CHAPTER I, SECTION-I

Introduction to Cancer

Chapter I, Sec I

1

CANCER

1.1.1 INTRODUCTION

Health is one of the most important domains which we human beings have

focused on in our society. However, cancer is a disease of striking significance in the

world today. It is the second leading cause of death after cardiovascular disease.

According to the International Agency of Research for Cancer (IARC), a 50% increase in

cancer rate within the next 20 years is expected.1 The prevalence of malignant cancers

and mortality due to cancer are also on the increase. This issue is a major concern,

especially in low to middle income countries where over a quarter of disease related

deaths are linked to cancer. 1, 2 With each passing minute, the cancer death toll are rising

and more people are being diagnosed with the disease. According to the World Cancer

report, 10 million new cancer cases are diagnosed annually, with over 7.1 million deaths

due to cancer each year that contribute to 12.6% of the global mortality rate.1 The report

estimates that about 22 million people worldwide are currently living with an oncological

disease. Since 1990, cancer incidence has risen about 19% and cancer mortality has

raised approximately 18% globally within the last decade. These numbers continue to

increase.

Cancer is the generic name for any malignant tumour.3 Hippocrates is credited

with naming the disease carcinos, which is Greek word meaning crab because of the

tumour’s crablike appearance. Later, carcinos was translated into the Latin word cancer.

Cancer is large and complex family of malignancies manifested with uncontrolled and

Chapter I, Sec I

2

undifferentiated cellular growth that replace older cells and affect virtually every organ in

the body. Cancer, a life threatening disease, is characterized by a shift in the controlled

mechanism that governs cell proliferation and differentiation. If this proliferation is

allowed to continue tumour spreading (a process called metastasis-local invasion,

intravasation, transport, extravasation, formation of micrometastasis, colonization) occurs

which can be fatal. Scientific research has elucidated the physiology, cause and treatment

of cancer.

In recent terminology, cancer describes a series of diseases in which abnormal

cells uncontrollably divide, invade other tissues and can spread throughout the body

using the lymph or circulatory systems. It is fundamentally a disease of failure of

regulation of tissue growth.

While there are more than 100 different types of cancer, there are five major categories: 4

Carcinoma is cancer that begins in the tissues that line organs.

Sarcoma is cancer that begins in bone, cartilage, muscle or other connective tissue.

Leukemia is cancer that starts in blood-forming tissue.

Lymphoma and myeloma are cancers of the immune system.

Central nervous system cancers affect the brain and spinal cord.

1.1.2 SYMPTOMS

Symptoms of cancer depend on the type and location of the cancer.5 For example;

lung cancer can cause coughing, shortness of breath or chest pain. Colon cancer often

causes diarrhoea, constipation and blood in the stool. Some cancers may not have any

Chapter I, Sec I

3

symptoms at all. In certain cancers, such as pancreatic cancer, symptoms often do not

start until the disease has reached an advanced stage.

The following symptoms can occur with most cancers:

Chills

Fatigue

Fever

Loss of appetite

Malaise

Night sweats

Weight loss

1.1.3 DIAGNOSIS

Like symptoms, the signs of cancer vary based on the type and locations of the tumour.5

Common tests include the following:

Biopsy of the tumour

Blood tests (which look for chemicals such as tumour markers)

Bone marrow biopsy (for lymphoma or leukemia)

Chest X-ray

Complete Blood Count (CBC)

Computed Tomography (CT) scan

Magnetic Resonance Imaging (MRI) scan

Chapter I, Sec I

4

Most cancers are diagnosed by biopsy. Depending on the location of the tumour, the

biopsy may be a simple procedure or a serious operation. Most patients with cancer

undergo CT scans to determine the exact location of the tumours.

1.1.4 FACTORS RESPONSIBLE FOR CANCER

Cancer causing factors are classified as follows:

1.1.4.1 External factors

a) Chemicals: Exposure to asbestos, benzene, benzidine, cadmium, nickel or vinyl

chloride in the workplace can cause cancer.6

b) Radiation: Radioactive fallout can come from accidents at nuclear power plants or

from the production, testing or use of atomic weapons. People exposed to fallout may

have an increased risk of cancer, especially leukemia and cancers of the thyroid, breast,

lung and stomach.7

c) Infectious organisms: Worldwide approximately 18% of cancers are related to

infectious diseases. This proportion varies in different regions of the world from high of

25% in Africa to less than 10% in the developed world.8

Viruses are usual infectious agents that cause cancer but bacteria and parasites

may also have an effect. A virus that can cause cancer is called an oncovirus. These

include human papillomavirus (cervical carcinoma), epstein-barr virus (B-cell

lymphoproliferative disease and nasopharyngeal carcinoma), kaposi's sarcoma

herpesvirus (kaposi’s sarcoma and primary effusion lymphomas), hepatitis B and

Chapter I, Sec I

5

hepatitis C viruses (hepatocellular carcinoma) and human T-cell leukemia virus-1 (T-cell

leukemias).

Bacterial infection may also increase the risk of cancer, as seen in helicobacter

pylori-induced gastric carcinoma.

Parasitic infections strongly associated with cancer include schistosoma

haematobium (squamous cell carcinoma of the bladder) and the liver flukes, Opisthorchis

viverrini and Clonorchis sinensis (cholangiocarcinoma)

d) Geographical location: Prostate cancer (PCa) occurrence and mortality are well

known to vary greatly in different geographic regions of the world, with low risks of PCa

mortality characteristic of Asia and high risks of PCa mortality characteristic of the US

and Western Europe.9

e) Lifestyle and Environment: Healthy life style behavior for cancer risk reduction

includes:

Diet: Fruits and vegetables contain many antioxidants and phytochemicals, such as

vitamins A, C, E and beta-carotene, which have been shown to prevent cancer.10 Studies

have shown the risk of prostate cancer drops for men who eat tomato products, possibly

because of the phytochemical lycopene. It has been shown that colon cancer declines

among those who drink green tea, which contains antioxidants and phytochemicals and

who regularly, eat soy products and foods rich in selenium, an antioxidant. High-fiber

diets are thought to reduce the risk of colon cancer because the fiber helps move food

Chapter I, Sec I

6

through the lower digestive tract, possibly reducing the contact of any carcinogens with

the bowel lining.

Recommendations of the American Cancer Society to reduce the risk of cancer

include consumption of a mostly plant-based diet, including five or more servings of

fruits and vegetables each day, consumption of whole grains in preference to processed or

refined grains and sugar, limited consumption of high-fat foods and avoiding excessive

use of overheated animal food.

Cessation of smoking and alcohol consumption: Tobacco use has been reported to be

the main cause of 90% of male and 79% of female lung cancers and about 90% of lung

cancer deaths are estimated to be due to smoking.11 The risk of the development of lung

cancer in lifelong smokers is 20-40 times higher than non-smokers. People who use

tobacco products regularly are more likely to develop acute myeloid leukemia (cancer

that starts in blood cells). Cigarette smoke like benzopyrene is carcinogenic. Metabolites

occurring during the activation of carcinogens bind covalently with DNA and DNA

adducts are formed which are regarded as an indicator of cancer risk in smokers. The risk

of individual cancer development is determined by the balance between the metabolic

activation and detoxification of the carcinogens in smoke. Free radicals in cigarette

smoke cause oxidative damage and mutations in DNA which leads to activation of

oncogenes and inhibition of tumour suppressor genes. Drinking small amounts of alcohol

has been shown to offer some protection for people at risk of heart disease, which

normally applies to people over the age of 40. However, heavy consumption of alcohol

Chapter I, Sec I

7

has also been shown to increase the risk of developing cancer of the mouth, pharynx,

larynx, esophagus, liver and breast.

1.1.4.2 Internal factors

a) Inherited mutations: The genetic changes that lead to unregulated cell growth may be

acquired in two different ways. It is possible that the mutation can occur gradually over a

number of years, leading to the development of a 'sporadic' case of cancer. Alternatively,

it is possible to inherit dysfunctional genes leading to the development of a familial form

of a particular cancer type.

