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GROUP MEMBERS:

NAME : NUR ADIBAH BINTI ADNAN – 2014690162

SAZLIN IMAZ BINTI MOHD ISMAIL - 2014409528

AINUL MARDHIAH BINTI ABDUL RAHIM – 2014437822

FACULTY : CHEMICAL ENGINEERING FACULTY (FKK)

PROGRAM : EH220

GROUP : EH2201A

CODE & COURSE : CHE434 / PROCESS CHEMISTRY

TOPIC : ASSIGNMENT 2

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QUESTION MARKSAbstract /3Research background /10Characterization /10Application /4References /3Total /30

1.1 Abstract

The development of novel nanomaterials and their use in biomedicine has received

much attention in recent years. Significant advances have been made in the synthesis

of nanomaterials with controlled geometry, physicochemical properties, surface charge,

and surface tailoring with bioactive polymers. These successful efforts have resulted in

improved biocompatibility and active targeting of tumour tissues, leading to the

development of a diverse range of nanomaterials that can recognize cancers, deliver

anticancer drugs and destroy tumours by a variety of therapeutic techniques. The focus

of this review is to provide an overview of the nanomaterials that have been devised for

the detection and treatment of various types of cancer, as well as to underline the

emerging possibilities of nanomaterials for applications in anticancer therapy.In the

present study,there are the ability of Titanium Dioxide nanoparticles to act as a drug

carrier for loading doxorubicin.It also bonds with an antibody and attaches itself to

cancer cells.This nanobio technology may eventually provide an alternative form of

therapy that targets only cancer cells and does not affect normal living tissues.Titanium

Dioxide is a versatile photoreactive nanomaterial that can bonded with

biomolecules.Under this study also the characterization method used consists of Atomic

force microscopy and Transmission electron microscopy in study of cancer

cells.However in the side of application for this study of nanomaterial in treating cancer

GROUP MEMBERS:

NAME : NUR ADIBAH BINTI ADNAN – 2014690162

SAZLIN IMAZ BINTI MOHD ISMAIL - 2014409528

AINUL MARDHIAH BINTI ABDUL RAHIM – 2014437822

FACULTY : CHEMICAL ENGINEERING FACULTY (FKK)

PROGRAM : EH220

GROUP : EH2201A

CODE & COURSE : CHE434 / PROCESS CHEMISTRY

TOPIC : ASSIGNMENT 2

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cells is drug carrier role of Titanium Dioxide nanoparticle and the second application is a

targeted cancer treatment using Titanium Dioxide nanomaterials.

1.2 Background Studies

Titanium dioxide

Titanium (Ti), the ninth most bountiful element in the earth's crust and having the

average concentration in the earth's crust is 4400 mg/kg. Due to its tendency for oxygen

and other element, Ti does not exist in the metallic state. The most common oxidation

state of Ti is +4, but +3 and +2 states also exist. Metallic Ti, TiO2, and TiCl4 are the

compounds most widely used in industry. TiO2 (CAS-No. 13463-67-7), also known as

titanium (IV) oxide, titanic acid anhydride, titania, titanic anhydride, or Ti white, is the

naturally occurring oxide of Ti. TiO2 is a white non-flammable and odourless powder

with a molecular weight of 79.9 g/mol, boiling point of 2972°C, melting point of 1843°C,

and relative density of 4.26 g/cm3 at 25°C. TiO2 is a poorly soluble particulate that has

been widely used as a white pigment.

Titanium dioxide has two crystal structures that is anatase and rutile, with anatase being

more chemically reactive. Indeed, anatase generates ROS when irradiated by UV light.

It has been suggested that TiO2 anatase has a greater toxic potential than TiO2 rutile.

However, anatase-generated ROS does not occur under ambient light conditions. TiO2

NPs are normally a mixture of anatase and rutile crystal forms. The principal parameters

of particles affecting their physicochemical properties include shape, size, surface

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characteristics and inner structure. TiO2 FPs (the rutile form) is believed to be

chemically inert. However, when the particles become progressively smaller, their

surface areas, in turn, become progressively larger, and researchers have also

expressed concerns about the harmful effects of TiO2 NPs on human health associated

with the decreased size. Surface modification such as coating, influences the activity of

TiO2 NPs. [1]

