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Presented By

R. VenkateshM. Pharm 1st year 2nd semDepartment : Pharmaceutics

Guide: Mr. RAGHU KIRANTKR College Of Pharmacy.

1

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CONTENTS

Introduction

Tumour Microenvironment and stages in tumordevelopment

Targeted drug delivery systems

Strategies to Deliver Drugs to Targets within theTumour (Cells) Liposomes Pro drug strategy Nanoparticles Monoclonal antibodies-mediated Therapeutics Dendrimers

Tumour targeting with folic acid Tumour targeting with peptides

Conclusion

References

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INTRODUCTION Cancer is a leading cause of death around the world.

Tumour is an abnormal new mass of tissue that serves no

purpose . The term tumour / tumor is derived from

the Latin word called "swelling". A tumour is the name for

a neoplasm or a solid lesion formed by an abnormal growth of

cells (termed neoplastic) which looks like a swelling. A tumor

can be benign, pre-malignant or malignant, whereas cancer is

by definition malignant.

The best treatment of malignancies such as gastric, colonic, and

cervical cancers is surgical removal of early-stage tumours that

are small and confined to a limited area, without metastasis.

http://en.wikipedia.org/wiki/Latinhttp://en.wikipedia.org/wiki/Neoplasmhttp://en.wikipedia.org/wiki/Neoplasmhttp://en.wikipedia.org/wiki/Benign_neoplasmhttp://en.wikipedia.org/wiki/Pre-malignanthttp://en.wikipedia.org/wiki/Malignanthttp://en.wikipedia.org/wiki/Malignanthttp://en.wikipedia.org/wiki/Pre-malignanthttp://en.wikipedia.org/wiki/Pre-malignanthttp://en.wikipedia.org/wiki/Pre-malignanthttp://en.wikipedia.org/wiki/Benign_neoplasmhttp://en.wikipedia.org/wiki/Neoplasmhttp://en.wikipedia.org/wiki/Neoplasmhttp://en.wikipedia.org/wiki/Latin

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Chemotherapy, and to a limited extent radiotherapy, have

been the last resort to control cancer.

Conventional chemotherapeutic agents are distributed non-

specifically in the body affecting both normal and tumoral cells.

Genes responsible for tumour development

Oncogene

Tumour suppressor genes

Suicide genes

DNA repair genes

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TUMOUR MICROENVIRONMENT

Numerous differences between tumour and normal tissue includingvascular abnormalities, oxygenation, perfusion, pH and metabolic

states.

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STAGES OF TUMOUR DEVELOPMENT

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The three groups of capillaries have been identified(a)continuousthe endothelial cells are connected via tight junctions to form a

continuous monolayer or an uninterrupted basement membrane.

(b) fenestratedendothelium is interrupted by fenestrae of diameter 30-80nm they are mainly found in tumours' .

(c)discontinuous or sinusoidalthey have a discontinuous endothelium and large

fenestrate with a mean diameter of about 100nm they predominantly found

in the liver , spleen , and bone marrow.

http://picasaweb.google.co.in/lh/photo/tbyvjUIUvQMkrr5ODEGBng?feat=embedwebsite

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Targeted drug delivery is a method of delivering

medication to a patient in a manner that increases the concentrationof the medication in tissues of interest while reducing the relative

concentration in other parts of the body. This

improves efficacy while reducing side effects .Targeted drug

delivery can be used to treat many diseases but the most important

application of targeted drug delivery is to treat cancerous tumours.

TARGETED DRUG DELIVERY SYSTEMS

SITE SPECIFIC DRUG DELIVERYIt is a part of targeted drug delivery system and includes the localization

of drug and carrier with in the desired target organ.(a.) Delivery to individual organs or tissues (organ targeting).

(b.)Targeting to specific cell types with in the tissue (cellular

targeting).