Some examples of cancers with known hereditary components include:

Breast cancer - Inheritance of mutant versions of the BRCA1 and BRCA2 genes are

known risk factors.12 Although many, if not most, individuals with breast cancer do not

have detectable alterations in these genes, having a mutant form increases the likelihood

of developing breast cancer.

Colon cancer - Defects in DNA repair genes such as MSH2 are known to predispose

individuals to hereditary non-polyposis colorectal cancer (HNPCC).13

Retinoblastoma - Defects in the Retinoblastoma tumour suppressor gene are known to

cause eye cancer and several other types of cancers.14

b) Hormones: Certain hormones may increase the risk of breast cancer, heart attack,

stroke or blood clots. For example, Diethylstilbestrol (DES) is a synthetic form of the

hormone estrogen that was prescribed to pregnant women to prevent miscarriage,

Chapter I, Sec I

8

premature labor and related complications of pregnancy. Women who took DES during

pregnancy have an increased risk of breast cancer.15

c) Immune conditions: Cancer is an immune-mediated disease. Immune system cells

participate in all stages of tumour genesis and immunosurveillance. Chronic infections

and inflammation associated with limited or polarized immune responses also contribute

to carcinogenesis and tumour progression.16

d) Age: The most important risk factor for cancer is growing older. Most cancers occur in

people over the age of 65.

1.1.5 CELL AND CELL CYCLE

Figure 1 Cell cycle

Cell is the basic structural and functional unit of all known living organisms.

Humans contain about 100 trillion cells. Cell cycle is the series of events that take place

Chapter I, Sec I

9

in a cell leading to its division and duplication. In cells without a nucleus (prokaryotic),

the cell cycle occurs via a process termed binary fission.

In cells with a nucleus (eukaryotes), the cell cycle can be divided in two brief periods:

interphase, during which the cell grows, accumulating nutrients needed for mitosis and

duplicating its DNA, and the mitosis (M) phase, during which the cell splits itself into

two distinct cells, often called "daughter cells". The cell cycle consists of four distinct

phases (Fig 1):17

Gap 1 (G1) phase: Cell grows in size and checks the status of its internal systems. If

everything is functioning normally and any damage to the DNA has been corrected,

the cell moves on through the cycle. If something is wrong and cannot be corrected,

the cell halts its progression through the cycle and may initiate apoptosis and close

down. In the accompanying diagram, R marks the point where restriction of the cycle

can occur.

Synthetic (S) phase: The cell constructs proteins, RNA and DNA replication occurs

during this phase.

Gap 2 (G2) phase: The cell continues to grow and The G2 checkpoint control

mechanism ensures that everything is ready to enter the M phase and divide.

Mitosis (M) phase: Cell growth stops at this stage and cell divide into two cells.

The total length of a cell cycle varies depending on the specialized function of a cell.

Chapter I, Sec I

10

1.1.6 TUBULIN AND MICROTUBULES

Microtubules are key components of the cytoskeleton. They are used as molecular

‘highways’ for transport of materials from one part of the cell to another. Tubulin

heterodimers made up of α- and β-tubulin (50 kDa each in size) are the basic structural

components that constitute microtubules. α- and β-tubulin both have a molecule of GTP

attached to them and are capable of forming heterodimers. These dimers attach to each

other with the hydrolysis of the GTP in the β-tubulin to form chains of alternating α and

β-tubulin called protofilament. Thirteen of these protofilaments come together to form a

tube like structure called microtubule.18 Each dimer in protofilament has directionality as

the β-tubulin and α-tubulin are not identical. The protofilaments arrange themselves in

such a way that the directionality is retained in the microtubule. Thus one end of the

microtubule is called the plus end and the other end is called the minus end. In a free

microtubule, the tubulin dimers keep adding at the plus end and keep falling off at the

minus end. This is called treadmilling.

While formation of the protofilament of the microtubule, the GTP attached to the

β-tubulin undergoes hydrolysis to form GDP. β-tubulin is more stable when it is

associated with a GTP molecule than when it is associated with a GDP molecule.19 So the

formation of microtubule which is driven by GTP hydrolysis leads to destabilization of

its own self. This makes microtubule capable of undergoing catastrophic destruction by

converting GDP to GTP and stabilizing β-tubulin monomers. Thus microtubules in the

cell keep undergoing random cycles of polymerization and de-polymerization.20

Chapter I, Sec I

11

Microtubules are involved in a wide variety of cellular functions such as cell

division, morphology, regulation of motility, signalling and various intracellular

processes.21 They are extremely important in the process of mitosis, during which the

duplicated chromosomes of a cell are separated into two identical sets before cleavage of

the cell into two daughter cells (Fig 2).22 In the mitotic phase of the cell cycle,

microtubules are in dynamic equilibrium with tubulin dimers as tubulin is assembled into

microtubules, which are disassembled to tubulin. Since inhibition of tubulin

polymerization increases the number of cells in metaphase arrest, microtubules are

attractive molecular targets for anticancer therapeutics.

Figure 2 Function of microtubules in mitosis: During mitosis replicated chromosomes

are positioned near the middle of the cytoplasm and then segregated so that each daughter

cell receives a copy of the original DNA. To do this cells utilize microtubules to pull

chromosomes into each cell. The centrioles are paired cellular organelle which functions

in the organization of the mitotic spindle during cell division in eukaryotes.

Chapter I, Sec I

12

1.1.7 CANCER TREATMENTS

In 1846, anesthesia became commonly available to surgeons, resulting in an

increase in the use of surgery as a cancer treatment option.23 As expected, surgery entails

removal of the tumour and often some tissue surrounding or adjacent to the tumour area.

Today treatment selection depends upon the specific form of cancer and its progression.

Current treatment options are sophisticated and widely varied; including targeted therapy,

immunotherapy, hormonal therapy, stem cell or bone marrow transplantation,

hyperthermia, photodynamic therapy, surgery, radiation and chemotherapy, with each

treatment pathway having inherent drawbacks as well as unique benefits. Typically

physicians and cancer professionals describe a cancer based on when the cancer was

detected and how far it has progressed, referred to as staging. Surgery also provides a

means to verify the presence and stage of cancer. One major drawback to surgery is the

fact that sometimes the cancer is widespread and not all of it can be removed. For this

reason and because of the natural cancer cell growth, surgery is usually used in tandem

with an additional form of treatment.

In 1895, cancer treatment was drastically changed when Wilhelm Conrad

Roentgen invented the X-ray, the resulting technology that would give rise to the option

of radiation therapy for cancer treatment. Radiation therapy uses X-rays to target and kill

cancer cells. There are several types of radiation therapy, including internal radiation and

proton therapy; the most common is external-beam radiation therapy in which a machine

positioned outside the patient’s body produces and projects the radiation beam.24 One

Chapter I, Sec I

13

benefit of radiation therapy is that it is a local treatment, affecting the specific part of the

body receiving the therapy. When used in conjunction with surgery, radiation often

proves effective at initially shrinking a tumour to improve the success of subsequent

surgery.

As revolutionary as radiation therapy has been it has many side effects such as

fatigue, mild skin reactions, upset stomach and loose bowel movements.25 Internal

radiation therapy has been cited as causing bleeding, infections and irritation after the

implant is removed.25 These are the short-term side effects, with long-term effects

including the risk of a second cancer, infertility, heart problems, gastrointestinal

problems, lung fibrosis, neurologic problems, thyroid problems or osteoporosis.26

Another cancer treatment, chemotherapy, became available in 1919 when it was

found that a component of mustard gas could reduce white blood cells.27 These

chemotherapeutic drugs halt a cancer cell’s unchecked ability to grow and divide, causing

cell death and reduction of the cancer. Chemotherapy drugs have resulted in more varied

treatment plans using combinations of surgery, radiation and chemotherapy drugs. Side

effects of chemotherapy depend upon the dosage level and how the patient reacts to the

drugs but typically involve fatigue, risk of infection, nausea, vomiting, loss of appetite

and diarrhea. While the side effects of these chemotherapy drugs are usually temporary,

disappearing when the treatment is over, all of the current treatments are physically and

psychologically taxing for the patient; thus, current research focuses on developing more

effective therapeutics with fewer and less severe side effects.