Titanium dioxide (TiO2) nanoparticles can act as photosenitizer which is a known photo

catalyst and reacts with water to produce oxidizing free radicals when exposed to UV

light, which can result in localized damage to nearby cells. Recent in vitro studies on

glioma cells have demonstrated the potential of such nanoparticles for photodynamic

therapy. A similar effect has recently been produced in TiO2 nanoparticles with

ultrasonic stimulation, which is able to kill nanoparticle-impregnated glioma cells when

exposed to ultrasound in a similar manner to UV-stimulated nanoparticles. TiO2

nanoparticles are also essentially non-toxic and hence show considerable promise as

cancer therapy agents. [2]

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synthesis of titanium dioxide

Solution route

precipitation

solvothermal

electrochemical

combustion

microemulsion

sol-gel

gas phase method

CVD

PVD

SPD

other method

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Solution route

The most preferred for the synthesis of nanostructured titanium dioxide for, especially

the synthesis of thin films. The benefit of this method is the ability to control over the

stoichiometry, producing homogeneous materials, allowing formation of complex

shapes, and preparation of composite materials. However, it might need expensive

precursors, long processing times, and the presence of carbon as an impurity.

Precipitation Method

These involve precipitation of hydroxides by the addition of a basic solution (NaOH,

NH4OH and urea) to a raw material followed by calcination to crystallize the oxide. It

usually produces anatase even though sulphate or chloride is used. In particular

conditions, rutile may be obtained at room temperature. The disadvantage is the tedious

control of particle size and size distribution, as fast (uncontrolled) precipitation often

causes formation of larger particles instead of nanoparticles as raw materials, TiCl3 or

TiCl4 are mainly used.

Solvothermal Method

These methods employ chemical reactions in aqueous (hydrothermal method) or

organic media (solvothermal method) such as methanol, 1,4 butanol, toluene under

self-produced pressures at low temperatures (usually under 250 0C). The solvothermal

treatment could be useful to control grain size, particle morphology, crystalline phase,

and surface chemistry by regulating the solution composition, reaction temperature,

pressure, solvent properties, additives, and ageing time. As sources of Titanium dioxide,

in hydrothermal synthesis, TiOSO4, H2TiO(C2O4)2, H2Ti4O9.0.25 H2O, TiCl4 in acidic

solution, and Ti powder are reported as examples.

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Hydrothermal Method

Hydrothermal synthesis is normally conducted in autoclaves with or without Teflon liners

under controlled temperature and/or pressure with the reaction in aqueous solutions.

The temperature can be elevated above the boiling point of water, reaching the

pressure of vapour saturation.

Titanium dioxide nanoparticles can be obtained by hydrothermal treatment of peptized

precipitates of a titanium precursor with water. The precipitates were prepared by using

solution of isopropanol and titanium butoxide into deionized water, and then they were

peptized at 70 °C for 1 hour in the presence of tetraalkylammonium hydroxides

(peptizer). After filtration and heat treatment, powder of Titanium dioxide nanoparticles

was obtained.

Titanium dioxide nanoparticles mainly with anatase phase were synthesized by using

titanium alkoxide, added drop wise to a mixed ethanol and water solution at pH 0.7 with

nitric acid, and reacted at 240 °C for 4 hour. Titanium dioxide nanorods have also been

synthesized with the hydrothermal method. Zhang et al. obtained titanium dioxide

nanorods by treating a dilute TiCl4 solution at 333-423 K for 12 hour in the presence of

acid or inorganic salts. A film of titanium dioxide nanorods deposited on a glass wafer

was reported by Feng et al. using titanium trichloride aquous solution supersaturated

with NaCl.

Titanium dioxide nanowires are obtained by treating titanium dioxide white powders in a

10-15 M NaOH aqueous solution at 150-200 °C for 24-72 hour without stirring within an

autoclave. Briefly, titanium dioxide powders are put into a 2.5-20 M NaOH aqueous

solution and held at 20-110 °C for 20 hours in an autoclave. Titanium dioxide nanotubes

are obtained after the products were washed with a dilute HCl aqueous solution and

distilled water.

