Nanomedicine

and

Nanoparticlesin Medicine

NanotechnologyHistoryApproachesInvestmentPolicy Statements and RegulationSummary

NanomedicineInvestmentPubblicationsAims

Drug deliveryIn vivo imagingMolecular Imaging and TherapyPhotodinamic therapyNanoparticle targetingMedical applications of molecular nanotechnologyNanorobots

Summary

NanoparticlesBackgroundCompositionShapesPropertiesNanotoxicityBiomedical ApplicationsSafety

What is Nanotechnology?

“’Nano-technology’ mainly consists of the processing of, separation, consolidation, and deformation of materials by one atom or by one molecule.”

-N. Taniguchi

“ Technology based on the manipulation of individual atoms and molecules to build structures to complex atomic specification.”

–K. Eric Drexler

Aims:● extensions of conventional device physics,● new approaches based upon molecular self-assembly, ● developing new materials with dimensions on the nanoscale to investigatingwhether we can directly control matter on the atomic scale.

Debate: future implications of nanotechnology. ● create many new materials and devices, ● applications in medicine, electronics, biomaterials and energy production, ● introduction of new technology,● toxicity and environmental impact of nanomaterials,● theirpotential effects on global economics,● speculation about various dangerous scenarios,● special regulation of nanotechnology is warranted.

Nanotechnology, (or"nanotech“), is the study of the controlling of matter on an atomic and molecular scale. Generally nanotechnology deals with structures sized between 1 to 100 nanometer in at least one dimension, and involves developing materials or devices within that size.

The first use of the concepts found in 'nano-technology' was in "There's Plentyof Room at the Bottom", a talk given byphysicist Richard Feynman at anAmerican Physical Society meeting at Caltech on December 29, 1959.

Feynman described a process by which the ability to manipulate individualatoms and molecules might be developed, using one set of precise tools tobuild and operate another proportionally smaller set, and so on down to the needed scale.

In the course of this, he noted, scaling issues would arise from the changingmagnitude of various physical phenomena: gravity would become lessimportant, surface tension and van der Waals attraction would becomeincreasingly more significant, etc.

History

Bottom-up approaches

These seek to arrange smaller components into more complex assemblies.

Top-down approaches

These seek to create smaller devices by using larger ones to direct their assembly.

Approaches

Investments in nanotechnology are on the rise.

These advances are in both basic university-basedresearch, as well as industry.

Many of these advances use nanoparticles in some form or other.

Investment

The U.S.A. is investing $1.5 billion in nanoscience in 2009. This includes the responsible development of nanoscience, but no Federal regulation yet exists.

“Existing statutory authorities are adequate to address oversight of

nanotechnology and its applications.”

“Where possible, regulatory approaches should enable rather than

hinder innovation…”

“Benefits of regulation should justify their costs.”

USA : Policy Statements

The Environmental Protection Agency issued a White Paper, and has a voluntary “Nanoscale Materials Stewardship Program”

The Food and Drug Administration have a task force, but feel that existing regulations can govern nanomaterials.

California and Massachusetts both have State and Municipal regulations of nano health and safety.

USA: Regulation

The European Union is more inclined to precaution.

“Where the full extent of a risk is unknown, but concerns are

so high that risk management measures are considered

necessary,…measures must be based on the Precautionary

Principle”

“The regulatory challenge is therefore to ensure that society

can benefit from novel applications of nanotechnology, whilst a

high level of protection of health, safety and the environment is

maintained”

European Union: Policy Statement

The Registration, Evaluation, Authorisation and Restriction of Chemical Substances (REACH) regulation has no specific statement on nano materials, except to differentiate carbon nanotubes from bulk carbon.

The “Cosmetics Directive” and “Novel Food Regulation” both mention specific assessment for nanomaterials, defining such as having one or more dimension on the scale of 1 to 100 nm.

European Union: Regulation

• Nanotechnology is not very new.• but our ability to image it (and so, modify it) has increased.

• Nanotechnology will modify existing technologies, and enable new ones.

• “Free” nanomaterials are a real health concern. “Nanoparticles” and “nanotubes” are a strong focus of toxicity.

• Governments range from trusting their existing regulations (U.S.A.) to defining and amending new regulations (E.U).

Nanotechnology - Summary

Nanomedicine is the medical application of nanotechnology.