Chapter I, Sec I

14

1.1.8 CHEMOTHERAPY IN CANCER TREATMENT

Chemotherapy is a kind of treatment that uses drugs to attack cancer cells. 28 It is

called a "systemic treatment" since the drug, entering through the blood stream, travels

throughout the body and kills cancer cells at their sites. The drugs may rarely be intended

to have a local effect, but in most cases, the intention is to destroy cancer cells wherever

they may exist in the body. Chemotherapeutic drugs are divided into several categories

based on how they affect specific chemical substances within the cancer cells, which

cellular activities or processes the drug interferes with and which specific phases of the

cell cycle the drug affects. These include:

DNA topoisomerase I and II inhibitors

Apoptosis inducing agents

Antimitotic agents

Antimetabolites

DNA interactive agents and miscellaneous agents

Chemotherapeutic drugs are chemically designed to target cells that are dividing and

growing rapidly. They target the carcinogenic sequence, generally exploiting the rapid

progression of cancer cells throughout the cell cycle. Once they reach the cancer cells,

they act to retard their growth, eventually resulting in their destruction. Chemotherapy

may be given at home, in a clinic or in a hospital. The frequency of chemotherapy can be

daily, weekly, monthly or an on-off schedule depending on the type of drug, the body's

response and the type of cancer. The chemotherapy is decided on the basis of the type of

Chapter I, Sec I

15

cancer. The dosage is calculated on the basis of the patient's body weight and the drug's

toxicity.

Ideal anticancer drugs would eradicate cancer cells without harming normal tissues.

Unfortunately no currently available agents meet this criterion. Two major concerns with

currently available anticancer drugs are their inability to discriminate between normal

and tumour cells and hence unpleasant drug toxicities and development of resistance due

to expression of drug transporters. Thus clinical use of drugs involves a weighing of

benefits against toxicity in a search of favorable therapeutic index. At present more than

50 anticancer drugs has been discovered. They are used in several ways:

Monotherapy or only one drug

Combination chemotherapy or a group of drugs which work together

Combined modality or chemotherapy along with other treatment such as surgery and

radiotherapy

The drugs are delivered to the affected cells in the following forms:

Oral (tablet form, by mouth)

Intravenous or Intramuscular (injected by needle into a vein or muscle)

Intrathecal chemotherapy (injected through a needle in the back)

1.1.9 CLASSIFICATION OF ANTICANCER DRUGS

Chemotherapeutic drugs can be divided into two main classes based on their

action on the cell cycle: cell cycle non-specific and cell cycle specific.

Chapter I, Sec I

16

1.1.9.1 Cell cycle specific drugs

These drugs act only at particular phases of the cell cycle and have a plateau with

respect to cell killing ability (Fig 3). With these drugs, the amount of cell kill will not

increase as drug dosage increases. Cell cycle specific drugs include antimetabolites, vinca

plant alkaloids and miscellaneous agents such as asparaginase and decarbazine and

because they work on cells undergoing division in the cell cycle, these drugs are most

effective against actively growing tumours which have a greater proportion of tumour

cells dividing. Cell cycle specific drugs are administered in minimal concentration via

continuous dosing methods.29 Antimetabolites exhibit their action by blocking essential

enzymes necessary for DNA synthesis or by becoming incorporated into the DNA so that

a false message is transmitted. They are most active during the S phase and examples

include methotrexate, fluorouracil and mercaptopurine.

Figure 3

Chapter I, Sec I

17

1.1.9.2 Cell cycle nonspecific drugs

These drugs are active in all phases of the cell cycle and may be effective in large

tumours that have few active cells dividing at the time of administration. Drugs of this

nature are often given as a single bolus injection.30 These have a linear dose-response

curve, which means that the greater the dose of drug that is given, the greater is the

fraction of cells within the tumour that are killed. These drugs are active on cells in either

a dividing or a resting state and include:

Nitrogen mustards - Meclorethamine, Cyclophosphomide, Ifosfamide, Chlorambucil,

Melphalan

Ethylanimine - Thiotepa

Alkyl sulfonate - Busulfan

Nitrosoureas- Carmustine, Lomustine

Triazine derivatives - Dacarbazine

Miscellaneous – L-Asparginase, Cisplatin, Procarbazine

1.1.10 ANTIMITOTIC AGENTS

Chemical compounds targeting microtubules exert their inhibitory effects on cell

proliferation primarily by blocking mitosis, which requires an exquisite control of

microtubule dynamics. Microtubule-targeting drugs are therefore also frequently referred

to as a group of antimitotic drugs and their actions on microtubule stability and dynamic

parameters differ from each other. They interact physically with tubulin by binding to one

Chapter I, Sec I

18

of the three main binding sites: colchicine-, vinblastine- or paclitaxel- binding sites.31

They are usually classified into two main groups:

1.1.10.1 Microtubule-destabilizing agents

Figure 4

Microtubule-destabilizing agents inhibit microtubule assembly and thereby stall

cells in mitosis. The vinca alkaloids, vinblastine and vincristine, were originally extracted

over 40 years ago from the leaves of the Madagascar periwinkle, formerly known as

Vinca rosea but reclassified as Catharanthus roseus. These compounds were initially

studied because of the hypoglycemic activities, but were discovered to have antileukemic

effects and cause bone marrow suppression32 since they have been widely used clinically

for the treatment of leukemias, lymphomas and some solid malignancies. The clinical

success of vinblastine and vincristine together with the elucidation of their mechanism of

Chapter I, Sec I

19

action on cellular microtubules, have facilitated the development of several semi-

synthetic derivatives notably vindesine, vinorelbine and vinflunine, which are now used

in the clinic for the treatment of cancer.33 The other microtubule destabilizing agents

include cryptophycin 52, hemiasterlins, estramustine, colchicine and combretastatins (Fig

4).

1.1.10.2 Microtubule-stabilizing agents

Figure 5

Microtubule-stabilizing agents stimulate the polymerization of tubulin and

stabilize the resultant microtubules. Isolated originally in the 1960s from the bark of the

Pacific yew Taxus brevifolia, paclitaxel did not receive much attention until it was

O

X

O

OR

N

S

OH

HO

R = H, X = O: Epothilone AR = CH3, X = O: Epothilone B

O

ON

N

O

H

H OR2

ORO

R = CH3, R2 = H Sarcodictyin AR = C2H5, R2 = H Sarcodictyin B

O

O

O

OO

O

OO

OHR2O

OH

NHR1

O

OH

R1 = Ph, R2 = CH3CO : PaclitaxelR1 = tert-C4H9O, R2 = H : Docetaxel

O

ON

N

O

H

H O

O

OO

OOH

HOEleutherobin

OO OH

H2N

O

OH

Discodermolide

Chapter I, Sec I

20

discovered to possess microtubule stabilizing activity.34 This drug is now in widespread

use for the treatment of breast, ovarian, prostate and non-small cell lung cancer, as well

as kaposi’s sarcoma. Its semisynthetic analog, docetaxel, is synthesized from a precursor

isolated from the needles of the European yew Taxus baccata. Docetaxel is more water-

soluble than paclitaxel and is also more active than paclitaxel against cancer cell

proliferation and is now used clinically for the treatment of breast, prostate and non-

small-cell lung cancer.35 The other microtubule-stabilizing agents include epothilones,

eleutherobin, discodermolide and sarcodictyins (Fig 5).

Chapter I, Sec I

21

REFERENCES

1. B. W, Stewart, P. Kleihues, World Health Report 2002: Reducing risks, promoting

healthy life., Geneva, WHO. 2002.

2. J. P, Bond, P. B. Celestino, M. C. Mahoney, C. D. Farrell, J. E. Bauer, J. L. Hastrup,

K. M. Cummings, J cancer educ., 2002 18, 96.

3. www.cancer.org/downloads/STT/ CAFF2007PWSecured.pdf.

4. R. G. McKinnell, R. E. Parchment, A. O. Perantoni, G. B. Pierce, Cambridge

University Press., newyork, 1998, 51.

5. a) J. A. Moscow, K. H. Cowan, Biology of cancer. In L. Goldman, A. I. Schafer eds.

Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011: chap 185. b) M. J.