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Sol–gel Method

Sol-gel methods are used for the synthesis of powders, membranes, and thin films of

Titanium dioxide nanoparticles, nanotubes, nanobelts etc. The sol–gel method has

many advantages such as purity, homogeneity, ease and flexibility in introducing

dopants in large concentrations, stoichiometry control, control over the composition, and

the ability to coat large and complex areas compared to other fabrication techniques. In

a typical sol-gel process, a colloidal suspension, or a sol, is formed from the hydrolysis

and polymerization reactions of the precursors, which are usually inorganic metal salts

or metal organic compounds such as metal alkoxides. Complete polymerization and

loss of solvent leads to the transition from the liquid sol into a solid gel phase. Sol-gel

method is mainly divided into two routes, namely non-alkoxide and the alkoxide. The

non-alkoxide route uses inorganic salts (such as nitrates, chlorides, acetates,

carbonates, acetylacetonates, etc.), which requires an additional removal of the

inorganic anion, while the alkoxide route uses metal alkoxides as starting material. In

alkoxide route a sol or gel of titanium dioxide is obtained by hydrolysis and

condensation of titanium alkoxides. As titanium sources, titanium-tetra-ethoxide,

titanium-tetraisopropaxide, and titanium-tetra-butoxide are most commonly used

alkoxides.

Micro emulsion method

Water in oil micro emulsion has been successfully utilized for the synthesis of

nanoparticles. Micro emulsions may be defined as thermodynamically stable, optically

isotopic solutions of two immiscible liquids consisting of micro domains of one or both

stabilized by an interfacial film of surfactant. The surfactant molecule generally has a

polar (hydrophilic) head and a long-chained aliphatic (hydrophobic) tail. Such molecules

optimize their interactions by residing at the two-liquid interface, thereby considerably

reducing the interfacial tension. In particular, hydrolysis of titanium alkoxides in micro

emulsions based on sol–gel methods has yielded uncontrolled aggregation and

flocculation except at very low concentrations.

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Combustion synthesis

Combustion synthesis (hyperbolic reaction) leads to highly crystalline fine/large area

particles. The synthetic process involves a rapid heating of a solution/compound

containing redox mixtures/redox groups. During combustion, the temperature reaches

about 650 0C for a short period of time (1–2 min) making the material crystalline. Since

the time is so short, particle growth of Titanium dioxide and phase transition to rutile is

avoided.

Electrochemical synthesis

Electrochemical synthesis may be used to prepare advanced thin films such as

epitaxial, superlattice, quantum dot and nanoporous ones. Also, controlling electrolysis

parameters like potential, current density, temperature and pH can easily control the

characteristic states of the films. Eventhough, electro deposition of titanium dioxide films

by various Ti compounds such as TiCl3, TiO(SO4), and (NH4)2TiO(C2O4)2 is reported, use

of titanium inorganic salts in aqueous solutions is always accompanied by hinder, due to

the high tendency of the salts to hydrolyze. Also, to that nanoporous titanium dioxide

thin films have been synthesized anodization of titanium sheet in aqueous solution of

fluorine containing compound.

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Gas phase methods

Used for the preparation of thin films. These methods can involve chemical or physical

reaction. Powders can also be synthesized by this method.

Chemical vapor deposition (CVD)

Chemical Vapor Deposition is a widely used versatile technique to coat large surface

areas in a short span of time. The family of CVD is extensive and split out according to

differences in activation method, pressure, and precursors. Compounds, ranging from

metals to composite oxides, are formed from a chemical reaction or decomposition of a

precursor in the gas phase.

Physical Vapor deposition (PVD)

Physical Vapor Deposition is another class of thin-film gas phase deposition techniques

in which precursor and product do not go under chemical changes because of the

stability of gas phase. The most commonly employed PVD technique is thermal

evaporation. PVD is a so-called line-of sight technique, example; the gaseous stream of

material follows a straight line from source to substrate. This leads to shadow effects

that does not present in CVD. In electron beam (Ebeam) evaporation, a focused beam

of electrons heats the selected material. These electrons in turn are thermally generated

from a tungsten wire that is heated by current. Titanium dioxide films, deposited with E-

beam evaporation, have superior characteristics over CVD grown films where

smoothness, conductivity, presence of contaminations, and crystallinity are concerned,

but on the other hand, production is slower and more laborious.

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Spray pyrolysis deposition (SPD)

SPD is a type of CVD in which aerosol deposition technique is used for the synthesis of

nanostructured titanium dioxide thin films and powders. There are several small

derivatives of this technique, mainly differing in the formation step of the aerosol and the

character of the reaction at the substrate (gas-to-particle synthesis and droplet-to-

particle synthesis). It has been used for preparation of (mixed) oxide powders/films and

uses mostly metal-organic compounds or metal salts as precursors. The size of the

particles formed and the morphology of the resulting film are strongly dependent on

deposition parameters like substrate temperature, composition and concentration of the

precursor, gas flow, and substrate–nozzle distance. Some of these parameters are

mutually dependent on each other.