Nanomedicine ranges from the medical applications of nanomaterials, tonanoelectronic biosensors, and even possible future applications of molecularnanotechnology.

Current problems for nanomedicine involve understanding the issues related totoxicity and environmental impact of nanoscale materials.

What is Nanomedicine ?

“…the application of nanotechnology (the engineering of tiny machines) to the prevention and treatment of disease in the human body.”

– Whatis.com

What is Nanomedicine?

Investment

Nanomedicine is a large industry, with nanomedicine sales reaching 6.8 billiondollars in 2004, and with over 200 companies and 38 products worldwide, a minimum of 3.8 billion dollars in nanotechnology R&D is being invested everyyear. As the nanomedicine industry continues to grow, it is expected to have a significant impact on the economy.

Nanomedicine research is receiving funding from the US National Institute ofHealth (NIH). Of note is the funding in 2005 of a five-year plan to set up fournanomedicine centers. In April 2006, the journal Nature Materials estimated that130 nanotech-based drugs and delivery systems were being developedworldwide.

Number of PubMed publicationsmentionning nanomedicine ornanomedicines in their title or abstract.

Pubblications

Nanomedicine seeks to deliver a valuable set of research tools and clinically usefuldevices in the near future.

New commercial applications in the pharmaceutical industry that may include: ● advanced drug delivery systems, ● new therapies, ● in vivo imaging.

Neuro-electronic interfaces and other nanoelectronics-based sensors are anotheractive goal of research. Further down the line, the speculative field of molecularnanotechnology believes that cell repair machines could revolutionize medicine and the medical field.

Aims of Nanomedicine

Approaches:● Drug delivery● In vivo imaging● Molecular Imaging and therapy● Nanoparticle targeting● Medical applications of molecular nanotechnology● Nanorobots● Nanoparticles

Bioavailability refers to the presence of drugmolecules where they are needed in the body and where they will do the most good.

Drug delivery focuses on maximizing bioavailabilityboth at specific places in the body and over a periodof time.

Drug delivery

Nanomedical approaches to drug delivery center on developing nanoscaleparticles or molecules to improve drug bioavailability.

This can potentially be achieved by molecular targeting by nanoengineereddevices. It is all about targeting the molecules and delivering drugs with cellprecision. More than $65 billion are wasted each year due to poor bioavailability.

Drug delivery systems, lipid- or polymer-based nanoparticles, can be designed toimprove the pharmacological and therapeutic properties of drugs. The strength ofdrug delivery systems is their ability to alter the pharmacokinetics and biodistributionof the drug. Nanoparticles have unusual properties that can be used to improve drugdelivery.

Where larger particles would have been cleared from the body, cells take up thesenanoparticles because of their size.

Complex drug delivery mechanisms are being developed, including the ability to get drugs through cell membranesand into cell cytoplasm.

Efficiency is important because many diseases dependupon processes within the cell and can only be impededby drugs that make their way into the cell. Triggeredresponse is one way for drug molecules to be used more efficiently. Drugs are placed in the body and only activate on encountering a particular signal.

If a drug is cleared too quickly from the body, this could force a patient to use high doses, but with drug delivery systems clearance can be reduced by altering the pharmacokinetics of the drug.

Poor biodistribution is a problem that can affect normal tissues throughwidespread distribution, but the particulates from drug delivery systems lower the volume of distribution and reduce the effect on non-target tissue.

Potential nanodrugs will work by very specific and well-understood mechanisms; one of the major impacts of nanotechnology and nanoscience will be in leadingdevelopment of completely new drugs with more useful behavior and less side effects.

In vivo imaging is another area where tools and devices are being developed. Using nanoparticlecontrast agents, images such as ultrasound and MRI have a favorable distribution and improvedcontrast. The new methods of nanoengineeredmaterials that are being developed might beeffective in treating illnesses and diseases such ascancer.

In vivo imaging

What nanoscientists will be able to achieve in the future is beyond current imagination. This might beaccomplished by self assembled biocompatiblenanodevices that will detect, evaluate, treat and report to the clinical doctor automatically.

Quantum dots (nanoparticles with quantum confinement properties, such as size-tunable light emission), when used in conjunction with MRI (magnetic resonanceimaging), can produce exceptional images of tumor sites.

These nanoparticles are much brighter than organic dyes and only need one light source for excitation. This means that the use of fluorescent quantum dots couldproduce a higher contrast image and at a lower cost than today's organic dyes usedas contrast media.

