ISSUE 24 MAY 2012 ISSN 1757-2517

Plus the latest & best news on nano for industry, society & the environment

THE MAGAZINE FOR SMALL SCIENCE

NANoPArtICLES

IN Food- NATuRE’S bARRIERS pROTEcT

Magnetic Hyperthermia for CancerAdvances in magnetic nanoparticles offer more effective ways to treat brain, pancreatic and prostate cancers.

Porous Silicon – revolutionising drug targeting & delivery Nanocarrier-mediated drug delivery systems are one of the most attractive applications of nanomedicine.

Nanoparticles in Food: close but not too close.Skin and mucosae pose barriers to the entry of nanoparticles into the human body.

Nanotechnologies for Soldier Enhancement, Protection & SupportA case study in portable Energy Generation, Storage and Management for Field Troops.

FEATURE

These bacteria synthesize iron oxide

nanoparticles and use them to orient

themselves in the earth’s magnetic field.

These nanoparticles are in the size

range 20-70 nm and have an impressive

crystallographic quality and display

heating power values which have not yet

been reached by chemically-synthesized

iron oxide ones. Recent results obtained

by a French team led by E. Alphandery

shows that these nanoparticles are more

efficient in destroying tumours grafted

on mice than their artificial counterparts.

This is not only due to their large heating

power, but also to their better ability to

penetrate the cells.

If one wants to reach larger heating

power values, a change in the nature of

the nanoparticles is required. Indeed,

the maximum heating power value is

directly proportional to the saturation

magnetization of the material used.

Iron oxides are not the best material for

this and magnetic materials composed

only of the ‘3d elements’ (Fe, co, Ni)

and their alloys, display a saturation

magnetization which can be more than

twice that of iron oxide. However, co

and Ni are known to be toxic and could

not of course be injected into humans.

This explains why our group has

focused its efforts on iron nanoparticles.

Synthesizing monodisperse iron

nanoparticle of a controlled size is a

real challenge, which has been taken up

by the chemists of our laboratory. This

effort has been rewarded by the fact that

our nanoparticles present the largest

heating power of any in the literature

so far. However, the use of iron needs

to address two important questions.

The first one concerns the protection of

these nanoparticles against oxidation

once inside the body, which requires

synthesizing an efficient protecting core.

The second concerns the toxicity: if

iron is not intrinsically toxic to humans,

the effect of injecting metallic iron, a

potential reducing agent, into the body

still raises the toxicity question.

Other medical applications of magnetic nanoparticlesIn addition to magnetic hyperthermia,

magnetic nanoparticles could be

used in several other approaches in

nanomedicine. For instance, a San Diego

team conducted by S. Jin has synthesized

nanocapsules containing both a drug and

magnetic nanoparticles. They have shown

that when they heat the nanoparticles

using the same principle as the one used

in magnetic hyperthermia, the increase

of temperature stimulates the release of

drugs out of the nanocapsule. This could

be used to release drugs very locally

inside the tumours and thus minimize

secondary effects during treatments.

Another advantage of combining drugs

and magnetic nanoparticles is drug

targeting, since the particles can be

guided or accumulated into a region of

interest using external static magnetic

fields.

Revolutionising Drug Targeting and Delivery

Putting a piece of ferromagnetic magnetic material into an alternative magnetic field increases its temperature in two different ways.

The first way is that the magnetization of the magnetic

material will try to follow the magnetic field variations

and to keep in alignment with it, but will do it with a

lag, conducting to a hysteresis loop. The area of this

hysteresis loop corresponds to irreversible energy losses

which are released by the magnetic nanoparticles, heating

its surrounding. Let’s call this phenomenon “heating by

hysteresis losses.”

The second way is due to the combination of two well-

known laws of the physics: Faraday’s law and Ohm’s law.

The first one stipulates that when any material is submitted

to a varying magnetic field, an electrical current is induced

into the material to try to compensate the magnetic field

variation (these currents are called by the French Foucault

currents and by the rest of the world as eddy currents!).