Other methods

Sputtering (either using direct current (DC) or radio frequency (RF) currents) is used

quite frequently to produce titanium dioxide films. Molecular beam epitaxy is a technique

that uses a (pulsed) laser to ablate parts of a titanium dioxide ceramic target. The

material is deposited on the substrate in an argon/oxygen atmosphere or plasma. Ion

implantation is seldom used to synthesize titanium dioxide and is based on the

transformation of precursor plasma to titanium dioxide, which only becomes crystalline

after an annealing step. It is, however, frequently used to implant ions in titanium

dioxide films (doping) to improve the photo catalytic activity. Another unusual technique

is dynamic ion beam mixing, which uses high-energy O2+ and/or O+ beams and Ti

vapour to deposit titanium dioxide films with high speed and control over the

composition. Sonochemical is another method in which ultrasound waves are used for

the formation of nanostructured titanium dioxide. Microwave method is also used for the

synthesis of Titanium dioxide nanomaterials. [3]

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1.3 CharacterizationAtomic force microscopy:

Atomic force microscopy or AFM is a relatively novel method. It was invented in 1986, the first new extension of scanning probe microscopy. Its technique is based on detection of forces acting between a sharp probe, known as AFM tip, and the sample’s surface. A very flexible cantilever attached to the tip. The various methods detected any motion of the cantilever. Laser light is reflected from the cantilever. The tip is brought to contact or near-contact with the surface of interest.

Scanning over the surface, AFM system records the deflection of the cantilever, due to very small forces between the atoms of the probe and the surface, with sub-nanometer precision. The only difference is the presence in AFM of a very sensitive detection system, microscopically sharp tips, and extremely high-precision tip sample positioning. The deflection signal (or any derivations of the deflection) is recorded digitally, and can be visualized on a computer in real-time.

Figure 1.1 schematic view of the AFM method

Laser source

Photo Detector

Sample surface

AFM cantilever scanning

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Modes of AFM Operation:

In contact mode, AFM tip is in actual contact with the sample’s surface. In principle, AFM in this mode can work precisely as described above. However, if there is a bump on the surface, the cantilever will be deflected more, and consequently, AFM tip scans over the surface with more force. When the tip comes across a bump on the surface, the deflection of the cantilever increases, and the feedback system elevates the whole cantilever holder so that the cantilever’s deflection is adjusted back to its original value, and the cantilever is returned to its original position. In the case, the same feedback system moves the cantilever down to again, maintain the same deflection. This provides the same so-called “load force” between the tip and the sample.

Pros of contact mode:

This is the simplest mode of operation. It requires minimum operational skill and basic hardware.

Allows very fast scanning (typically 0.1–0.5 second per scan line). The load force can be controlled. Good signal to noise ratio even in a noisy environment. Cheaper and more robust cantilevers can be used.

Cons of contact mode:

The tip can stretch or even scratch the surface. This will lead to artifacts, therefore disrupting the sample and leading to images and measurements that are not representational of the original sample.

The tip can remove poorly attached parts of the sample. Apart from just damaging the surface, this can contaminate the tip surface and prevent it from being used any further.

Contact Mode

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Can provide only limited information about the surface. Contact mode is the best on solid and well-fixed surfaces. It normally requires rather soft cantilevers (spring constant (a characteristic measure) in the range of 0.001–1 Nm−1).

To further minimize the tip impact onto the surface, dynamicor intermittent contact mode, also commonly known as Tapping mode was introduced. Another name use for this mode is AC mode. In this mode the tip “taps,” or oscillates up and down very fast, touching the sample surface for a very short period of time during relatively slow lateral scanning. This considerably decreases scratching (although it does not eliminate it completely). While in contact mode cantilever deflection is detected and measured, in this mode the amplitude of oscillation typically measured. Positive feedback works in a similar manner to contact mode, by keeping amplitude constant while scanning.

Pros of intermittent contact mode:

The tip does not scratch the surface, thereby avoiding artifacts. This is extremely important for soft samples.

The tip typically does not remove parts of the sample. The Tapping regime allows the collection of various kinds of information related

to the properties of the surface material (phase contrast).

Cons of intermittent contact mode:

Requires extensive operational skill and additional hardware. The load force cannot be precisely controlled in particular in liquid environments. The mode does not allow for fast scanning (typically 0.5–2 seconds per scan

line).

Tapping/AC/Intermittent Contact Mode

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Force mode not an imaging mode .It is used to measure forces acting between AFM tip and the surface of interest at a specific point. In contrast to the previous modes, the cantilever does not move in lateral direction. The scanner goes up and down, elevating and approaching the cantilever to the surface.

