach

BBB Intra
Intra cerebral

Disruption ventricular Physiologic Pharmacologic
implants

infusion

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INVASIVE APPROACH

BBB DISRUPTION

Osmotic mediated BBB destruction

BBB Disruption Ultrasound mediated BBB opening

Bradykinin mediated BBB opening

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 OSMOTIC MEDIATED BBB DESTRUCTION
BBB is made permeable by

Administering intracarotid injection of an hypertonic solution
such as mannitol or arabinose

Osmotic shrinking of cerebrovascular endothelial cells

Opening or widening of interendothelial tight junctions

This technique is used for the delivery of chemotherapy to CNS

 ULTRASOUND MEDIATED BBB OPENING
BBB disruption is made by

IV injection of preformed microbubbles followed by MRI
guided ultrasound

This technique was used to deliver liposomal doxorubicin for
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Produces mechanical stress to
Microbubbles

walls of blood vessels

Low power Produces reversible opening of
ultrasound tight junctions

 BRADYKININ RECEPTOR MEDIATED BBB OPENING

BBB opening is made by

Administering Lobadimil, a synthetic bradykinin analogue

Binds with B2 receptor

Causes opening of tight junctions through a calcium mediated
mechanism

This technique offers highly specific opening and targeted drug
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INTRACEREBRAL IMPLANTS

 They are bioartificial implants composed of neurosecretory cell
core surrounded by a semi permeable membrane.

Semipermeable
membrane

Neuro secretory
cell core

 Similar to controlled release systems in that it allows for site
specific delivery to affected brain areas.

 The cell core is kept alive by passive exchange of nutrients and
waste products with surrounding extra cellular fluid through pores
in encapsulating membrane.

 It functions as a Biological sustained release system which can
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both synthesize and release neuroactive molecules.
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 Has both synthetic and release capabilities – delivery of
secretory products longer than conventional controlled release
implants.

INTRACEREBRO VENTRICULAR INFUSION

 Pharmacological effect is seen if the target receptors of the drug are
located near the ependymal surface of the brain.

 Drug is infused using an ommaya reservoir, a plastic reservoir
implanted subcutaneously in the scalp and connected to ventricles.

 Limitations:

The diffusion of the drug in the brain parenchyma is very low .

Unless the target is close to the ventricles it is not an efficient
method of drug delivery.

 Example: Glycopeptide and an aminoglycoside antibiotics used in
meningitis.

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Non- invasive
approach

Physiologic Pharmacologic

Carrier
Receptor Adsorptive

mediated Chemical Colloidal
mediated mediated

transport delivery carriers
trancytosis transcytosis

system

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NON INVASIVE APPROACH

PHYSIOLOGIC STRATEGY

 CARRIER MEDIATED TRANSPORT SYSTEM

 These systems acts as the transport systems for essential nutrients,
which carries them across the capillary endothelial cells of BBB.

 Eg: The hexose transport system for glucose and mannose

The neutral aminoacid transport for Phenylalanine

The peptide transport system for small peptides

 So the polar small molecules which mimics the molecular structure
of these essential nutrients undergoes carrier mediated transport
through BBB.

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 RECEPTOR MEDIATED TRANSCYTOSIS

 Receptor mediated drug delivery to the brain involves chimeric

peptide technology, deals with the peptide receptors which mediate

peptide transcytosis through BBB.

 Eg: Insulin gets transported via BBB mediated Insulin receptor &

Transferrin gets transported via BBB mediated Transferrin receptor

By receptor
Drug + peptide or Transported

mediated
protein vector through BBB

transcytosis

 Eg: BDNF-HIR mAb fusion (Brain Derived Neurotrophic factors
conjugated to Human Insulin Receptor monoclonal antibodies)

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 ADSORPTIVE MEDIATED TRANSCYTOSIS

 This process involves endocytosis in vesicles of charged
substances and it mainly involves brain delivery of proteins and
peptides especially “cationic proteins”.

 “Cationic antibodies” are also delivered via adsorptive mediated
transcytosis.

 Peptides such as Histone, cationized Albumin, Avidine and
Ebiratide penetrate BBB via AMT.

 Ebiratide, a synthetic ACTH analogue that is used to treat
Alzheimer’s disease is positively charged with an isoelectric point
of 10.