Thun, A. Jemal, Epidemiology of cancer. In L. Goldman A. I. Schafer, eds. Cecil

Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011: chap 183.

6. P. A. Oliveira, A. Colaço, R. Chaves, H. G. Pinto, L. F. P. D. L. Cruz, C. Lopes, An.

Acad. Bras. Ciênc., 2007, 79, 593.

7. A. Frieben, Fortsch. Geb. Roentgenstr., 1902, 6, 106.

8. a) P. Pisani, D. M. Parkin, N. Munoz, J. Ferlay, Biomarkers Prev., 1997, 6, 387. b) D.

M. Parkin. Int. J. Cancer., 2006, 118, 3030.

9. S. Bingham, E. Riboli, Nat. Rev. Cancer., 2004, 4, 206.

10. H. S. Garewal, S. Schantz, Arch. Otolaryngol. Head Neck Surg., 1995, 121, 141.

11. C. L. Vecchia, S. Franceschi, Eur. J. Cancer Prev., 2003, 12, 5.

12. R. L. Milne, Antoniou, Ann. Oncol., 2011, 22, i11

Chapter I, Sec I

22

13. A. K. Rustg, Genes Dev., 2007. 21, 2525.

14. C. J. Sherr, F. McCormick, Cancer Cell, 2002, 2,103.

15. a) J. R. Palmer, L. A .Wise, E. E. Hatch, R Troisi, L. T. Ernstoff, W. Strohsnitter, R.

Kaufman, A. L. Herbst, K. L. Noller, M. Hyer. R. N. Hoover Cancer Epidemiol.

Biomarkers Prev., 2006, 15, 1509. b) M. M. Rubin, Obstet. Gynecol. Surv., 2007, 62,

548.

16. B. F. Zamarron, W. Chen, Int. J. Biol. Sci., 2011, 7, 651.

17. B. Alberts, D. Bray, J. Lewis, M. Raff, K. Roberts, J. D. Watson, Molecular Biology

of the Cell, 5th edn (New York, Garland Publishing, Inc.) 2007.

18. L. Amos, A. Klug, J. Cell Sci., 1974, 14, 523.

19. V. I. Gelfand, A. D. Bershadsky, Annu. Rev. Cell Biol., 1991, 7, 93.

20. H. P. Erickson, E. T. O'. Brien, Annu. Rev. Biophys. Biomol. Struct., 1992, 21, 145.

21. M. A. Jordan, L. Wilson, Nat. Rev. Cancer, 2004, 4, 253.

22. G. F.V. Ismael, D. D. Rosa, M. S. Mano, A. Awada, Cancer Treat. Rev, 2008, 34, 81.

23. http://www.aarp.org/health/conditions-treatments/info-03-2012/history-of-cancer-

timeline.html (Accessed Feb 23, 2013).

24. http://www.cancer.gov/cancertopics/coping/radiation-therapy-and-you/page3

(Accessed Feb 23, 2013).

25. W.D. Bloomer, S. Hellman, New Engl. J. Med., 1975, 293, 80.

26. O. A. Mefty, J. E. Kersh, A. Routh, R. R. Smith, J. Neurosurg., 1990, 73, 502.

27. V.T. DeVita, E. Chu, Cancer Res., 2008, 68, 8643.

Chapter I, Sec I

23

28. A. Desai T. J. Ann, Rev. Cell Dev. Biol., 1997, 13, 83.

29. G. Morgan, Cancer Nurs. Pract., 2003, 2, 27.

30. M. A. Jordan, L. Wilson, Nature Rev., 2004, 4, 253

31. M. N. Islam, M. N. Iskander, Mini-Rev. Med. Chem., 2004, 4, 1077.

32. a) I. S. Johnson, H. F. Wright, G. H. Svoboda, J. Vlantis, Cancer Res., 1960, 20,

1016. b) J. H. Cutts, C. T. Beer, R. L. Noble, Cancer Res., 1960, 20, 1023.

33. A. Duflos, A. Kruczynski, J. M. Barret, Curr. Med. Chem. Anti-Canc Agents, 2002, 2,

55.

34. P. B. Schiff, S. B. Horwitz, Proc. Natl. Acad. Sci. USA, 1980, 77, 1561.

35. Ringel, S. B. Horwitz, J. Natl. Cancer Inst., 1991, 83, 288.

CHAPTER I, SECTION-II

Introduction to Catalysis

Chapter 1, Sec II

24

CATALYSIS

1.2.1 INTRODUCTION

In the early part of the 19th century, when the scientific study of chemistry was just

beginning, it was observed that the occurrence of a number of chemical reactions was

conditional upon the presence of trace amounts of substances that did not themselves take

part in the reaction. In 1836, Swedish scientist J. J. Berzelius conveyed these

observations into the body of chemical knowledge by attributing their action to what he

called their catalytic power, this action he named as catalysis by analogy.1 He assumed

that catalysts possess special powers that can influence the affinity of chemical

substances. The word catalysis comes from Greek word meaning ‘to break down’. Later,

William Ostwald was the first to write down a definition of the catalyst: “a catalyst

accelerates a chemical reaction without affecting the position of the equilibrium.”2

Ostwald recognized catalysis as a ubiquitous phenomenon that was to be explained in

terms of the laws of physical chemistry. While it was formerly assumed that the catalyst

remained unchanged in the course of the reaction, it is now known that the catalyst is

involved in chemical bonding with the reactants during the catalytic process.

Thus catalysis is a cyclic process: the reactants are bound to one form of the

catalyst and the products are released from another, regenerating the initial state. Apart

from accelerating reactions, catalysts have another important property that they can

influence the selectivity of chemical reactions. This means that completely different

products can be obtained from a given starting material by using different catalyst

Chapter 1, Sec II

25

systems. Industrially, this targeted reaction control is often even more important than the

catalytic activity.

Catalysts can be gases, liquids, or solids. Most industrial catalysts are liquids or

solids, whereas the latter react only via their surface. They have been successfully used in

the chemical industry for more than 100 years, examples includes the synthesis of

sulfuric acid, the conversion of ammonia to nitric acid and catalytic hydrogenation. In

fact that 75% of all chemicals are produced with the aid of catalysts; in newly developed

processes, the figure is over 90%. Many organic intermediates and products, synthetic

fibers, pharmaceuticals, dyes, crop-protection agents, resins and pigments can only be

produced by catalytic processes.3 Most of the processes involved in crude-oil processing

and petro-chemistry, such as purification stages, refining and chemical transformations

require catalysts. Manufacturing protocols can be made more economic, green and

sustainable by the design and vigilant use of catalysts.

Catalysis can be broadly divided into two branches: homogeneous and heterogeneous.

1.2.2 HOMOGENEOUS CATALYSIS

A homogeneous catalyst, where the catalyst is in the same phase as the reactants, is

generally accepted by chemists.4 The most attractive property is that all catalytic sites are

accessible because the catalyst is generally a soluble metal complex. Furthermore, it is

possible to tune the chemo-, regio- and enantio-selectivity of the catalyst. Homogeneous

catalysts have a number of other advantages such as high selectivities, better yield and

easy optimization of catalytic systems by modification of ligand and metals. Despite their

advantages and their wide use in a number of applications, many homogeneous catalytic

Chapter 1, Sec II

26

systems have not been commercialized because of the difficulty encountered in

separating the catalyst from the final reaction product. Removal of trace amounts of

catalyst from the end product is essential since metal contamination is highly regulated,

especially by the pharmaceutical industry. Even with the extensive and careful use of

various techniques such as distillation, chromatography or extraction, removal of trace

amounts of catalyst remains a challenge. To overcome the separation problems in

homogeneous catalysis, chemists and engineers have investigated a wide range of

strategies and the use of heterogeneous catalyst systems appears to be the best logical

solution.5

1.2.3 HETEROGENEOUS CATALYSIS

Heterogeneous catalysis involves a reaction in which one or more of the

constituents are in different phases. Thus, a heterogeneous catalyst is normally insoluble

in the reaction medium. From an industrial point of view, heterogeneous catalysts are of

interest for a number of reasons and comparison of the properties of homogeneous and

heterogeneous catalysts are summarized in Table 1. Heterogenization is commonly

achieved by entrapment or grafting of the active species on surfaces or inside the pores of

a solid support, such as silica, alumina or ceria. Although grafting can be achieved by

covalent binding or by simple adsorption of the active catalytic species, covalent binding

is preferred because it is generally sufficiently robust to survive the harsh reaction

conditions; this binding and adsorption process minimizes catalyst leaching and allows

the catalyst to be reused several times.6 A vast majority of the industrial heterogeneous

catalysts are high-surface area solids onto which an active component is dispersed or

Chapter 1, Sec II

27

attached. Attempts have been made to make all active sites on solid supports accessible

for reaction thus allowing rates and selectivities comparable to those obtained with

homogeneous catalysts. Unfortunately, the sites on the surface are only available for

catalysis, which decreases the overall reactivity of the catalyst system. Another problem

is the leaching of active species/complex from solid supports because of breaking of

bonds between metal and ligand during catalytic reactions, which again necessitates

separation of trace metals from final product.