Pros of force mode:

Information about surface viscoelastic and elastic properties are provided. Able to detect long-range forces. Record the information about tip-surface adhesion force.

Cons of force mode:

Not record the topographical information. Requires a very clean and homogeneous surface.

Force Mode

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AFM In Study Of Cancer Cells:

Oncogenically transformed cells differ from normal cells in terms of cell–cell interaction, cell growth, morphology, organization of cytoskeleton, and interactions with the extracellular matrix. Atomic force microscopy is capable of detecting most of these changes. It is interesting that in the majority of these applications AFM has not been used as just straight microscopy. In another study, AFM was used as a highly sensitive microscope for early detection of cytotoxic events. In others, AFM was used as a high-resolution detector of erosion of collagen substrate surface caused by cancer cells.

Apart from these applications, confocal microscopy (fluorescent optical, in particular) is still superior to AFM for overall imaging of cells. Using these optical techniques, one can identify many cancer cells by means of immunofluorescent tags, or just by looking for generally larger than normal nuclei (in proportion to cell size). Optical imaging is quick and provides robust statistics. The real advantage of AFM comes from its ability to detect surface interaction, extremely high sensitivity to any vertical displacements, and capability to measure cell stiffness and mechanics.

Figure 1.2. Fluorescent images of human cervical cells:(left) normal and(right) cancer.

The real advantage of AFM comes from its following features:

Ability to detect surface interaction, high sensitivity to any vertical displacements and capability to measure cell stiffness and mechanics.

Ability to study biological objects. There are virtually no limitations on the temperature of the solution/sample,

chemical composition, and the type of the medium (can be either non aqueous or aqueous liquid).

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AFM can get information about surfaces in situ and in vitro, in air, in water, buffers, and other ambient media.

It can scan surfaces with up to nanometer resolution, and up to 0.01 nm vertical resolution.

True 3D surface topographical information is provided. It can scan with different forces.

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Transmission Electron Microscopy (TEM)

The transmission electron microscope (TEM), the first type of EM, has many commonalities with the optical microscope and is a powerful microscope, capable of producing images 1 nanometer in size. They require high voltages to increase the acceleration speed of electrons, which, once they pass through the sample (transmission), increase the image resolution. The 2-d, black and white images produced by TEMs can be seen on a screen or printed onto a photographic plate. Although recent innovations in software help to minimize, TEM resolution is hampered by spherical and chromatic aberrations. The TEM is a popular choice for nanotechnology as well as semiconductor analysis and production.

A Transmission Electron Microscope (TEM) utilizes energetic electrons to provide morphologic, compositional and crystallographic information on samples.

At a maximum potential magnification of 1 nanometer, TEMs are the most powerful microscopes. TEMs produce high-resolution, two-dimensional images, allowing for a wide range of educational, science and industry applications.

TEMs consist of the following components:

An electron source Thermionic Gun Electron beam Electromagnetic lenses Vacuum chamber 2 Condensers Sample stage Phosphor or fluorescent screen Computer

Advantages

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A Transmission Electron Microscope is an impressive instrument with a number of advantages such as:

TEMs offer the most powerful magnification, potentially over one million times or more

TEMs have a wide-range of applications and can be utilized in a variety of different scientific, educational and industrial fields

TEMs provide information on element and compound structure Images are high-quality and detailed TEMs are able to yield information of surface features, shape, size and

structure They are easy to operate with proper training

Disadvantages

Some cons of electron microscopes include:

TEMs are large and very expensive Laborious sample preparation Potential artifacts from sample preparation Operation and analysis requires special training Samples are limited to those that are electron transparent, able to tolerate the

vacuum chamber and small enough to fit in the chamber TEMs require special housing and maintenance Images are black and white

Characterization of TiO2 nanoparticles.

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A representative transmission electron microscopic image of the TiO2 nanoparticles is

shown in Figure 1. The particles had a spherical shape with a diameter of about 25 nm.

The particles had dimensions suitable for escaping rapid renal excretion, as well as

avoiding components of the reticular endothelial system, thus facilitating potentially

passive targeting of drugs to tumors via the enhanced permeation and retention effect

and increasing drug accumulation in tumor cells after endocytosis.

Figure 1 Transmission electron microscope image of magnetic titanium oxidenanoparticles.