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PHARMACOLOGIC STRATEGY

 CHEMICAL DELIVERY

 It involves delivery of chemically modified drugs that have better
permeability across the brain capillaries.

 Here mostly prodrugs (pharmacologically inactive compounds
that on metabolism produces pharmacologically active metabolites)
are involved in chemical delivery.

 Eg: Levodopa, Valproate etc

 A classic example is Dihydropyridine – pyridinium salt redox
delivery which is used to deliver Dopamine – gives better BBB
permeability to Dopamine.

 Another classic example is AZT- 5’ trigonellate which gives better
BBB permeability to Zidovudine.

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 COLLOIDAL CARRIERS

➢ LIPOSOMES

 They are biocompatible and biodegradable lipid carriers made of
phospholipids and sphingoloipids.

 The basic mechanism involved is drug transport via receptor
mediated and adsorptive mediated transcytosis.

 Polymeric miscelles are used for tumour specific delivery of
Antineoplastic agents across BBB to treat brain tumours.

 Eg: Pluronic P85 miscelles loaded with neuroleptic drugs are targeted
to brain cells.

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➢ NANOPARTICLES

 Nanosystems employed for nano drug delivery include polymeric
nanoparticles, nanospheres, nanosuspensions etc.

 Nanoparticles enter into the brain through BBB by endocytosis.

 Coating of nanoparticles with surfactants alters their distribution in
the body.

 Coating nanoparticles with polysorbate 80 induces endocytic
uptake of the particles by endothelial cells of the blood vessels.

 Coating nanoparticles with poloxamine 908 increased the blood
concentrations after IV injection.

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TUMOUR TARGETED DRUG DELIVERY SYSTEM

 TUMOUR- DEFINITION

 A tumour is an abnormal mass of tissue which is a classic sign of
inflammation.

 It is a fluid filled lesion that may or may not be formed by an
abnormal growth of neoplastic cells that appears enlarged in size.

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 Factors that give rise to tumours

 Agents that damage genes that controls cell proliferation and that
increases the tumour cell migration

 Agents that do not damage genes that enhances the growth of
tumour cells and their precursors.

Tumour Classification

Benign tumour – slow growing, non-invasive,
well differentiated and do not metastatize

Malignant tumour – fast growing, invasive,
poorly differentiated and they undergo

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NORMAL VASCULATURE VS TUMOUR VASCULATURE

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STAGES OF TUMOUR DEVELOPMENT OF EPITHELIAL
ORIGIN

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TDDS
 DRUG DELIVERY STRATEGIES

LOAD

EVADE

PRINCIPAL
RETAIN

REQUIREMENTS
TARGET

RELEASE

 The main drug delivery methods are:

 Site specific drug delivery

 Liposomes

 Nanoparticles

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TUMOUR TARGETING AND DRUG DELIVERY SYSTEMS

 SITE SPECIFIC DRUG DELIVERY

Localization of Recognition Interaction of
Drug

drug and carrier in the target carrier with
delivery

with target cell cell target cell

CLASSIFICATION

ORGAN TARGETING

CELLULAR TARGETING

INTRACELLULAR
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 From the strategies discussed before two strategies are most commonly
employed in site specific drug delivery. They are

❑ Active targeting

❑ Passive targeting

 Multidrug resistance

 Due to the initial and subsequent chemotherapy, tumours develop resistance and
due to variety of mechanisms, a multidrug resistant tumour evolves.

 This is the main cause of failure of chemotherapy.

 This is improved by employing drug carriers.

 Various delivery systems such as liposomes and nanoparticles or microspheres
are involved in destroying tumours.

 Several mechanisms are proposed through which liposomes and nanoparticles
are employed to avoid multidrug resistance.
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 LIPOSOMES

 Liposomes provides sustained high levels of drug to the resistant
cells over a prolonged period of time.

 Tumor targeting strategies using liposomes

 Natural targeting of conventional liposomes (Passive vectorization)

 Use of long circulatory liposomes (stealth liposomes)

 Use of ligand mediated targeting (active targeting)

 Use of anti-receptor antibodies (immunoliposomes)

 Use of angiogenic peptides as ligands against the receptors
represented on tumours

 Use of triggered release of liposomes in tumour therapy which
includes pH sensitive liposomes, Thermosensitive liposomes,
magneto-activated liposomes and photoactivated liposomes.