These circulating currents heat the material by the Ohm’s

law and are thus limited in resistive materials, but very

present in metals. Eddy currents are strongly enhanced in

ferromagnetic metals compared to non-magnetic ones since

the reversal of the magnetization by the external magnetic

field is equivalent to a gigantic change of magnetic field

inside a ferromagnetic material. For a given material, the

respective importance of the heating by hysteresis losses

compared to the heating by eddy currents depends on the

size of the piece of material put into the magnetic field. For

a large piece of material, eddy currents dominate. Thus,

they are the ones which mainly heat the pot (which needs

to have a ferromagnetic iron bottom) put on an induction

plate.

Note that the frequency and amplitude of the magnetic field

used in an induction plate are very similar to the ones used

in magnetic hyperthermia. On the contrary, if a nanoparticle

is put into the magnetic field, eddy current are very limited

and the only sources of heat are the hysteresis losses.

Finally….

All progress in these fields is only

possible with close collaboration

between various scientists:

physicists to predict, measure

and explain hyperthermia

experiments; chemists and bio-

chemists to synthesize high-

quality functionalized nano-

particles; biologists to perform

toxicity and efficiency assays

on cells and animals; engineers

to develop the hyperthermia

equipment adapted to humans,

and physicians to perform

clinical trials. Nowadays, many

major scientific advances are the

product of a large community

of collaborating scientists, and

nanomedicine is, in that sense,

a good example of the beauty of

modern collaborative science.

*At the Laboratoire de physique et chimie des Nano-Objets, Toulouse, France (http://lpcno.insa-toulouse.fr), researchers have been working on the properties of magnetic nanoparticles. Since 2005, several members of the laboratory have been working on the optimisation of nanoparticles for magnetic hyperthermia. Their work is funded by the Midi-pyrénées Region and by the InNabioSanté foundation.

By Hélder A. Santos, Division of Pharmaceutical Technology, Faculty of Pharmacy, University of Helsinki, Finland

Nanomedicine and drug nanocarriersOne of the biggest challenges in the modern world is to find healthcare solutions that

can fully benefit humankind. This means that scientists are expected to come up with

great ideas and develop tools that can be applied to the diagnosis and treatment of

diseases, such as cancer. In this respect, considerable attention has been focused on

the field of nanomedicine. Nanomedicine makes use of nanoparticles (structures with

at least one dimension bellow 100 nanometers), as offering new solutions to previously

insoluble medical problems and proposing new therapies.

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FEATURE

Porous Silicon -

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FEATURE FEATURE

In recent years, a great variety of

nanotechnology based platforms have

been developed and employed to

improve the delivery of therapeutics

to the disease site. currently, the

nanoparticles used in the clinic, and

the majority of nano-therapeutics

/ diagnostics under investigation,

accommodate single- or multiple-

functionalities on the same entity.

The biological barriers are very

heterogeneous which may prevent

the therapeutic and imaging agents

from reaching their intended targets

in sufficient concentrations. Therefore,

there is an emerging requirement to

develop multimodular nanoassemblies

in which different components

with specific functions may act in a

synergistic manner.

unfavourable physicochemical properties

of many drug molecules may affect their

bioavailability and, consequently, affect

their therapeutic efficacy and efficiency.

In the past, researchers have struggled

to develop advanced drug delivery

systems for controllable and enhanced

drug release, as well as for targeted drug

delivery. In this context, nanocarrier-

mediated drug delivery systems are one

of the most attractive applications of the

emerging nanomedicine field. Targeted

and controlled drug delivery systems

improve drug bioavailability, as well as

their pharmacological and therapeutic

properties, while minimizing collateral

effects.

The pharmaceutical industry has been

increasing funding for research in the

development of advanced drug delivery

systems with investments of $131.6

billion in 2010, estimated to increase

in 2016 to $175.6 billion (http://www.

bccresearch.com/report/advanced-drug-

delivery-systems-phm006h.html).

The birth of nanostructured pSi for the biomedical world The element silicon (Si) is a tetravalent

metalloid , and the second most

abundant element (after oxygen) in the

Earth’s crust, representing about 25.7%

of it by mass. Si very rarely occurs as the

pure free element in nature, but is more

widely distributed in various forms as

silicon dioxide (silica), SiO2, or silicates.

