NANOTECHNOLOGY

IN
CANCER TREATMENT

CANCER - WORLDWIDE

Worlds first documented cancer case was in 1500 b.c. in ancient

Egypt.

Now, Cancer is a leading cause of death worldwide around 13% of

all deaths

7.6 MILLION people worldwide died from cancer in 2008.

Approximately 70% of cancer deaths occur in low- and middleincome countries.

Global cancer incidence could increase to 15 million by 2020

WHO estimates 12 MILLION cancer deaths worldwide in 2030.

IN INDIA

Cancer is the second biggest cause of death in

India, growing at 11 per cent annually. There are
2.5 million cancer cases and four lakh deaths
a year in India

One in five Indian men dies between age 30 and

69 due to tobacco-related cancers.

CANCER
Complex

disease caused by genetic instability and

accumulation of multiple molecular alteration
(Kumar et al., 2009)

Activation

of oncogenes and inactivation of tumor

suppressor genes
(Sarkar et al., 2007)

Rapid

growth of abnormal cells which invade adjacent

parts of body and metastases

CONVENTIONAL
CHEMOTHERAPY

Most anticancerous agents do not differentiates

between cancer and normal cells
Leads to systemic toxicity and adverse effects
Severe side effects bone marrow suppression,
cardiomyopathy, neurotoxicity, hair loss
Multidrug resistant :
Cancer

cells acquire resistance upon repeated

chemotherapy
(OConnor et al., 2007)
Cross resistance to wide range of drugs
(Higgins et al., 2007)

RADIATION THERAPHY

Early side effects - nausea, fatigue and hair loss.

Late side effects - lung & heart problems.
Depending on the part of body being treated side
effects are
Diarrhea
Hair

loss in the treatment area

Mouth problems
Nausea and vomiting
Swelling
Trouble swallowing
Urinary and bladder changes

NEW TECHNOLOGY is needed..

12.6M CANCER CASES AND 7.6M DEATHS AROUND

THE WORLD

NANO TECHNOLOGY

Small Science with a Huge Potential

DEFINITION
Self-guiding, adaptive, multicomponent
systems on the nanoscale for diagnostic and
therapeutic prevention or treatment of
disease

UNIQUENESS IN THERAPHY

Nanotechnology allow treatments that target cancer

cells without harming nearby healthy cells

Allows creation of therapeutic agents that have a

controlled, time-release strategy for delivering
drugs.

NANOPARTICLES

10 100 nm in size
Consists of core from simple to complex
Core contains 1 or several drugs and permeation &
visibility enhancers
Surface may be bare or conjugated to target ligands
Antibody
PEG

ligands

(Singer et al., 1959)

(Mehvar et al., 2000)

Should be larger than 10 nm to avoid single-pass

renal clearance
Not to be positively charged to great extent

Two major concerns

1. To be large enough they dont just pass through

the body.
2. Need to be small enough they dont accumulate in
vital organs and create toxicity problems.

NANOPARTICLES

Typically between 10 and 100 nanometers

NANOPARTICLES

Liposomes
Polymeric micelles
Nanoshells
Fullerene based derivatives
Carbon nanotubes
Dendrimers
Solid lipid nanoparticles
Magnetic nanoparticles

LIPOSOMES

Microscopic synthetic vesicles composed of phospholipid and

cholesterol

Closed vesicles consisting of single lipid bilayer encloses aqueous

compartment
(Bawarski et al., 2008)

Drugs can loaded either in aqueous compartment or in liposomal

membrane.

Fatty layers protects the drug until it delivered to target tumor

cells.

Size less than 400 nm readily penetrates to the tumor cells.

(Arayne et al., 2007)

They are rapidly degraded and cleared by liver

macrophage
Coating liposomes with polyoxyethylene prevent
phagocytosis
Have the ability to reduce side effects.

