CANCER THERAPY USING MAGNETIC

NANOPARTICLES

-A Review

Rashmi Rao B (rashmie.raoh@gmail.com ),

Roshna Rajan George (roshnageorges@gmail.com),

V1 Semester,B.E,Biotechnology

M.S Ramaiah Engineering College,

Bangalore -54

Abstract:

Novel immunological treatment approaches are required that attack the molecular and

biological features of invasive malignant tumors. The magnetic nanoparticle technique

has emerged as a potential multifunctional clinical tool for cancer cell-specific detection,

treatment, and monitoring. Current magnetic nanoparticle technology relies mostly on

iron-oxide nanoparticles (IONPs).These particles are mostly made of a core of magnetite

and coated with biocompatible vectors/stablizers generally suspended in a colloidal

dispersion. The nanoparticles suspended in the magnetic fluid possess a “magnetic

moment” which enables them to be stimulated by application of an alternating magnetic

field. The nanoparticles absorb the energy of the magnetic field which is then released

into the surrounding area as heat through magnetic “relaxation processes” to produce

temperatures of between 41 °C and 45 °C (hyperthermia), or even higher temperatures of

between 46 °C and 70 °C (thermo ablation). At temperatures above 46 °C, virtually all

biomolecules within the cells are affected, and the tumor cells containing the

nanoparticles are directly destroyed as a result of overheating. The remains of the cells

are then naturally broken down through normal bodily processes. The nanoparticles

which are released from the destroyed cells are then either reabsorbed by surrounding

tumor cells which are still intact or else eliminated by macrophages, part of the body’s

immune system.

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1 .Introduction:

Scientists have learned that cancer is caused by changes in genes that normally control

the growth and death of cells. Certain lifestyle and environmental factors can change

some normal genes into genes that allow the growth of cancer. Many gene changes that

lead to cancer are the result of tobacco use, diet, exposure to ultraviolet (UV) radiation,

exposure to carcinogens or some gene alterations are inherited. Scientists continue to

examine the factors that may increase or decrease a person's chance of developing cancer.

Cancer treatment can include surgery, radiation therapy, chemotherapy, hormone therapy,

and biological therapy. Generally one method or a combination of methods is used,

depending on the type and location of the cancer, whether the disease has spread, the

patient's age and general health, and other factors. Because treatment for cancer can also

damage healthy cells and tissues, it often causes side effects.

Nanotechnology for cancer therapy:

Conventional cancer therapies stated above employ drugs/radiation that are known to kill

cancer cells effectively. But the limited accessibility to the tumor, the risk of operating on

a vital organ, the spread of cancer cells throughout the body and the lack of selectivity

toward tumor cells increases the probability of affecting healthy cells in addition to tumor

cells, leading to adverse side effects such as nausea, neuropathy, hair-loss, fatigue, and

compromised immune function. They risk damage to normal tissues or incomplete

eradication of the cancer. Nanotechnology offers the means to aim therapies directly and

selectively at cancerous cells. Here in our review we focus on a novel approach of

targeting the cancer cells effectively by using magnetic nanoparticles.

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2.Magnetic Nanoparticles:

Magnetic nanoparticles show remarkable new phenomena such as superparamagnetism,

high field irreversibility, high saturation field, extra anisotropy contributions or shifted

loops after field cooling. These phenomena arise from finite size and surface effects that

dominate the magnetic behaviour of individual nanoparticles(8)

Frenkel and Dorfman (2) were the first to predict that a particle of ferromagnetic

material, below a critical particle size (<15 nm for the common materials), would consist

of a single magnetic domain, i.e. a particle that is a state of uniform magnetization at any

field. The magnetization behaviors of these particles above a certain temperature, i.e. the

blocking temperature, is identical to that of atomic paramagnets (superparamagnetism)

except that an extremely large moment and thus, large susceptibilities are involved (3)

Magnetic nanoparticles can be used as drug carriers for chemotherapeutics to deliver

medication or directly rupture the tumor by applying suitable form of energy while

sparing healthy tissue. This technology has several advantages over conventional

therapies.

They can:

Protect drugs from being degraded in the body before they reach their target.

Enhance the absorption of drugs into tumors and into the cancerous cells

themselves.