The great boost for the research on

porous silicon (pSi) occurred when

in 1989 Leigh canham revealed the

potential of nano-engineered Si as a

semiconductor while working at the

Defence Research Agency (now QinetiQ)

in Malvern, uK. canham explored the

various practical uses of the luminescent

properties of the pSi materials. However,

the great breakthrough occurred in

1995 when canham demonstrated that

pSi materials were both biodegradable

and biocompatible (non-toxic), and

thus, could be safely adsorbed and

eliminated by the body after it has been

nano-engineered (canham 1997). This

brilliant discovery led to groundbreaking

achievements in the biomedical field

ever since.

because the nanostrcutured Si

materials were both luminescent

and biodegradable opened a world of

possibilities for the versatility of the

material in applications in biosensing,

pharmaceuticals, biomedicine and the

food industry. Regarding the biomedical

applications, there is today an increasing

interest in using pSi materials as carriers

for controlled drug delivery, targeted

cancer therapy, medical imaging, tissue

engineering and improved health and

beauty products.

The properties of nanostructured pSi materialspSi, often designated as mesoporous

silicon, is a material with a honeycomb

structure containing pores with

diameters between 2 and 50 nm, and

sometimes referred to as nanoporous

to emphasize its nanoscale size nature.

These pores can be filled with drugs,

peptides, genes, proteins, radionuclides

and other therapeutics or vaccines. The

most extraordinary properties of these

materials are their large surface area

(200–500 m2/g), porosity (50–80%) and

large pore volume (0.5–2.0 cm3/g), which

can act as reservoirs for storing drug

molecules for drug delivery applications.

The pore diameters of pSi can be

tuned allowing for the loading of

various therapeutic compounds. Due

to the stable and rigid framework of

pSi materials, it makes therapeutic

compounds resistant to mechanical

stress, pH, and fast degradation when in

the body. In this context, the interest and

the applicability of pSi-based materials

is increasing due to its potential to

revolutionize the biomedical field, in

particular as drug delivery carriers

or implantable devices. pSi materials

(micro- and nanoparticles) have well-

defined structures and surfaces, and they

are also chemically inert and thermally

stable.

Nanostructured pSi materials are

produced typically from Si wafers via

electrochemical etching, where the

control of the nano-enginered structures

is possible. These nanostructures are

stable under the harsh conditions of

the stomach and gastrointestinal (GI)

lumen. by fine-tuning the porosity of

the pSi materials it is possible to make

it degradable in the body. For example,

nanostructured pSi with porosities >70%

dissolves in all simulated body fluids

(except gastric fluids), whereas pSi with

porosities <70% is bioactive and slowly

biodegradable.

In addition to that, pSi exhibits a number

of properties that make it an attractive

material for controlled drug delivery

applications (Figure 1). For example,

the electrochemical production allows

the construction of tailored pore sizes

and volumes that are controllable from

the scale of microns to nanometers.

A number of convenient chemistries

exist for the modification of pSi surfaces

that can be used to control the amount,

identity, and in vitro/vivo release rate of

therapeutic payloads. Another important

feature of pSi is that in the body it

degrades into silicic acid, [Si(OH)4], which

is the most natural form of Si in the

environment, non-toxic, important in

human physiology in protecting against

aluminium toxic effects, and is efficiently

excreted by the kidneys. Si is also an

essential nutrient for the human body

and in the Western world the average

daily dietary intake of Si is about 20−50

mg/day. A major source of Si intake

comes from beer.

How nanostructured pSi can revolutionary the healthcare?The pharmaceutical industry faces

great challenges in the development of

therapeutic compounds that are both

efficient for the treatment of the disease

in question, with minor side effects.

However, in most cases this cannot be

achieved, particularly because many

drug molecules administrated orally

suffer from poor bioavailability, i.e. they

are poorly soluble with low dissolution

rates in the intestinal lumen, as well as

suffering from poor permeability across

the GI wall. Furthermore, cytostatic drug

compounds usually lead to very adverse

side effects after administration.

