NANOTECHNOLOGY IN

CANCER TREATMENT

CANCER - WORLDWIDE World’s 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 middle-income 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 (O’Connor 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

12.6M CANCER CASES AND 7.6M DEATHS AROUND THE WORLD

NEW TECHNOLOGY is needed…..

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

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.

UNIQUENESS IN THERAPHY

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 (Singer et al., 1959)

PEG ligands (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 don’t just pass through the body.

2. Need to be small enough they don’t 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:

Therapeutic agents to Nanoparticles

Incorporation

Adsorbtion

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 of nanoparticles at the tumor site

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 binds to receptor on tumor surface

Plasma 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 P-glycoprotein

(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,

Kaposi’s 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