Allow for better control over the timing and distribution of drugs to the tissue,

making it easier for oncologists to assess how well they work.

Prevent drugs from interacting with normal cells, thus avoiding side effects.

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3.Biomedical applications of magnetic nanoparticles:

We can classify biomedical applications of magnetic nanoparticles In vivo into :

1. Diagnostic

Nuclear Magnetic Resonance (NMR)imaging

2. Therapeutic

Hyperthermia

Drug-targeting

3.1.Diagnostic applications:

Nuclear magnetic resonance imaging: A medical imaging system that enables the

discovery of malignant tissue ,utilizing contrast agents and heating agents made of

magnetic nanoparticles that are delivered to tumor sites .The thermal contrast agents may

be temperature self-controlled magnetic nanoparticles that may be encapsulated in a

biocompatible coating. The thermal contrast agents may be uploaded into the tumor

tissue. An alternating magnetic field device with a prescribed frequency range may be

used to induce heating of the magnetic nanoparticles in the patient, and a thermal scan

may be utilized to identify tumors. In another embodiment, the contrast agent may be

formed from magnetic nanoparticles having distinct magnetic moment profiles, and a

MRI system may be utilized to identify tumors with such contrast agent(4)

3.2.Therapeutic applications:

3.2.1.Drug targeting using magnetic nanoparticles:

In these systems, therapeutic compounds are attached to biocompatible magnetic

nanoparticles and magnetic fields generated outside the body are focused on specific

targets in vivo. The fields capture the particle complex resulting in enhanced delivery to

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the target site. The potential of drug delivery systems based on the use of nano and

microparticles stems from significant advantages such as:

(i)the ability to target specific locations in the body;

(ii) the reduction of the quantity of drug needed to attain a particular concentration in the

vicinity of the target; and

(iii) the reduction of the concentration of the drug at nontarget sites minimizing severe

side effects

(In this review we have concentrated on the therapeutic applications of

hyperthermia/thermal ablation. Drug targeting using magnetic nanoparticles will not be

addressed, although the general implications between both therapies based on magnetism

can be inferred. Applications in diagnosis, where magnetic nanoparticles are widely used

as contrast agents, will not be addressed here either)

3.2.2.Hyperthermia using magnetic nanoparticles:

Hyperthermia therapy, a form of cancer treatment with elevated temperature in the range

of 41–45°C, has been recently paid considerable attention because it is expected to

significantly reduce clinical side effects compared to conventional therapies and can be

effectively used for killing localized or deeply seated cancer tumors. Accordingly,

various forms of hyperthermia have been intensively developed for the past few decades

to provide cancer clinics with more effective and advanced cancer therapy techniques.

However, in spite of the enormous efforts, all the hyperthermia techniques introduced so

far were found to be not effective for completely treating cancer tumors. The low heating

temperature owing to the heat loss through a relatively big space gap formed between

targeted cells and hyperthermia agents caused by the ineffective control agent transport,

as well as killing of healthy cells attributed to the difficulties of cell differentiations by

hyperthermia agents, are considered as the main responsibilities for the undesirable

achievements.(5) In a possible breakthrough, it has been reported that very promising and

successful methods of cancer therapy can be achieved using magnetic nanoparticles.

Different from conventional magnetic hyperthermia, in-vivo magnetic nanoparticle

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hyperthermia is expected to be one of the best solutions for killing tumor cells which are

deeply seated and localized inside the human body. The recent development of magnetic

nanoparticle technology accelerated a new form of hyperthermia treatment, so-called “in

vivo hyperthermia,” because magnetic nanoparticles are expected to provide a great deal

of technical advantages for hyperthermia which include:

1) Direct injection of hyperthermia agents through blood vessel.

2) Easy transport of nanoparticles to the targeted cell by externally controlled magnetic

field.

3) Small heating loss during hyperthermia due to direct heating of cell.

4) Possibility for differentiation of tumor cells from healthy cells by using antibody-

antigen biological reaction(6)

Overview of hyperthermia:

1.Preparation and selection of magnetic nanoparticles

2.Modification of magnetic nanoparticles

3.Treatment by applying suitable magnetic

4.Preparation of magnetic nanoparticles for hyperthermia:

The preparation method of the magnetic nanoparticles represents one of the most

important challenges that will determine the particle size and shape, the size distribution,

the surface chemistry of the particles and consequently their magnetic properties.