(c.)Delivery to different intracellular compartments (intracellular

targeting).

http://en.wikipedia.org/wiki/Efficacyhttp://en.wikipedia.org/wiki/Adverse_reactionhttp://en.wikipedia.org/wiki/Drug_deliveryhttp://en.wikipedia.org/wiki/Cancerous_tumorhttp://en.wikipedia.org/wiki/Cancerous_tumorhttp://en.wikipedia.org/wiki/Cancerous_tumorhttp://en.wikipedia.org/wiki/Cancerous_tumorhttp://en.wikipedia.org/wiki/Drug_deliveryhttp://en.wikipedia.org/wiki/Drug_deliveryhttp://en.wikipedia.org/wiki/Drug_deliveryhttp://en.wikipedia.org/wiki/Adverse_reactionhttp://en.wikipedia.org/wiki/Adverse_reactionhttp://en.wikipedia.org/wiki/Adverse_reactionhttp://en.wikipedia.org/wiki/Efficacy

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Liposomes Structure of phospholipid

9

Targeted Drug Delivery To Tumours

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Liposomes could serve as tumour specific vehicles (even without

special targeting)

Liposomes better penetrate into tissueswith disrupted endothelial lining

Fig 16: Penetration of liposomes into normal and tumour tissue

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TYPES OF LIPOSOMES

Multilamellar vesicles (MLVs)- It has a size of 5000nm.

Multivesicular vesicles (MVVs)- It has a size of several

microns of more than 1000nm.

Oligolamellar vesicles (OUVs)-It has a size range of 100-

1000nm.

Unilamellar vesicles(ULV)-It has a size range ranging from20-1000nm.

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Mostly for therapy 50 to 100nm Liposomes are used.

CLASSES OF LIPOSOMESConventional Liposomes : which can store both water and fat solubledrugs in them with no attachments on its surface. Having a half life of

two and a half days.

Stealth Liposomes : These are also called as pegylated Liposomes

because the surface of this liposome is covered with many PEG (polyethylene glycol )molecules which are attached to the surface

covalently.

Immune Liposomes : The surface of these Liposomes is attached with

specific antibody which attacks the antigen for which it is made anddestroys it.

Cationic liposomes orDOTAP : when these cationic liposomes bind

with negatively charged nucleic acids on its surface through

electrostatic interaction these are called lipoplexes .

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Because of their reduced recognition anduptake by the phagocytic system, these

liposomes are referred to as stealth liposomes.

Stealth Liposomes

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Pro-drug Strategy

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NANOPARTICLES

A nanoparticle is a particle containing adsorbed or entrapped drug ina sterilizable ,nontoxic and biodegradable polymer , e.g.:

polyalkylcyanoacrylate , poly ( lactide -co - glycolide ) and polyvinyl-

pyrrolidone . (50-200nm)

CLASSES OF NANOPARTICLES

Expansile Nanoparticles : when they are up taken by endosomes they

swell in response to acidic pH and destabilize endosome which causes

the release of drug into the cytoplasm and eventually tumor death.Quantum dots Nanoparticles : these are used to identify the bio

markers in tumor tissue.

Nanocarriers : these are the Nanoparticles which contain both drug as

well as nucleic acid.

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MagneticNanoparticles: They are commonly composed of magnetic

elements like Fe, nickel, Cobalt and their oxides like magnetite (Fe3O4),

Magnemite (Y-Fe2O3), cobalt ferrite (Fe2CoO4), chromium dioxide

(CrO2). Magnetic biocompatible materials provide the ability to bedirected and concentrated with in the target tissue by means of external

magnetic field and to be removed once therapy was completed.

C60 are spherical molecules about

1nm in diameter, comprising 60carbon atoms arranged as 20 hexagons

and 12 pentagons: the configuration of

a football.

On the other hand with development

of various chemical substitutes for

C60, it is possible to develop

functionalized C60 with better drug

targeting properties

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MONOCLONAL ANTIBODIES

The Monoclonal antibodies are very small protein particles

with size of less than 10 nm. The tissue accessibility depends onthe route of administration

Intravenous: Direct access to vasculature.

Subcutaneous: Access to local lymph (indirect access to

vasculature).

MAbs are purified antibodies produced by a single source

or clone of cells.

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Chemotherapeutic agents when

attached with antibodies are

specifically delivered to tumour sites

thus curtailing the dose and hence

associated side and toxic effects.