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TRIGGERED RELEASE OF LIPOSOMES

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 NANOPARTICLES

 They are the most promising carriers used for anti-tumour drugs
in targeting to tumor tissues.

 Enhanced endocytic activity and leaky vasculature of the tumour
favours accumulation of nanoparticles in the specific site of the
tumour

 Stealth nanoparticles are prepared by coating them with soluble
polyoxyethylene and phospholipids.

 Mostly polyalkylcyanoacrylates nanoparticles are used for
targeting drugs to the specific site of the tumours.

 Eg: Doxorubicin in polyisohexylcyanoacrylate nanoparticles

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NANOPARTICLES IN TUMOUR TARGETING

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IMMUNOTHERAPY

 Immunotherapy aims at attacking disease with the defense
mechanism of the body which involves various
immunocomponents of the body such as tumour antigens
(vaccines), antibodies, monoclonal antibodies, cytokinins etc.

 Antibodies as targeting tools

 Antibodies binds to antigens of tumour cells and makes these cells
susceptible to destruction by host defense mechanism.

 Antibodies can target and attack the blood vessels and connective
tissues supporting it.

 They also block the action of growth factors that a tumour needs to
grow.

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 They also act as missiles to deliver therapeutic compounds.

Specifically
Chemotherapeutic Attached to

targeted to
agents antibodies

tumours

Toxins inhibiting Attached to Offers a better
tumour growth antibodies immunotherapy

Due to
Cytokines which

Causes tumour localization of
induce tumour

destruction inflammatory
necrosis

responses

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 Recombinant antibodies

 Immunoglobulins on the surface of the target cell exposes its tail
region (Fc) to be recognized by the Fc receptors (FcR) present
on the surface of macrophages.

 Instead of using IgG or IgM, fragments with antigen binding sites
(Fab) is exploited as ligand for FcR.

 FcR dependent tumour cell killing of antibody coated tumour
cells proceeds via receptor mediated phagocytosis.

 Monoclonal antibodies are available for all Fc receptors.

 A current new trend is the use of recombinant antibody fragments
instead of using the whole immunoglobulin.

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GENE THERAPY

 Gene therapy aims at modifying the genetic program of a cell
towards a therapeutic goal.

 Gene therapy
strategies

Modification of functions of oncogenes
and tumor suppressor genes

Suicide gene therapy involving
conversion of a prodrug into cytotoxic
substance by gene expressed enzymes

Disruption of tumor neovascularization

Lysis of tumour cells with replication
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 Various methods of drug delivery in gene therapy:

 Ex vivo delivery

Genes transferred into the stem cells and then the cells are injected
into the body.

 In vivo delivery

Direct gene delivery by using viral vectors and the genes are
transferred by ligand mediated DNA conjugates and through lipid
vesicles.

Viruses propagate
By

Made Therapeutic in the helper cell
Viral deletion of

replication agents are line that
vectors essential

defective inserted complements the
genes

essential gene

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REFERENCES

 Vyas SP, Khar RK, Targeted and Controlled Drug Delivery Novel
Carrier Systems. New Delhi; CBS publishers and Distributors
Pvt.Ltd.

 Jain NK, Controlled and Novel Drug Delivery. New Delhi; CBS
publishers and Distributors Pvt.Ltd.

 Nidhi Mishra, Prerna Pant, Ankit Porwal, Juhi Jaiswal,
Mohd.Aquib Samad, Suraj Tiwari, Targeted drug delivery,
American Journal of Pharmtech Research. 2016; Vol 6(1), ISSN:
2249-3387: Pg 1-25.

 Aman kumar, Ujjwal Nautiyal, Charanjeet Kaur, Vaishali Goel,
Neha Piarchand, Targeted drug delivery system : current and
novel approach, International Journal of Pharmaceutical and
Medicinal Research. 2017; Vol 5(2), ISSN: 2347-7008: Pg 448-
454.

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 Bora CR, Prabhu RH, Patravale VB, Lymphatic delivery :
concept, challenges and applications, Indian drugs. 2017;
Vol 54 (8) : Pg 5-22.

 Liangliang Dai, Junjie Liu, Zhong Luo, Menghuan Li,Kaiyong
Cai, Tumour therapy : targeted drug delivery systems, Journal of
Meterials Chemistry. 2016.

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THANK YOU
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