For most of the in vivo applications, they are generally used in the form of magnetic

fluids. Biocompatibility of aqueous magnetic fluids is determined by both core material

and the coatings. Most widely used biocompatible magnetic fluid is magnetite (Fe3O4)

based. (7)

Several methods have been explained for the preparation of such magnetite ferrofluids.(8)

4.1.Precipitation from solution:

In general these methods allow the preparation of magnetic nanoparticles with a rigorous

control in size and shape in a simple way and thus are very appropriate for their use in

biomedical applications.The preparative techniques under this principle are:

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4.1.1 Coprecipitation.

There are two main methods for the synthesis in solution of magnetite spherical particles

in the nanometer range.

In the first, ferrous hydroxide suspensions are partially oxidized with different oxidizing

agents . For example, spherical magnetite particles of narrow size distribution with mean

diameters between 30 and 100 nm can be obtained from a Fe(II) salt, a base and a mild

oxidant (nitrate ions).

The other method consists in ageing stoichiometric mixtures of ferrous and ferric

hydroxides in aqueous media, yielding spherical magnetite particles homogeneous in

size. In addition, it has been shown that by adjusting the pH and the ionic strength of the

precipitation medium, it is possible to control the mean size of the particles over one

order of magnitude (from 15 to 2 nm). The size decreases as the pH and the ionic strength

in the medium increases. Both parameters affect the chemical composition of the surface

and consequently, the electrostatic surface charge of the particles. Under these conditions,

magnetite particles are formed by aggregation of primary particles formed within an

Fe(OH)2 gel. This is an ordered aggregation that gives rise to spherical crystalline

particles. The smallest particles can also be generated after adding polyvinylalcohol

(PVA) to the iron salts.

4.1.2 Polyols.

In this method, fine metallic particles can be obtained by reduction of dissolved metallic

salts and direct metal precipitation from a solution containing a polyol .

In the polyol process, the liquid polyol acts as the solvent of the metallic precursor, the

reducing agent and in some cases as a complexing agent for the metallic cations. The

metal precursor can be highly or only slightly soluble in the polyol. The solution is stirred

and heated to a given temperature reaching the boiling point of the polyol for less

reducible metals. By controlling the kinetic of the precipitation, non-agglomerated metal

particles with well-defined shape and size can be obtained. Iron particles around 100 nm

can be obtained by disproportionation of ferrous hydroxide in organic media. Fe(II)

chloride and sodium hydroxide reacts with ethylene glycol (EG) or polyethylene glycol

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(PEG) and the precipitation occurs in a temperature range as low as 80–100˚C.

Furthermore, iron alloys can be obtained by coprecipitationof Fe, Ni, and/or Co in EG

and PEG.

Figure 1:Preparation of magnetic nanoparticles by precipitation from

solution:

(a) Coprecipitation (maghemite).

(b) Polyol process (Fe-based alloy). Reprinted from [9].

(c) Microemulsions (maghemite).Reprinted from [10].

4.1.3. Microemulsions.

Water-in-oil (W/O) microemulsions(i.e. reverse micelle solutions) are transparent,

isotropic, thermodynamically stable liquid media. In these systems, fine microdroplets of

the aqueous phase are trapped within assemblies of surfactant molecules dispersed in a

continuous oil phase. The surfactant-stabilized microcavities (typically in the range of 10

nm) provide a confinement effect that limits particle nucleation, growth, and

agglomeration . W/O microemulsions have been shown to be an adequate, versatile and

simple method to prepare nano-sized particles. Ferrous dodecyl sulfate, Fe(DS)2,

micellar solution can be used to produce nanosized magnetic particles whose size is

controlled by the surfactant concentration and by temperature. Magnetite nanoparticles

around 4 nm in diameter have been prepared by the controlled hydrolysis with

ammonium hydroxide of FeCl2 and FeCl3 aqueous solutions within the reverse micelle

nanocavities generated by using AOT as surfactant and heptane as the continuous oil

phase.

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4.2. Aerosol/vapour methods.