Radioactive isotopes, such as131I or 99Y, kill tumour cells by

damaging their DNA.

Prostascint: monoclonalantibody for imaging prostate

cancer.

Zevalin : used for the treatment of

non Hodgkins lymphoma

Some of the examples of

MAbs:

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CLASSES OF ANTIBODIES

Figure 8 : Types of antibodies

F(ab) : Univalent fragments with one

antigen binding site. Has a half life of

less than 12 Hrs, with a molecular sizeof 50kD.

F(ab)2 : Bivalent with covalently

linked F(ab) fragments. It has a half life

of 2 days, with a molecular weight of

100kD.

Fv : It is same as the ScFv but the

polypeptide linker is not present which

prevents the VH and VL domain from

falling apart.

Bispecific antibodies : This type of

antibody is made by joining two halfs of

two different antibodies. It is also called

as Trifunctional antibody.

Chemically linked F(ab)2 : In this Fab

parts of two antibodies are linked by

polypeptide linker.

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DENDRIMERS

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These are highly branched, monodispersive , polymacro

molecules. In this the multifunctional core molecule is attached to

polymer branches. Drug can be inserted b/w the branches and held

until interactions release it. Many classes of Dendrimers vary by

functional groups on it. The polymer used in Dendrimers

preparation is poly( amido-amine) or PAMAM. Dendrimers are 10

times smaller than the liposomes.

CLASSES OF DENDRIMERS

Folate conjugated: Many tumor cells over express folate

receptors so when a folate conjugated Dendrimers is given it will

directly go to the tumour site and kill it.

Glycodendrimer: Increased glycosylation occurs on tumor cells,

Glyco Dendrimers can be released at the site of tumour to increase

tumour specific antigens. This increases the number of antibodies

for tumour cell destruction.

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pH dependent: Polymers are made so when pH change occurs,

the polymer branch interactions promote the release of drug.

Because the pH at tumor site is generally more acidic

polypropylene imines can be used as polymer branch.

Tumor-targeting with folic acid

Folic acid taken from food is delivered to epithelial cells through a

kind of receptor-mediated endocytosis, potocytosis.(Fr-a and Fr-b),Theexpression of Fr in normal tissues is low and is restricted to various

epithelial cells .In contrast Fr is over expressed in various tumours

,particularly in ovarian and endometrial cancers.

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Tumor targeting with peptides

Peptide-based targeting of tumor-associated receptors is an

attractive approach in tumor-specific drug delivery because high-

affinity sequences can be discovered through screening of

combinatorial libraries.

Gastrointestinal (GI) peptides have many physiological functions

as hormones, neurotransmitters, and growth factors. Each of these

peptides usually targets more than one receptor. Thus, these peptides

and their truncated analogs, possessing appropriate recognition

properties, could serve as tumor-targeting molecules in combination

with cytotoxic agents.

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CONCLUSION AND FUTURE PROSPECTIVES

The innovation in the field of research on the targeted drug

delivery in the coming years would be a shift from receptor to

nucleus reflecting a desire to construct defined pathway linking the

end points of different regulatory cellular events. In the future,

targeted drug-delivery systems may also prove particularly valuableto enable the use of drug that seems to be ineffective or toxic, if

delivered systemically e.g., neural growth factor (which need to

cross blood brain barrier) or vaccines (which need to be taken up by

antigen presenting cells). Many of the new drug delivery systemsare going to come based on the concept ofmagicbullet.

REFERENCES

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REFERENCES

WEBSITEShttp://www.differencebetween.net/science/health/difference-between-tumor-and-cancer/#ixzz1E56SWv4vhttp://www.pharmainfo.net/reviews/recent-trends-targeted-drug-delivery-systems on cancer an-overview

BOOKS

S.P.Vyas and R.K.Khar- targeted drug delivery to tumours- chapter 14- page

number 512-561.

JOURNALS

Weinberg, Robert A. (September 1996). "How Cancer Arises; An

explosion of research is uncovering the long-hidden molecular

underpinnings of cancerand suggesting new therapies" (PDF).Scientific American: 6270.

http://www.bme.utexas.edu/research/orly/teaching/BME303/Weinb

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