Table 1 Advantageous and disadvantageous of homogeneous and heterogeneous

catalysis.

Consequently, new catalyst systems that not only shows high activity and

selectivity (like a homogeneous system) but also possesses the ease of catalyst separation

and recovery (like a heterogeneous system) desired for ‘‘greening’’ the chemical

manufacturing processes. These goals can be achieved by nanocatalysis. Nanocatalysts

bridge the gap between homogeneous and heterogeneous catalysis, preserving the

desirable attributes of both systems.

Chapter 1, Sec II

28

1.2.4 NANOCATALYSIS

One of the most stimulating features of nanotechnology is its potential use in

almost any field. Nanotechnology refers to techniques that offer the ability to design,

synthesize (or manufacture) and control at the length scale ranging from 1 to 100 nm of

the material. The discovery of nanoparticles with varied size, shape and composition has

stretched the limits of technology in ways that scientists would never have dreamt of a

century ago. Nature makes and chemistry reshapes; huge varieties of nanoparticles have

emerged in our daily life, in every field from drugs and electronics to paints and beauty

care products. The evolution from vacuum tubes to diodes and transistors and miniature

chips resulted in smaller and smaller devices with more powerful computing ability. Now

these electric circuits are approaching nano-dimensions and when this realm is entered,

nanocomputers only visible through microscope will appear.7 Among the current

research, application of nanoparticles in catalysis has attracted a lot of attention, because

nanoparticles have a large surface-to-volume ratio relative to bulk materials, they by

offering an attractive alternative to conventional catalysts.8

Nanocatalysis involves a substance or material with catalytic properties that

possesses at least one nanoscale dimension, either externally or in terms of internal

structures. This field is undergoing an explosive development. Nanocatalysis can help

design catalysts with excellent activity, greater selectivity and high stability. These

characteristics can easily be achieved by tailoring the size, shape, morphology,

composition, electronic structure and thermal and chemical stability of the particular

nanomaterial. The nanocatalytic systems are active due to the following reasons:

Chapter 1, Sec II

29

As size decreases, the surface area to volume ratio increases. Therefore, nanocatalysts

are small in size and have an enormous surface area to volume ratio.

The available surface area of the active component of a nanocatalyst is large.

Therefore, it increases contact between the reactant molecules and the catalyst to a

great extent. This enhanced interaction facilitates the heterogeneous catalytic system

and helps to achieve a better reaction rate that is closer to its homogeneous

counterpart.

Easy control of nanocatalysts over size, shape and morphology makes it possible to

rationally design the materials that are specifically needed for a particular catalytic

application. Thus, tuning the properties of a material is easily possible when working

at the nanoscale, which would be difficult with their macroscopic counterparts.

1.2.5 BENEFITS OF NANOCATALYSTS IN CHEMICAL INDUSTRY

Figure 1

Chapter 1, Sec II

30

Increased selectivity and activity of catalysts by controlling pore size and particle

characteristics.

Replacement of precious metal catalysts by catalysts tailored at the nanoscale and use

of base metals, thus improving chemical reactivity and reducing process costs.

Catalytic membranes by design that can remove unwanted molecules from gases or

liquids by controlling the pore size and membrane characteristics.

Thus, nanocatalysts enjoy several advantages over conventional catalyst systems;

however, isolation and recovery of these tiny nanocatalysts from the reaction mixture is

not easy. Conventional techniques (such as filtration) are not efficient because of the

nano size of the catalyst which can lead to the blocking of filters and valve by the

catalyst. This limitation hampers the economics and sustainability of these nanocatalytic

protocols. To overcome this limitation, the use of magnetic nanoparticles has emerged as

a viable solution; their insoluble and paramagnetic nature enables easy and efficient

separation of the catalysts from the reaction mixture with an external magnet.

1.2.6 MAGNETIC NANOPARTICLES (MNPs)

Magnetic nanoparticles are a class of nanostructured materials of current interest,

due largely to their advanced technological and medical applications, envisioned or

realized.6 Among the various magnetic nanoparticles under investigation, magnetic

ferrites nanoparticles are arguably the most extensively studied.9a,e,10 They have been

used in recent years as a versatile support for a variety of heterogeneous catalysts for

diverse classes of organic transformation,11 such as oxidation,11c hydrogenation,11d C-C

coupling,11e asymmetric aldol reaction11f and CO2 cycloaddition reaction11f. Magnetic

Chapter 1, Sec II

31

nature allows catalysts to be separated using external magnet thus facilitating

recyclability and reusability (Fig 2).

Figure 2 Catalyst separation by magnetic attraction

Magnetic ferrites are commonly composed of iron oxides often arranged in spinel

crystallite structures of the formula AB2O4, where A = Co, Fe, Ni, Cu or Mn and B = Fe.

In the spinel structure, there are twice as many octahedral (B) cationic sites as tetrahedral

cationic (A) sites.

In normal spinels, A cations occupy tetrahedral sites and B cations occupy

octahedral sites. (A) tet [B2] octO4 . Examples: MgAl2O4 FeCr2O4, Mn3O4, FeCr2S4

In inverse spinels, B cation occupy the tetrahedral sites and all the A cations together

with the other half of the B cations occupy the octahedral sites.

(B) tet [ AB] octO4. Examples: Fe3O4, TiMn2O4, TiFe2O4.

Fe3O4 has a cubic inverse spinel structure with a space grouping of Fd3m.12 The unit

cell of Fe3O4 has 32 O2 ions which are regular cubic close packed along the [110]

direction. The lattice constant is a = 0.839. The crystal structure of Fe3O4 consists of two

Chapter 1, Sec II

32

different iron sites: tetrahedral sites which are occupied by Fe+3 and octahedral sites

which are occupied by Fe+2 and Fe+3. Generally, Fe3O4 crystals are overlaid with

octahedral and mixed octahedral/tetrahedral layers along the {111} direction (Fig 3).

Figure 3 Crystal structure of Fe3O4

1.2.7 SYNTHESIS OF MAGNETIC NANOPARTICLES

It has long been of scientific and technological challenge to synthesize the

magnetic nanoparticles of customized size and shape. Especially during the last few

years, many publications have described efficient synthetic routes to shape-controlled,

highly stable and monodisperse magnetic nanoparticles. Several popular methods

including co-precipitation, thermal decomposition and/or reduction, micelle synthesis,

hydrothermal synthesis and laser pyrolysis techniques can all be directed at the synthesis

of high-quality magnetic nanoparticles. Physical methods such as gas phase deposition

and electron beam lithography are elaborate procedures that suffer from the inability to

control the size of particles in the nanometer size range.13 Wet chemical routes to

synthesis magnetic nanoparticles are simpler, more tractable and more efficient with

Chapter 1, Sec II

33

appreciable control over size, composition and sometimes even the shape of the

nanoparticles. 14

Co-precipitation is a facile and convenient way to synthesize magnetic ferrites

(MFe2O4) nanoparticles.15 In this method they are usually prepared in an aqueous

medium which chemical reaction of formation may be written as Eq. (1). The

nanoparticles are precipitated by the addition of base at a pH levels between 8 and 14,

with a stoichiometric ratio of 2:1 (Fe3+/M2+) in a non-oxidizing oxygen environment. The

size, shape and composition of the MNPs very much depends on the type of salts used

(e.g. chlorides, sulfates, nitrates), M2+/Fe3+ ratio, reaction temperature, pH value, type of

base, also mixing rate, ionic strength of the media, with the addition sequence and

bubbling of nitrogen gas are all important.