These methods have proven to be excellent techniques for the direct and continuous

production of well-defined magnetic nanoparticles under exhaustive control of the

experimental condition. The preparative techniques under this principle are:

4.2.1 Spray pyrolysis.

Spray pyrolysis is a process in which a solid is obtained by spraying a solution into a

series of reactors where the aerosol droplets undergo evaporation of the solvent and

solute condensation within the droplet, followed by drying and thermolysis of the

precipitated particle at higher temperature. This procedure gives rise to microporous

solids, which finally sinter to form dense particles. This method represents a convenient

procedure for obtaining finely dispersed particles of predictable shape, size and variable

composition. The resulting powders generally consist of spherical particles, the final

diameter of which can be predetermined from that of the original droplets. The method

offers certain advantages over other more commonly used techniques (such as

precipitation from homogenous solution) as it is simple, rapid, and continuous. Most of

the pyrolysis based processes employed to produce maghemite nanoparticles start with a

Fe3+ salt and some organic compound that acts as the reducing agent. It was shown that

in this procedure Fe3+ is partially reduced to a mixture of Fe2+ and Fe3+ in the presence

of organic compounds with the formation of magnetite, which is finally oxidized to

maghemite. Without the presence of a reducing agent,

hematite is formed instead of maghemite.

Figure 2: Preparation of magnetic nanoparticles of

maghemite by:

(a) Spray pyrolysis.

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(b) Laser pyrolysis. Reprinted from [12]

4.2.2. Laser pyrolysis.

The method involves heating a flowing mixture of gases with a continuous wave carbon

dioxide laser, which initiates and sustains a chemical reaction. Above a certain pressure

and laser power, a critical concentration of nuclei is reached in the reaction zone, which

leads to homogeneous nucleation of particles that are further transported to a filter by an

inert gas. Three characteristics of this method must be emphasized:

(a) The small particle size.

(b) The narrow particle size distribution.

(c) The nearly absence of aggregation.

Pure, well-crystallized and uniform γ -Fe2O3 nanoparticles can be obtained in one single

step by a CO2 laser pyrolysis

Figure 3: Schematic representation of the spray pyrolysis device used for the preparation

of maghemite nanoparticles. This device consists of an aerosol generator (atomizer or an

ultrasonic bath), one furnace and a particle recovery system.

4.3. Encapsulation of magnetic nanoparticles in polymeric matrixes.

Encapsulation of inorganic particles into organic polymers endows particles with

important properties that bare uncoated particles lack. Polymer coatings on particles

enhance compatibility with organic ingredients, reduce susceptibility to leaching, and

protect particle surfaces from oxidation. Consequently, encapsulation improves

dispersibility, chemical stability, and reduces toxicity. Polymer-coated magnetite

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nanoparticles have been synthesized by seed precipitation polymerization of methacrylic

acid and hydroxyethyl methacrylate in the presence of the magnetite nanoparticles.

Cross-linking of polymers has also been reported an adequate method for the

encapsulation of magnetic nanoparticles. To prepare the composites by this method, first,

mechanical energy needs to be supplied to create a dispersion of magnetite in the

presence of aqueous albumin , chitosan, or PVA polymers. Depending upon composition

and reaction conditions the addition of a cross-linker and heat results in polydispersed

magnetic latex, 0.3 microns in diameter, with up to 24 wt% in magnetite content.

5. Selection of nanoparticles:

Thermotherapy utilizes the magnetic properties of the nanoparticles in magnetic fluids.

Furthermore, these applications also depend on the hydrodynamic size. Therefore, in

many cases only a small portion of particles contributes to the desired effect. The relative

amount of the particles with the desired properties can be increased by the fractionation

of magnetic fluids. Common methods currently used for the fractionation of magnetic

fluids are centrifugation and size-exclusion chromatography . All these methods separate

the particles via non-magnetic properties like density or size.

Preference should be given, however, to partitions based on the properties of interest, in

this case the magnetic properties. So far, magnetic methods have been used only for the

separation of magnetic fluids, for example, to remove aggregates by magnetic filtration

like field–flow fractionation, a family of analytical separation techniques , in which the

separation is carried out in a flow with a parabolic profile running through a thin channel.