Due to the properties of nanostructured

pSi materials, the most challenging

drug compounds can be loaded into

nanoporous pSi in order to overcome

the abovementioned problems. because

the drug molecules are confined inside

the pores, usually not much larger

than the drug molecules themselves,

their physicochemical properties can

be enhanced (Salonen et al., 2008). This

ensures that the therapeutic compounds

carried by the pSi materials will be

released from the pores efficiently in

a controlled manner, so that they are

pharmacologically active with very

minimal side effects to the patients. This

enables the control and local release

of the drug where its action is required

and simultaneously controls the drug

concentration in the blood.

Scientists have successfully loaded a

large variety of therapeutic compounds

into the nanopores of pSi materials, and

their release properties have extensively

been studied in the literature mainly

for oral drug delivery applications, but

also for other routes of administration,

such as intravenous (Santos et al., 2011).

Similarly, peptide or protein molecules

have also been successfully loaded into

nanostructured pSi or attached to its

surface, and their efficient sustained /

fast release and activity evaluated. This

is particularly interesting because many

peptides or proteins, such as insulin for

diabetes, have to be administrated as

solutions or suspensions frequently as

injections, due to the short duration of

action of the peptides in vivo, as well

as due to their rapid degradation and

elimination from the blood circulation.

Recent research has demonstrated that

nanostructured pSi carriers containing

food or water intake regulating peptides

could prolong the effect of the peptide,

which could reduce the frequency of

injections to the patients in the future,

or even be administrated via other route,

e.g. orally.

Other application of pSi materials is in

ocular therapy. Scientists have employed

nanostructured pSi-based technology

to delivery drug compounds inside the

eye of rabbits in order to minimize the

invasiveness of the treatments, with

controllable and monitorable drug

delivery concentrations enabling long-

acting local treatment of intraocular

diseases, which could help in the future

patients with problems in the retina and

choroid.

Another very important and more

recent application of nanostructured

pSi materials is in targeted delivery

for cancer therapy. Targeted and

controlled drug delivery also improves

drug bioavailability, as well as the

pharmacological and the drug

therapeutic properties, minimizing

detrimental adverse effects. The large

number of defense mechanisms in the

body prevents injected foreign agents

such as chemicals, biopharmaceutics,

and nanostructures from homing in to

their intended destinations. Therefore,

more sophisticated nanocarriers need to

be developed and tested.

Targeted delivery systems are designed

to deliver the drug precisely to the body

sites where it is needed, in proximity to,

or inside a cell, and to release a desired

amount of drug over a controllable

period of time. In specific (targeted)

delivery, the surface of a nanocarrier

is often bio-functionalized with

biological recognition ligands loaded

with anticancer drug, and may also

contain simultaneously an imaging

agent (Figure 2). These multifunctional

properties make nanocarriers capable

of targeting cancer cells and, at the

same time, imaging the cancer and

deliver appropriate therapeutic drugs.

Another advantage of such an approach

is the accuracy of targeting and the

preservation of healthy tissue, without

compromising the patients’ health.

Taking this into account, a multistage

pSi-based system comprising several

nanocomponents or “stages” was also

developed (Goding et al., 2011). Stage 1

nanostructured pSi particles are designed

in a nonspherical geometry to enable

superior blood margination and increase

cell surface adhesion. The idea is to be

able to load the nanoparticles (so-called

Stage 2) and efficiently transport them

from the administration site to the

disease lesion. Stage 2 nanoparticles can

be any available nanoparticles such as

liposomes, micelles, inorganic/metallic

nanoparticles, etc., within the size

Figure 1: List of the most relevant properties of the nanostructured pSi nanocarriers: Si wafer and pSi powder-based microparticles (left); mesoporous structure (~ 10 nanometers) and pSi solution-based nanoparticles (right). Other properties emphasized are: the small pore sizes yet, large or small enough to allow a fast or slow drug release; the possibility to functionalize the surface of pSi materials for targeted therapy; the pSi nanocarriers can be hydrophilic (or hydrophobic) enhancing its wettability properties; considerable amounts of therapeutic compounds can be loaded inside the pSi nanopores; the nanostructured pSi fabrication can be fine-tuned to produce a certain surface chemistry, pore size and shape, and morphology of the material; due to its top-down manufacture approach, nanostructured pSi can be easily scaled-up.

FEATURE

References

range of 5−100 nanometers in diameter.