M2+ + 2Fe3+ + 8OH¯ → MFe2O4 + 4H2O Eq. 1

1.2.8 PROPERTIES OF MAGNETIC NANOPARTICLES

Ferromagnetic materials are subdivided into areas known as domains.16 In an

unmagnetized sample, the moments of these domains are randomly orientated, but tend to

align themselves in the direction of an external applied magnetic field. As the particle

size approaches a certain minimum critical size, often in the nanoscale range, the

formation of domain walls becomes energetically unfavorable. Changes in magnetization

occur through the rotation of spins rather than through the motion of domain walls.

Particles exhibiting these properties are called single domain. As particle size is

decreased further, spins are affected by thermal fluctuations and the particles become

superparamagnetic. This superparamagnetic property of materials is useful in that

Chapter 1, Sec II

34

individual particles become magnetized only when exposed to an external magnetic field.

Once the external magnetic field is removed, thermal fluctuations again randomize the

magnetic moments of the particles, again resulting in zero net magnetic moment.17

It is this phenomenon of reversible on/off magnetism that makes these

superparamagnetic nanoparticles interesting candidates for catalyst supports. Because

MNPs exhibit no net magnetic moment by themselves, they can be dispersed into

reaction media. Immobilized catalysts on the MNPs can promote reactions in solution

and upon completion, the MNPs and supported catalyst can be easily recovered with an

external magnet. In addition to the novel magnetic recovery method, MNPs also possess

other positive attributes. They exhibit high surface areas (above 200 m2/g) resulting from

the small particle diameters.18 As the diameter of any particle decreases, the surface area

per unit mass increases on the order of 1/D particle. Because MNPs possess only external

surface area, reactions are generally not diffusion limited, unlike porous catalyst supports

or in solid-phase synthesis resins which can suffer from internal diffusion limitations.19

The particles are also thermally and chemically stable under some conditions. In addition,

the particle size provides a large surface area for functionalization which makes them

suitable for catalyst immobilization and dispersible in organic or aqueous solution.

1.2.9 APPLICATIONS OF MAGNETIC NANOPARTICLES

Magnetic nanoparticles with good stability will be of great interest in catalysis

and in biotechnology/biomedicine applications. Such magnetic nanoparticles can be very

useful to assist an effective separation of catalysts, nuclear waste, biochemical products

and cells. 20

Chapter 1, Sec II

35

1.2.9.1 Applications in catalysis

Catalyst recovery and reuse are the two most important features for many

catalytic processes and most heterogeneous systems require a filtration or centrifugation

step and/or a tedious workup of the final reaction mixture to recover the catalyst.

Magnetic nanoparticles are considered as ideal supports for the heterogenization of

homogeneous catalysts since they efficiently disperse catalytic active sites in the reaction

medium. Furthermore, magnetic separation is a “green” process since it avoids the

complications of filtration (such as loss of catalyst, oxidation of sensitive metal

complexes and usage of additional solvents for precipitation steps). Thus, waste and costs

can be greatly reduced.

1.2.9.1.1 Magnetic nanoparticles stabilized with carboxylic- and phosphonic-acid

derivatives

Carboxylic acid sites are predominant among the most common capping agents

for ferrite nanoparticles.21 Thus, a very early example for magnetic nanoparticles coated

with a homogeneous catalyst is provided by a Rh-based cationic catalyst modified with

benzoic acid, namely [Rh(COD)-η6-benzoicacid]BF4.22 Co-ferrite (CoFe2O4) was chosen

as support, possessing a deviation from the nominal structure of a spinel ferrite in the

shell. An amorphous ferric hydroxide layer on the surface was proposed,23 thus

explaining the non-stoichiometric composition. The nano magnet-supported catalyst

showed an activity and regioselectivity toward the hydroformylation of 4-vinylanisole,

which is comparable to its homogeneous counterpart, although it has to be stated that

reactions with the unsupported catalyst require only one third of the reaction time

Chapter 1, Sec II

36

(Scheme 1). However, the activity is still extraordinarily high relative to catalysts

immobilized on conventional supports, e.g. polymers,24 and shows no loss in activity

upon recycling via magnetic decantation.

Scheme 1

Phosphonic acid derivatives were successfully used to stabilize the magnetite

nanoparticles in N-arylation and asymmetric hydrogenation reactions.25 Lin et al., used a

Ruthenium(II)complex with phosphonic acid-substituted BINAP

[Ru(BINAPPO3H2)(DPEN)Cl2] tethered to magnetite nanoparticles which were

synthesized either by thermal decomposition26 or a co-precipitation methods.27 Especially

magnetite synthesized by the latter route demonstrated outstanding stability and

immobilized catalyst possesses impressive efficacy and recyclability in the hydrogenation

of 1-acetonaphthone (Scheme 2). A drop in conversion was observed in the 15th cycle

(35%) whereas selectivity remained high (95% ee).

Chapter 1, Sec II

37

Scheme 2

1.2.9.1.2 Dopamine stabilized ferrite nanoparticles

Enediol-ligands such as catechols are known to have a high affinity to under

coordinated surface sites of metal oxide nanoparticles.28 Therefore, dopamine has

gathered attention, possessing an additional amine moiety which allows either

immobilization of metal centers or further covalent modification.29 Manorama and

coworkers30 reported several examples of palladium(0) doped ferrite particles (Scheme

3). The dopamine (DOPA) layer was formed by refluxing or sonicating the ferrites

together with the catecholamine in water.

Fe3O4

PO

OO

PPh

Ph

PPh

PhRu

Cl HN

NHCl

Ph

Ph

O OH

H2, KOtBu, 20 h, 25 o C

conversion: >99%ee: 97-98%14 cycles

Chapter 1, Sec II

38

Scheme 3 Synthesis of ferrite-dopamine nanocomposite doped with Pd(0).

For a series of hydrogenation reactions including aromatic nitro and azide

compounds to their respective amine derivatives with catalysts NiFe2O4–DOPA-Pd and

F3O4–DOPA-Pd, an activity is observed that exceeds those of previous studies.31 The

activity of Fe3O4–DOPA-Pd is somewhat inferior due to a lower palladium loading on the

surface. Even after 10 cycles, no deterioration in the catalytic efficacy of both catalysts

observed.30c In addition, the spinel supported catalyst NiFe2O4–DOPA-Pd was applied for

Suzuki and Heck coupling reactions of aromatic halides (Scheme 4).

Cl

K3PO4, DMF, TBAB,110 °C, 36 h

B(OH)2

K2CO3, DMF,130 °C, 36 h

Scheme 4

Chapter 1, Sec II

39

1.2.9.1.3 Silica coated iron oxide nanoparticles

Apart from enediol-ligands, silanes are frequently used to coat ferrites.32 The

deposition and adhesion of silica can be achieved via hydrolysis of a sol-gel precursor to

give shells with a thickness between 2 and 100 nm and because of the strong affinity of

iron oxide surfaces toward silica, no primer is required. An advantage of the silica

coating is that this surface is terminated by silanol groups which can react with various

coupling agents to covalently attach linkers, ligands, metals or complexes.

Nanocomposites of this kind were extensively used for palladium catalyzed cross-

coupling reactions.

Connon et al., reported on an organocatalyst tethered to a Fe3O4@SiO2-

nanomagnet which was of unprecedented activity and recyclability.33 They evaluated

DMAP analog catalyst in the acetylation of 1-phenylethanol by acetic anhydride where it

furnished 90 in 14 cycles with 94->98% conversion in each case (Scheme 5).

Scheme 5

Chapter 1, Sec II

40

The recovered material was subsequently found to be even active when employed

at loadings as low as 0.2 mol% (79%). The reaction scope was examined by subjecting

recycled catalyst to promote a range of distinct transformations where it acted as a

nucleophilic catalyst. After 30 consecutive cycles, recycled catalyst (0.2 mol%) was still

able to achieve an identical level of conversion (80%) in the acetylation of 1-

phenylethanol.