An external field is applied at a right angle to force the particles toward the so-called

accumulation wall.(8)

6. Modification of the nanoparticles:

Why modify nanoparticles?

Stabilisation in different solvents

Functionalisation of surface (e.g. for coupling with a protein etc.)

Activation for (electro-)chemical reactions

Passivation against corrosion

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The magnetic nanoparticles are modified using several surfactant-and polymer-based

coating materials like citrate, polyaspertic acid, dextran. Dextran coating has been used

mostly because of its biocompatibility. Dextran and PEG-coated iron oxide nanoparticles

when suitably modified to enable conjugation with molecular targeting agents, provide

opportunities to target cancer cells. Monoclonal antibodies, scFv, and peptides

conjugated to 20 nm nanoparticles have been reported to target cancer for hyperthermia

or alternating magnetic field (AMF) therapy. Radioimmunoconjugates can be conjugated

to nanoparticles using 25 µg of RIC/mg of nanoparticles by carbodimide chemistry(11)

The physical characteristics of the magnetic nanoparticles can affect their in vivo

performance. Surface morphology, surface charge density, and particle size are

considered important factors that determine pharmacokinetics, toxicity, and

biodistribution. The nanoparticles are encased in a functional aminosilane coating which

provides sufficient stabilization (14) against agglomeration and sedimentation within the

magnetic nanoparticle therapy fluid. The coating thus maximizes the concentration of

iron oxide within the magnetic fluid, which is essential for the subsequent success of the

thermotherapy. This enables the desired temperature to be attained with small amounts of

fluid and with a relatively low magnetic field strength. Due to this nano-chemical

coating, the nanoparticles once injected into the tumor do not clump together but rather

distribute themselves evenly so that they can be absorbed into the cancer cells in

sufficiently large quantities.(13)

7. Therapy Procedure and Method of action:

The basic principle (13) behind the therapy is to inject modified magnetic nanoparticles

directly into the tumor as a minimally invasive procedure. The particles are brought into

oscillation by a magnetic field which changes its polarity 100,000 times per second,

transforming this magnetic energy into heat. The resulting high heat production is

determined by the particle type, the frequency of the radiated alternating magnetic field

and the magnetic field intensity. The nanoparticles suspended in the magnetic fluid

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possess a “magnetic moment” which enables them to be stimulated by application of an

alternating magnetic field.

They absorb the energy of the magnetic field which is then released into the surrounding

area as heat through

(1) Hysteresis

(2) Frictional losses

(3) Magnetic “relaxation processes” (Brown and Néel relaxation).

In this way, the energy of the magnetic field is transformed into thermal energy, with the

efficiency of this process being determined by the “specific absorption rate”(SAR) of the

material. SAR is an extremely important parameter in thermotherapy since it serves as a

precise measure of the heat generating capacity of the magnetic fluid in the alternating

magnetic field. SAR is a measure of the rate at which energy is absorbed by the body

when exposed the magnetic field. It is defined as the power absorbed per mass of tissue

and has units of watts per kilogram(18).Once the SAR of the particles is known, the exact

quantity of magnetic fluid necessary for a thermotherapy procedure can be readily

determined.

The nanoparticles are directly injected into the tumor and, because of the special

coating(like aminosilane)are not transported out but rather remain there.The

thermotherapy can thus be limited to tumor tissue, sparing the surrounding healthy tissue.

(13)

At temperatures of up to 45 °C, the efficacy of simultaneously applied radiation therapy

or chemotherapy is substantially increased. In the case of

Radiotherapy: The degree to which efficacy is increased depends on the extent to

which certain enzymes which would normally repair radiation damage cease to

function because of the higher temperature, thus allowing the tumor cells to be

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destroyed. Once these important enzymes have been degraded by the warmth, the

tumor cells die even with relatively small doses of radiation.

Chemotherapy: The warmth effects proteins, such as those within chemoresistant

tumor cells which act to eject cytostatics from those cells, preventing them from

being destroyed by conventional chemotherapy. Once these “pumps” are shut

down by the higher temperatures, then the chemo-resistant tumor cells can also be

destroyed because the chemotherapy agents remain in the cells.