POLYMERIC MICELLES

Supramolecular, spherical, colloidal nanoparticles

Inner core serve as nanocontainer for hydrophobic molecules

Outer shell is hydrophillic, have flexible strands of polymer

(Kataoka et al., 2001)

Have high durability in blood stream and effective tumor

accumulation
(Nishiyama et al., 2006)

Water soluble and administered i/v

Advantages:
Prolonged

half life
Efficient drug loading
capacity
Evading defenses
Selective accumulation at
tumor site
Lower toxicity

CARBON NANOTUBES

Consist of carbon atom arranged in series

Two categories:

Single wall CNT

Multi wall CNT

(Lacerda et al., 2006)

Absorb materials on their surface and heating up upon absorbing near

IR rays.

When exposed to NIR, CNT release energy as heat

(Mansoori et al., 2007)

Cancer cells express folate receptors

Functionalisation of CNT with folate moiety, binds to folate receptor in

cancer cells and cause death

Single walled

Multi walled

DENDRIMERS

Size : 10 100 nm in diameter

Macromolecules with regular and multiple branches
emerging from a single radial centre
(Morrow et al., 2007)

Multiple branches are used for covalent attachment

of special targeting moieties,
Sugar

(Bhadar et al., 2005)

Folic

acid
(Licciardi et al., 2006)
Antibodies
(Patri et al., 2004)
Biotin
(Yang et al., 2009)
Epidermal growth factor

(Hussain et al., 2004)

MAGNETIC NANOPARTICLES

Size: 50-300 nm

Magnetic effect of MNP is due to superpara magnetic iron oxides

(Moffat et al., 2001)

Iron oxides core is surrounded by silicon coat or dextron or

polyacrylamide

Polymer coating prevents their cytotoxicity

MNPs are sensitive to magnetic field and electromagnetic radiations

This induces hyperthermia which kills cancer cells

FULLERENES

Crystalline particle in the form of carbon atoms

Buckminster fullerenes (C60) resembles soccer ball

Fullerene cages 0.7 to 1.5 nm in diameter

Cage structure attaching anticancer agents

Potential to carry multiple drug payloads

Good stability, safe delivery

(Moghimi et al., 2001)

NANOSHELLS
Metal based nanoparticles
Composed of solid core of silica with a surrounding thin
metallic layer, often gold
(Shi et al., 2005)
Enter tumor tissue by large pores in the regular blood
vessel walls
Absorb light in the NIR region and convert this to heat
destroying cancer cells
Antibodies may also attached to nanoshells to promote
tumor specificity.

DIAMONDOIDS

Caged hydrocarbons
Smallest diamondoid adamantone
Adamantyl amino-pyrimidines & pyridines are
strong stimulants of TNF alpha
(Kazimierczuk et al., 2001)

Dimethyl adamantylmaleimide inhibits human

colon cancer
(Wang et al., 2001)

DRUG NANOPARTICLES

Designed by:

Incorporation
Incorporation
Adsorbtion
Adsorbtion

Therapeutic agents to
Therapeutic agents to
Nanoparticles
Nanoparticles

ROUTES OF ADMINISTERATION

Oral: Most convenient but duodenal enzymes &

bile salts are barriers

Oral: NP containing alpha- tocopheryl PEG 1000

succinate

S/C or I/P: Regional lymph nodes

I/V: Most commonly practised

STEALTH NANOPARTICLES

Nanoparticles are easily recognised by immune system

and cleared by phagocytes

Hydrophobicity of NP determines opsonization and

once opsonised, it is readily cleared by MPS

To minimise opsonization NPs are coated with

biodegradable coplymers such as PEG, Polyethylene
oxide,Polyoxamer,Poloxamine

PEG causes steric repulsion by creating hydrated barrier

on nanoparticle surface that prevent opsonization

PEGylated NPs not only have long half life but also
able to extravasate in leaky vasculature sites

In conventional NPs cytotoxicity against Kupfer cells

occur and also targets bone marrow causes
myelosupression

Drug release:

Incorporation method: Small burst effect & better

sustained release

If nanoparticle is coated by polymer, release depend on

diffusion across polymeric membrane

Rate of release depend on:

-solubility of drug
-desorption of surface bound drug
-diffusion through NP matrix
-NP matrix erosion

NANOPARTICULATE TARGETING

Nanoparticles are delivered to specific sites by

Passive targeting

Active targeting

PASSIVE TARGETING

Fast growing cancerous tissue have leaky defective

blood vessels and impaired lymphatic drainage

Enhanced Permeability and Retention effect

Cancer

cells have a constant need for oxygen and

nutrients
Multiple

disorganized pores in tumor blood vessels and

inflated gap junctions between endothelial cells
(Duncan et al., 2003)

EPR effects results in accumulation

nanoparticles at the tumor site

of

Size and surface properties of nanoparticle must be

controlled to avoid uptake by RES.

Size less than 100 nm in diameter and hydrophillic

surface to maximize circulation time and
targeting ability

Tumour activated pro-drug therapy:

Drug is conjugated to tumour specific molecule and

remain inactive till it reaches target

Direct local delivery:

Highly invasive

PASSIVE TARGETING

ACTIVE TARGETING

Targeting ligand is incorporated on NP surface

Bind to tumour associated antigen/receptor and

facilitates delivery of NP

Increases intracellular drug delivery to cancer cells

Cancer cell over expresses folate and transferrin

receptors

LIGANDS TO TARGET CANCER

Ligands to target cancer cells:

Antibody
Small peptides
Lectin
Aptamers

Surface receptor targeting:

LHRH receptor in plasma membrane ovarian, breast and
prostrate cancer
(Darap et al., 2005)
Asialo glycoprotein target for hepatoma cells

ACTIVE TARGETING

Antigen expression of the tumor:

Involves linking antibodies with nanoparticles that will bind

with tumor antigens

Complimentary surface receptors must be located only on

cancerous cells

Receptors must be expressed equally on all target cells

Receptors must never be shed into bloodstream.

ACTIVE TARGETING

Internalization of nanoparticles:
Ligands
Plasma

binds to receptor on tumor surface

membrane invaginates forming an endosome

Endosomes

transported to target organelles

Bond

between drugs and nanoparticles are broken by

either hydrolysis or enzymes

Lysozymes

are triggered when pH becomes acidic

ACTIVE TARGETING

MULTI DRUG RESISTANCE

Anticancer drugs even if they are located in tumour interstitium

have limited efficacy against numerous solid tumours

MDR occur due to over expression of plasma membrane Pglycoprotein

(Krishna et al.,2000)

Use of colloidal carrier, NPs can restore tumoural cells sensitivity

P-glycoprotein recognize the drug to be effluxed out of cell only

when it is present in plasma membrane
(Lassen et al.,2000)

Active targetting mechanism provide alternative route

for overcoming multiple drug resistance

ANTICANCER DRUG NANOPARTICLES

Doxorubicin:
PEGylated liposomal nanoparticle

Treatment of ovarian carcinoma, metastatic breast cancer,

Kaposis sarcoma
Doxil, FDA approved drug NP

Paclitaxel:
Albumin bound
Treatment of breast cancer
Abraxane (100mg paclitaxel+900mg albumin)

RECENTLY DEVELOPED
NANODRUGS

APPLICATION OF NANOTECHNOLOGY

ADVANTAGES OF
NANOPARTICLES

Nanoparticles controls and sustain the release of drug

at site of localization

Site specific targeting is achieved by attaching

targeting ligand

Particle size and surface characteristics of NP can be

modified easily

Reversion of multi drug resistance

TOXICITY OF NANOPARTICLES

Have higher chemical reactivity and biological activity

due to its smaller particle size

Increased production of free radicals,ROS

NPs such as carbon nanotubes,fullerenes induces ROS

production

ROS production is the primary mechanism of NP

toxicity

Thank U