Recently, the “click”-reaction34 has proved its versatility on silica coated

magnetite particles. A propargylated dipyridyl-ligand was attached to 3-

azidopropylsilane-capped Fe3O4@SiO2 under formation of a triazole moiety (Scheme

6).35 The catalyst demonstrated its efficacy for a range of Suzuki-couplings and could be

reused four times in the coupling of 4-bromoacetophenone and phenylboronic acid with

only a slight gradual decrease in yield (95-99%).

Scheme 6 Preparation of a magnetite@silica-supported di(2-pyridyl)methanol-Pd-

complex using a CuAAC protocol.

Chapter 1, Sec II

41

1.2.9.1.4 Bare magnetic nanoparticles

Besides using magnetic nanoparticles as supports, they themselves might also

serve directly as catalysts. Ji et al., used nano-Fe3O4 as a recyclable catalyst for

intramolecular C - N cross-coupling reaction under ligand-free conditions (Scheme 7).

They have developed a novel and efficient method for the synthesis of various 1,4-

dihydroquinoline derivatives from o-halobenzaldehyde and a wide range of -

enaminones.36 Noteworthy, the catalyst is highly efficient for the inactive aryl chlorides

and arylamine derivatives.

Scheme 7

Kantam et al., presented magnetically recoverable nano-CuFe2O4 for asymmetric

hydrosilylation of several ketones.37 Up to 99% enantiometric excess was obtained at

room temperature using polymethylhydrosiloxane as the stoichiometric reducing agent

(Scheme 8). The copper ferrite nanoparticles were magnetically separated and the

efficiency of the catalyst remains almost unaltered up to three cycles.

Scheme 8

Chapter 1, Sec II

42

1.2.9.2 Medicinal applications

The use of magnetic nanoparticles in medical applications is a novel and highly

interdisciplinary field offering great potential in therapeutic and diagnostic testing, in

vitro and in vivo.38 Initial medical applications used iron powder or magnetite directly in

treatment methods. In this form, however, particles are recognized by the macrophages of

the mononuclear phagocyte system and are eliminated from the body.39 In order to

improve biocompatibility, to reduce toxicity and to ensure non-immunogenicity, particles

have been encapsulated (e.g., with chitosan, dextran, poly(lactic acid), starch, carbon,

polysaccharides, gelatine and proteins) to yield “stealth” particles .40

One of the main envisaged therapeutic applications of coated magnetic

nanoparticles is for targeted chemotherapeutic drug delivery to tumors. Particles coated

with a drug could be injected intravenously, transported to a site of action (e.g., cancerous

tumor or arterial blockage) and be retained at the site by application of a magnetic field

gradient. This form of drug delivery is advantageous in that a specific site in the body can

be targeted by the magnetic field gradient, the doses required for systemic drug delivery

are reduced, localized drug levels can be increased significantly with reduced potential

toxic side effects at non-targeted tissues and a prolonged release of high localized drug

concentrations at a required site can be obtained.41 An interesting extension of this

technique is the use of implanted magnetized stents which can be used as capture sites for

magnetic particles carrying therapeutic agents and offer the possibility of reapplication of

a tailored drug and optimum dosage.42 A second important therapeutic application is in

the field of hyperthermia, which involves heating organs or tissues to between 41 and 46

Chapter 1, Sec II

43

°C to obtain tumor cell necrosis.43 The application of an external alternating magnetic

field to nanosized magnetic particles causes heating via hysteresis energy losses .

Superparamagnetic particles are used as magnetic resonance imaging (MRI)

contrast agent in diagnostics applications. MRI may be used to enhance the image

contrast between normal and diseased tissue and/or indicate the status of organ functions

or blood flow. Small superparamagnetic iron oxides (SPIOs) have been developed for

imaging liver metastases and to distinguish loops of bowel from other abdominal

structures.

Medical applications require particles with high saturation magnetization,

exhibiting superparamagnetic behavior and small enough to interact in the region of

interest. Fundamental research must still be performed into areas such as the uniformity

of magnetic particles with an equal probability of magnetic capture and determination of

the fate of the particles in the body. Despite much fundamental research still to be

conducted, the potential for use of magnetic nanoparticles in a variety of biomedical

applications such as for cell separation, lab-on-a-chip applications and for the extraction,

purification and re-injection of patient stem cells after cancer treatment is significant.44

Chapter 1, Sec II

44

REFERENCES

1. G. C. Bond in: Heterogeneous Catalysis: Principles and Applications, Clarendon

Press, Oxford, 1987.

2. B. C. Gates in: Catalytic Chemistry, John Wiley & Sons Inc., New York, 1992.

3. R. A.V. Santen, P. W. N. M. V. Leeuwen, J. A. Moulijn, B. A. Averill, Catalysis: An

integrated approach, 2nd ed, Elsevier: Amsterdam, 1999.

4. a) D. J. C. Hamilton, Science, 2003, 299, 1702. b) R. T. Baker, W. Tumas, Science,

1999, 284, 1477.

5. a) C. Coperet, M. Chabanas, R. P. S. Arroman, J. M. Basset, Angew. Chem. Int. Ed.,

2003, 42, 156. b) J. M. Basset, A. Choplin, J. Mol. Catal., 1993, 21, 95. c) N.

Mizuno, M. Misono, Chem. Rev., 1998, 98, 199. d) F. Lefebvre, J. M. Basset, J. Mol.

Catal. A: Chem., 1999, 146, 3.

6. M. Benaglia, Recoverable and Recyclable Catalysts, John Wiley and Sons, Chichester

2009.

7. B. L. Cushing, V. L. Kolesnichenko, C. J. O. Connor, Chem. Rev., 2004, 104, 3893.

8. a) D. Astruc, Nanoparticles and Catalysis;, Ed.; Wiley-VCH: Weinheim, 2008. b) G.

A. Somorjai, H. Frei, J. Y. Park, J. Am. Chem. Soc., 2009, 131, 16589.

9. a) C. T. Yavuz, J. T. Mayo, W. W. Yu, A. Prakash, J. C. Falkner, S. Yean, L. L. Cong,

H. J. Shipley, A. Kan, M. Tomson, D. Natelson, V. L. Colvin, Science, 2006, 314,

964. b) S. H. Sun, C. B. Murray, D. Weller, L. Folks, A. Moser, Science, 2000, 287,

1989. c) J. Gao, W. Zhang, P. Huang, B. Zhang, X. Zhang, B. Xu, J. Am. Chem. Soc.,

2008, 130, 3710. d) J. Lu, S. H. Yang, K. M. Ng, C. H. Su, C. S. Yeh, Y. N.Wu, D. B.

Chapter 1, Sec II

45

Shieh, Nanotechnology, 2006, 17, 5812. e) Z. Li, L. Wei, M. Gao, H. Lei, Adv.

Mater., 2005, 17, 1001. f) M. K. Yu, Y. Y. Jeong, J. Park, S. Park, J. W. Kim, J. J.

Min, K. Kim, S. Jon, Angew. Chem., Int. Ed., 2008, 47, 5362.

10. a) A. G. Roca, M. P. Morales, K. O’Grady, C. J. Serna, Nanotechnology, 2006, 17,

783. b) Y. H. Zheng, Y. Cheng, F. Bao, Y. S. Wang, Mater. Res. Bull., 2006, 41, 525.

c) C. Lang, D. Schueler, D. Faivre, Macromol. Biosci., 2007, 7, 144. d) P. Majewski,

B.Thierry, Crit. Rev. Solid State Mater. Sci., 2007, 32, 203.

11. a) S. Roy, M. A. Pericas, Org. Biomol. Chem., 2009, 7, 2669. b) R. B. N. Baig, R. S.

Varma, Chem. Commun., 2013, 49, 752. c) V. Polshettiwar, R. S. Varma, Org.