At temperatures above 46 °C, virtually all biomolecules within the cells are effected, and

the cells are directly destroyed as a result of overheating. The remains of the cells are

then naturally broken down through normal bodily processes. The nanoparticles which

are released from the destroyed cells are then either reabsorbed by surrounding tumor

cells which are still intact or else eliminated by macrophages, part of the body’s immune

system.

Tumor targeting with magnetic nanoparticles may use passive or active strategies.(15)

Passive targeting occurs as a result of extravasation of the nanoparticles at the

diseased site (tumor) where the microvasculature is hyper-permeable and leaky, a

process aided by tumor-limited lymphatic drainage. . Fortunately, these leaky

membranes can be used as an advantage to deliver the magnetic nanoparticles

which can accumulate in tumor tissue enabling its diagnosis and therapy. This

enhanced permeability of the molecules of certain sizes in the tumor cells as

opposed to normal tissue is defined as Enhanced Permeability and Retention

(EPR) effect. [17]

Active targeting is based on the over or exclusive expression of different

epitopes or receptors in tumoral cells, and on specific physical characteristics.

This  second  degree  of specificity  preferentially  links  the  nanoparticles to the 

tumor  and not  to  neighbouring healthy  cells. Scientists can  then  externally 

supply  energy  to these  cells. The specific properties of the vectors associated 

with  nanoparticles  allow for  the  absorption of  this  directed energy,  creating 

an  intense  heat  that selectively  kills  the tumor  cells. 

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Such vectors sensitive to physical stimuli (e.g. temperature, pH, electric charge, light,

sound, magnetism) have been developed.

8. Overview of the procedure:

1 2 3

4 5

1. Introduction of several milliliters of the magnetic fluid directly into the tumor, with the

exact amount depending on the type and size of the tumor.

2. Following this minimally invasive procedure, the magnetic nanoparticles gradually

distribute themselves within the tumor tissue

3. An alternating magnetic field is then applied to bring the nanoparticles into oscillation,

without the need for any physical contact

4. This results in the generation of heat within the tumor which can be precisely

controlled.

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5. Once the target temperature (41 °C – 70 °C) has been attained,the tumor cells become

more susceptible for accompanying radiotherapy or chemotherapy, or in the case of

higher temperature are irreparably damaged by the heat.

9. Fundamental advantages of using magnetic nanoparticles:

The nanotechnological design of the biocompatible magnetic nanoparticles enables

differentiated intracellular absorption, preferably into rapidly proliferating cells such as

tumor cells. Furthermore, thermotherapy with magnetic nanoparticles offers other

fundamental advantages:

The magnetic fluid can be meted out in the target volume in the amounts as small

as necessary and therefore be dispensed almost continuously.

Due to the known energy absorption per nanoparticle, the energy transmission can

be calculated from the density distribution which is measured in the CT. This

enables the three-dimensional calculation and planning of the temperature

distribution.

The introduction of a defined total quantity into a target volume enables an ability

to exercise control which is not provided in any other interstitial procedure.

Through the intracellular absorption of the particles into the tumor cells, tumor

cells in the surroundings of the macroscopic tumor - which are generally not

covered by non-specific therapy, that is, therapy which is oriented solely along the

contrast enhanced image - are also reached. Furthermore, the cancer cells are not

able to eject the particles again.

The collapse of tissue barriers with corresponding heating causes improved

diffusability and therefore a spread of the magnetic fluid in the target volume. In

the course of the external contact-free activation of the particles by means of the

alternating magnetic field applicator, any desired number of treatments is possible

without additional traumatization

10. Safety : Influence of the magnetic field

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Although all the components of the body are either dia-, para-, superpara-, ferri- or

ferromagnetic, the magnetic fields required to produce obvious effect in the body are very

large. Even red blood cells, which each contain micrograms of the Fe protein

hemoglobin, show a relatively low response to large fields or steep field gradients,

although this low value is enough to be used in thermotherapy. The other natural Fe

containing compounds in the body are hemosiderin, ferritin, transferrin, and the

cytochromes. Based on positive clinical and safety experience, the FDA classified

magnets with field strength of less than 2 T as nonsignificant risk devices in 1987.Further

positive experiences led the FDA to increase this threshold to 4 T in 1996 and again in