1.4 Application

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Cancer treatment

In mid-1980s Fujishima and co-workers used

the strong oxidizing power of illuminated

titanium dioxide to kill tumor cells. In the

experiment, polarized illuminated titanium

dioxide film electrodes and colloidal

suspensions is used for effective in killing HeLa

cells. A series of experimental conditions is observed, including the effect of superoxide

dismutase (effect enhancer) due to the production of peroxide. There is also possibility

in selectively kill a single cancer cell using a polarized, illuminated titanium dioxide

microelectrode. Collaborating with few urologists, an experiment of cancer implanted

under animal skin (mice) to cause tumor to form. About 0.5 cm grew, a solution

containing fine particles of titanium dioxide is injected and after 2 or 3 days irradiated

tumor and repeated it again after 13 days, and observed a marked antineoplastic effect.

Photo excited titanium dioxide particles also suppressed the growth of HeLa cells

implanted in nude mice, compared with those receiving titanium dioxide alone or UV

irradiation alone. However, this technique was not effective in stopping a cancer that

had grown beyond a certain size. The results of animal experiments have shown that

near-UV rays, with wavelengths of 300–400 nm, which are used in photo catalytic

reactions, are safe and do not cause mutation to the cell. [2] But this has been improved

from recent research, so now, nanobio technology provide an alternative form of

therapy that targets only cancer cell and does not affect normal living tissue.

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Figure 1: Animal test of photocatalytic cancer therapy; photograph of nude mouse just

after initial treatment (A) and 4 weeks after treatment.

Recent studies:

Scientists from the U.S. Department of Energy’s (DOE) Argonne National Laboratory

and the University of Chicago Medical Center’s Brain Tumor Center achieved a way to

specifically target brain cancer cells. This experiment was using inorganic titanium

dioxide which bonded to antibodies. These composite nanoparticles provide an

alternative therapy that target to cancer cells only. Titanium dioxide also do not

affecting nearby normal living tissue.

This new therapy relies on a two-pronged approach. Titanium dioxide is a versatile

photo reactive nanomaterial. It recognize and bind specifically to cancer cells when

linked to an antibody. Focused visible light is shined onto the region, and the localized

titanium dioxide reacts to the light by creating free oxygen radicals that interact with the

mitochondria in the cancer cells. Mitochondria act as cellular energy plants, and it

receives a signal to start cell death when free radicals interfere with their biochemical

pathways.

Figure 2: titanium dioxide as targeted drug delivery

Titanium dioxide, is used for targeted drug delivery. Surface is modified with

polyethylene glycol. Folic acid is used as the ligand to target Folate receptor. Paclitaxel

is attached to the surface modified titanium dioxide nanoparticle. A controlled delivery of

paclitaxel in vitro is observed. [4]

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X-ray fluorescence microscopy was performed also showed that the tumors’

invadopodia, actin-rich micron-scale protrusions that allow the cancer to invade

surrounding healthy cells. It can also be attacked by the titanium dioxide nanoparticles.

So far, tests have been done only on cells in a laboratory setting. Following a 5-minute

exposure to focused lights, there was an almost 100% cancer cell toxicity rate 6 hours

after exposure and 80% toxicity 48 hours after exposure. The National Cancer Institute

supported that a high-performance nanobiophoto catalyst for targeted brain cancer

therapy. [5]

References[1] Hongbo Shi, Ruth Magaye, Vincent Castranova and Jinshun Zhao, (15 April 2013), Titanium dioxide nanoparticles: a review of current toxicological data.

[2] Leon Smith, Zdenka Kuncic, Kostya (Ken) Ostrikov, and Shailesh Kumar, (2012), Nanoparticles in Cancer Imaging and Therapy. Available from http://www.hindawi.com/journals/jnm/2012/891318/. Retrieved 14/12/2014.

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[3] S.C. Singh, D.P. Singh, J. Singh, P.K. Dubey,R.S. Tiwari and O.N. Srivastava, (No Date), Metal Oxide Nanostructures; Synthesis, Characterizations and Applications.

[4] Elsevier B.V, (2013), Folate targeted PEGylated titanium dioxide nanoparticles as a nanocarrier for targeted paclitaxel drug delivery available from http://www.sciencedirect.com/science/article/pii/S0921883113000113. Retrieved14/12/2014.

[5] No name, (September 2009), Titanium Dioxide Nanoparticles Catalyze Brain Tumor Death.Available from http://nano.cancer.gov/action/news/2009/sep/nanotech_news_2009-09-23b.asp. Retrieved 14/12/2014.

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