Such systems have been demonstrated

to efficiently act as nanocarriers for

magnetic resonance imaging contrast

agents and to efficiently deliver small

interfering RNA (siRNA) for cancer

therapy.

Although therapy is one of the most

promising applications of nanostructured

pSi materials, pSi has also great

potential in pre-diagnostics in imaging

applications. Due to its intrinsic

luminescence nanostructured pSi

materials can be imaged in the body

by, for example, near-infra-red imaging

techniques. Another advantage is that

the pSi surface is easily modified by

radiotracers, such as fluorine-18 (Santos

et al., 2011) and others, which can be

used in positron emission tomography

for clinical diagnostics and drug

development.

Figure 2: Schematic representation of a spherical-shaped nanostructured pSi nanocarrier and its potentialities in drug delivery, cancer therapy and bio-imaging: (i) first the therapeutic compounds (drug/peptide) are loaded into the pores of nanostructured pSi; (ii) the surface of pSi nanocarriers can then be modified (functionalized) with different biological ligands and polymers, labelled with fluorophores and/or radioactive isotopes for non-invasive imaging applications; the pSi nanocarriers can then travel in the bloodstream and release the therapeutic compounds in the vicinity of unhealthy cells or tissues and simultaneously provide a real-time monitoring of its actions.

SummaryNanostructured pSi-based materials have

many interesting properties that can be

useful for biomedical applications such

as detection, identification, imaging,

and delivery of therapeutics to tissues,

organs or cells of interest. The great

advantages of the nanostructured pSi

materials are the good biocompatibility,

biodegradability, high pore volume

necessary for hosting large amounts of

therapeutics, different pore sizes for fine

control of drug loads and release kinetics,

high surface area for drug adsorption,

easy surface chemistry modification for

further biofunctionalization and control

of drug loading and release.

The nanostructured pSi properties enable

it to dissolve in the body at a controlled

rate while releasing drugs over minutes,

hours, days, months, or even years.

After the loaded drug is released, all

that is left in the body is pure Si, which

dissolves into non-toxic silicic acid

and is safely excreted from the body.

Doctors have then a range of options for

introducing drug-loaded nanostructured

pSi materials into the body: orally, via

injection, transdermally, or with a patch,

implant or coating.

One can envisage that future

generations of nanostructured pSi-based

nanocarriers will effectively improve the

quality of life of patients by efficiently

transporting drugs to targeted areas

without damaging healthy cells. These

nanocarriers can be strictly designed

for the intent of their application, with

a proper response and, in the future,

also for the delivery of drug dosages

according to the clinical needs of the

patient and pathology. The versatility

of the nanostructured pSi platform and

its emerging properties will enable the

creation of personalized solutions with

broad clinical implications within and

beyond the realm of cancer theranostics.

This is because nanostructured pSi-

based materials have the capacity to

incorporate and take advantage of a

variety of existing, novel, or clinically

used, therapeutic and imaging agents

from a “nano-toolbox”, while enabling

synergistic application of these

nanotechnologies to form a higher

generation nanosystem in the future.

canham LT (1997). properties of porous silicon. London, Short Run press Ltd.

Salonen J, Kaukonen AM, Hirvonen J, Lehto V-p (2008). Mesoporous silicon in drug delivery applications. J. pharm. Sci. 97: 632−653.

Anglin EJ, cheng L, Freeman WR, Sailor MJ (2008). porous silicon in drug delivery devices and materials. Adv. Drug. Delivery Rev 60: 1266-1277.

Santos HA, bimbo LM, Lehto V-p, Airaksinen AJ, Salonen J, Hirvonen J (2011). Multifunctional porous silicon for therapeutic drug delivery and imaging. curr. Drug Discov. Tech. 8: 228-249.

Godin b, Tasciotti E, Liu X, Serda RE, Ferrari M (2011). Multistage nanovectors: from concept to novel imaging contrast agents and therapeutics. Acc. chem. Res. 44: 979–989.

Nanoparticles

in Food: close, but not too closeSkin and mucosae pose barriers to the entry of nanoparticles into the human body. Eleonore Fröhlich, Center for Medical Research, Medical University of Graz, and Eva Roblegg, Institute of Pharmaceutical Sciences, Karl-Franzens University, Graz.

FEATURE

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