2003 (for adults) to 8 T. Even though experiments with strong static magnetic fields (8 T)

have been shown to reduce the flow rate of human blood by 30% in in vitro tests(19) and

it has been reported that magnetic fields above 3 T might affect the normal behavior of

erythrocytes, recent studies evaluating human subjects for adverse effects in

physiological or neurocognitive functions resulting from exposure to static magnetic

fields (up to 8 T) from MRI systems have not shown any clinically relevant effects. (15)

11. Toxicity and Limitations:

When discussing the toxicity of nanoparticles, generalization becomes difficult

because their toxicity depends on numerous factors including the dose, chemical

composition, method of administration, size, biodegradability, solubility,

pharmacokinetics, biodistribution, surface chemistry,shape, and structure, to name but a

few. With the magnetic nanoparticles, as with any new biomedical discovery, the risk-

benefit trade-off must be considered to assess whether the risks can be justified. In

general, the size, surface area, shape, composition, and coating of an nanoparticles are the

most important characteristics regarding cytotoxicity, and modifications of the

nanoparticles surface are a key tool to minimize toxicological effects. It is well

documented that the large surface-to-volume ratio of all nanosized particles can

potentially lead to unfavorable biological responses if they are inhaled and subsequently

absorbed via the lung or swallowed and then absorbed across the gastrointestinal tract.

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Interestingly, it has also been reported that, in 20-100 mg/ml concentrations, large

magnetic particles show higher cytotoxicity than smaller ones even after normalizing for

surface area despite the lower surface-to-volume ratio, although it is difficult to perform

comparable experiments with differently sized particles. In any case, toxicity studies

should consider not only acute toxicity but also that of degradation products, the possible

stimulation of cells with subsequent release of inflammatory mediators, and long term

toxicity. For a magnetic carrier with potential as a drug delivery vector, it is necessary, at

the very least, to analyze its:

(i)Toxicity (acute, subacute,chronic toxicity, teratogenicity and mutagenicity) in

cellular and animal models.

(ii) Hematocompatibility.

(iii) Biodegradation

(iv) Immunogenicity.

(v)Pharmacokinetics (body distribution, metabolism, bioavailability, elimination,

organspecific toxicity) before the start of preclinical testing.(15)

Magnetic drug delivery constitutes a promising technology to treat cancer, and several

products are already on the market. The limitations inherent in the use of external

magnetic fields can, in some cases, be circumvented by means of internal magnets

located in the proximity of the target by minimally invasive surgery. Magnetic fluid

Hyperthermia/thermal ablation is also promising and is currently being applied (i.e.

MagForce Nanotecnologies AG), but is limited by the fact that the tumor needs to be

localized. This route, therefore, cannot be used in preventive medicine, or for treating

early-stage tumors. The greatest therapeutic potential is probably associated with

applications involving ‘intelligent’ particles with a magnetic core(to direct the particles to

the vicinity of the target and also for hyperthermia or for temperature-enhanced release of

the drug), a recognition layer (to which suitable receptors are attached), and a therapeutic

load (adsorbed inside the pores or hosted within internal cavities of the particles). The

challenges are formidable, especially those related to the development of suitable

recognition layers. Not only must useful recognition moieties be identified and attached

to the particles, but they must be loaded to a high density while maintaining their desired

characteristics.

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12. Future:

MagForce Nanotechnologies AG, the Berlin-based medical technology company

majority owned by Nanostart AG, has already announced the successful completion of

phase II clinical trials demonstrating the efficacy of its Nano-Cancer® therapy which

involves thermotherapy in patients with recurrent glioblastoma, a frequent form of brain

tumor which is highly malignant. Greater degree of research and implementation is

required in this field of magnetic nanoparticles for targeted tumor degeneration. This

could reduce the harmful side effects of chemotherapy, since the harsh drugs would no

longer be poisoning the entire body. The nanoparticles provides researchers with the

opportunity to study and manipulate macromolecules in real time and during the earliest

stages of cancer progression. These magnetic nanoparticles are expected to facilitate and

accelerate the diagnosis and treatment of serious diseases in the future, creating new

treatment options which offer ease of use to the physician and fewer side effects to the

patient.

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