Biomol. Chem., 2009, 7, 37. d) V. Polshettiwar, B. Baruwati, R. S. Varma, Green

Chem., 2009, 11, 127. e) B. Baruwati, D. Guin, S. V. Manorama, Org. Lett., 2007, 9,

5377. f) S. Luo, X. Zhenga, J. P. Cheng, Chem. Commun., 2008, 5719. g) X. Zheng,

S. Luo, L. Zhang, J –P. Cheng, Green Chem., 2009, 11, 455.

12. U. Schwertmann, R. M. Cornell, The Iron Oxides: Structure, Properties, Reactions,

Occurrences and Uses, 2nd edn, WILEY-VCH, Weinheim, 2003. b) U.

Schwertmann, R. M. Cornell, Iron Oxides in the Laboratory, Wiley-VCH, Wienheim,

2000.

13. a) S. Stolnik, L. Illum, S. S. Davis, Adv. Drug Delivery Rev. 1995, 16,195. b) T. T.

Kodas, M. H. Smith, Aerosol processing of materials New York: Wiley-VCH; 1999.

c) C. S Lee, H. Lee, R. M. Westervelt, Appl. Phys. Lett., 2001, 79, 3308. d) A.

Rishton, Y. Lu, R. A Altman, A. C Marley, C. Bian Hahnes, R. Viswanathan, G.

Xiao, W. J. Gallagher, S. S. P Parkin, Microelectron. Eng., 1997, 35, 249.

Chapter 1, Sec II

46

14. a) A. K. Gupta, S. Wells, IEEE Trans. Nanobiosci., 2004, 3, 66. b) A. K. Gupta, A. S.

G. Curtis, Biomaterials, 2004, 25, 3029.

15. a) V. Polshettiwar, B. Baruwati, R. S. Varma, Green Chem., 2009, 11, 127. b) I.

Nedkov, R. E. Vandenberghe, T. Marinova, P.Thailhades, T. Merodiiska, I.

Avramova, Appl. Surf. Sci., 2006, 253, 2589. c) J. E. Tasca, A. Ponzinibbio, G. Diaz,

R. D. Bravo, A. Lavat, M. G. Gonzalez, Top. Catal., 2010, 53, 1087.

16. J. P. Jakubovics, Magnetism and Magnetic Materials, Cambridge University Press,

Cambridge, 1994.

17. A. H. Latham, M. E. Williams, Acc. Chem. Res., 2008, 41, 411.

18. J. Fan, Y. Gao, J. Exp. Nanosci., 2006, 1, 457.

19. A.R. Vaino, K.D. Janda, J. Comb. Chem., 2000, 2, 579.

20. S. Giri, B. G. Trewyn, M. P. Stellmaker, V. S.-Y. Lin, Angew. Chem. Int. Ed., 2005,

117, 5166; Angew. Chem. Int. Ed., 2005, 44, 5038.b) C. Bergemann, D. Muller-

Schulte, J. Oster, L. Brassard, A. S. Lubbe, J. Magn. Magn. Mater., 1999, 194, 45. c)

L. Nunez, M. D. Kaminski, J. Magn. Magn. Mater., 1999, 194, 102.

21. J. Jin, T. Iyoda, C. Cao, Y. Song, L. Jiang, T. J. Li, D. B. Zhu, Angew. Chem. Int. Ed.,

2001, 40, 2135.

22. T. J. Yoon, W. Lee, Y. S. Oh, J. K. Lee, New. J. Chem., 2003, 27, 227.

23. M. H. Sousa, F. A. Tourinho, J. Depeyrot, G. J. da Silva, M. S. F. L. Lara, J. Phys.

Chem. B, 2001, 105, 1168.

24. a) S. C. Bourque, F. Maltais, W. J. Xiao, O. Tardif, H. Alper, P. Arya, L. E. Manzer,

J. Am. Chem. Soc., 1999, 121, 3035. b) S. C. Bourque, H. Alper, J. Am. Chem. Soc.,

Chapter 1, Sec II

47

2000, 122, 956. c) J. K. Lee, T. J. Yoon,Y. K. Chung, Chem. Commun., 2001, 1164.

c) T. Malmström, H. Weigl, C. Andersson, Organometallics, 1995, 14, 2593. d) K.

Nozaki, Y. Itoi, F. Shibahara, E. Shirakawa, T. Ohta, H. Takaya, T. Hiyama, J. Am.

Chem. Soc., 1998, 120, 4051.

25. a) A. Hu, G. T. Yee, W. Lin, J. Am. Chem. Soc., 2005, 127, 12486. b) G. Chouhan, D.

Wang, H. Alper, Chem. Commun., 2007, 4809.

26. S. Sun, H. Zeng, J. Am. Chem. Soc., 2002, 124, 8204.

27. Y. Sahoo, H. Pizem, T. Fried, D. Golodnitsky, L. Burstein, C. N. Sukenik, G.

Markovich, Langmuir, 2001, 17, 7907.

28. T. Rajh, L. X. Chen, K. Lukas, T. Liu, M. C. Thurnauer, D. M. Tiede, J. Phys. Chem.

B., 2002, 106, 10543.

29. C. Xu, K. Xu, H. Gu, R. Zheng, H. Liu, X. Zhang, Z. Guo, B. Xu, J. Am. Chem. Soc.,

2004, 126, 9938.

30. a) B. Baruwati, K. M. Reddy, S. V. Manorama, R. K. Singh, O. Parkash. Appl. Phys.

Lett., 2004, 85, 2833. b) D. Guin, B. Baruwati, S. V. Manorama, J. Mol. Catal. A,

Chem., 2005, 242, 26. c) D. Guin, B. Baruwati, S. V. Manorama, Org. Lett., 2007, 9,

1419. d) B. Baruwati, D. Guin. S. V. Manorama, Org. Lett., 2007, 9, 1419.

31. R. Raja, B. V. Glovko, M. J. Thomas, A. B. Murcia, W. Zhou, S. Xie, G. F. B.

Johnson, Chem. Commun., 2005, 2026.

32. a) Y. Yu, Y. Yin, B. T. Mayers, Y. Xia, Nano Lett., 2002, 2, 183. b) N. Kohler, G. E.

Fryxell, M. Zhang, J. Am. Chem. Soc., 2004, 126, 7206.

Chapter 1, Sec II

48

33. C. A. Dalaigh, S. A. Corr, Y. Gunko S. J. Connon, Angew. Chem. Int. Ed., 2007, 119,

4407.

34. a) C. W. Tornøe, M. Meldal, In American Peptide Symposium; M. Lebl, R. A.

Houghten, Eds, American Peptide Society and Kluwer Academic Publishers: San

Diego, CA, 2001, 263. b) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B.

Sharpless, Angew. Chem. Int. Ed., 2002, 41, 2596. c) C. W. Tornøe, C. Christensen,

M. Meldal, J. Org. Chem., 2002, 67, 3057.

35. G. Lu, W. Mai, R. Jin, L. Gao, Synlett, 2008, 9, 1418.

36. X. J. Wu, R. Jiang, Bi. Wu, X. M. Su, X. P. Xu, S. J. Jia, Adv. Synth. Catal., 2009,

351, 3150.

37. M. L. Kantam, J. Yadav, S. Laha, P. Srinivas, B. Sreedhar, F. Figueras, J. Org.

Chem., 2009, 74, 4608.

38. P. Tartaj, In Encyclopedia of Nanoscience and Nanotechnology, Vol. 1, H. S. Nalwa

(Ed.), p. 177, American Scientific Publishers, Stevenson Ranch, CA, 2004.

39. U. O. Häfeli, Int. J. Pharm., 2004, 277, 19.

40. D. Portet, B. Denizot, E. Rump, J. J. Lejeune, P. Jallet. J. Colloid Interface Sci., 2001,

238, 37.

41. C. H. Ahn, J. W. Choi, H. J. Cho. In Encyclopedia of Nanoscience and

Nanotechnology, Vol. 6, H. S. Nalwa (Ed.), p. 815, American Scientific Publishers,

Stevenson Ranch, CA, 2004.

42. a) A. J. Rosengart, M. D. Kaminksi, H. Chen, P. L. Caviness, A. D. Ebner, J. A.

Ritter, J. Magn. Magn. Mater., 2005, 293, 633. b) B. B. Yellen, Z. G. Forbes, D. S.