The downside, however, is that quantum dots are usually made of quite toxicelements.

A schematic illustration showing hownanoparticles or other cancer drugs

might be used to treat cancer

Molecular Imaging and Therapy

The small size of nanoparticles endowsthem with properties that can be veryuseful in oncology, particularly in imaging.

Cancer

Another nanoproperty, high surface area tovolume ratio, allows many functional groups to beattached to a nanoparticle, which can seek out and bind to certain tumor cells.

Additionally, the small size of nanoparticles (10 to100 nanometers), allows them to preferentiallyaccumulate at tumor sites (because tumors lackan effective lymphatic drainage system).

“Is it possible to manufacture multifunctional nanoparticles that would detect, image, and then proceed to treat a tumor?” This question is under vigorous investigation; the answer to which could shape the future of cancer treatment.

A promising new cancer treatment that may one day replace radiation and chemotherapy is edging closer to human trials. Kanzius RF therapy attachesmicroscopic nanoparticles to cancer cells and then "cooks" tumors inside the body with radio waves that heat only the nanoparticles and the adjacent (cancerous) cells.

Light may also be used to produce high energy oxygen molecules which willchemically react with and destroy most organic molecules that are next to them(like tumors).

This therapy is appealing for many reasons. It does not leave a “toxic trail” ofreactive molecules throughout the body (chemotherapy) because it is directedwhere only the light is shined and the particles exist.

Photodynamic therapy has potential for a noninvasive procedure for dealing withdiseases, growth and tumors.

Photodinamic Therapy

In photodynamic therapy, a particleis placed within the body and isilluminated with light from the outside. The light gets absorbed by the particle and if the particle is metal, energy from the light will heat the particle and surrounding tissue.

Even at a relatively small size of 5 nm , though, these particles can becomecompartmentalized in the peripheral tissues, and will therefore accumulate in the body over time. While advancement of research proves that targeting and distribution can be augmented by nanoparticles, the dangers of nanotoxicitybecome an important next step in further understanding of their medical uses.

Nanoparticle targeting

It is greatly observed that nanoparticles are promising tools for the advancementof drug delivery, medical imaging, and as diagnostic sensors.

However, the biodistribution of these nanoparticles is mostly unknown due tothe difficulty in targeting specific organs in the body.

Current research in the excretory systems of mice, however, shows the ability of gold composites toselectively target certain organs based on their size and charge. These composites are encapsulated by a dendrimer and assigned a specific charge and size. Positively-charged gold nanoparticles were found toenter the kidneys while negatively-charged goldnanoparticles remained in the liver and spleen.

Molecular nanotechnology is a speculative subfield of nanotechnology regardingthe possibility of engineering molecular assemblers, machines which could re-order matter at a molecular or atomic scale.

Molecular nanotechnology is highly theoretical, seeking to anticipate whatinventions nanotechnology might yield and to propose an agenda for future inquiry.

The proposed elements of molecular nanotechnology, such as molecularassemblers and nanorobots are far beyond current capabilities.

Medical applications of molecular nanotechnology

Nanomedicine would make use of these nanorobots introduced into the body, torepair or detect damages and infections.

According to Robert Freitas of the Institute for Molecular Manufacturing, a typicalblood borne medical nanorobot would be between 0.5-3 micrometres in size, because that is the maximum size possible due to capillary passagerequirement. Carbon could be the primary element used to build these nanorobots due to the inherent strength and other characteristics of some forms of carbon(diamond/fullerene composites), and nanorobots would be fabricated in desktop nanofactories specialized for this purpose.

Nanorobots

Nanodevices could be observed at work inside the body using MRI, especially if their components weremanufactured using mostly 13C atomsrather than the natural 12C isotope ofcarbon, since 13C has a nonzeronuclear magnetic moment.

Medical nanodevices would first be injected into a human body, and would then go towork in a specific organ or tissue mass.

The doctor will monitor the progress, and make certain that the nanodevices havegotten to the correct target treatment region. The doctor will also be able to scan a section of the body, and actually see the nanodevices congregated neatly around theirtarget (a tumor mass, etc.) so that he or she can be sure that the procedure wassuccessful.

Modern nanotechnology is not the fabrication of tiny mechanical devices that can and will enter human systems to repair or damage cells.

Our dream!(J. Lertola)

Nanorobots

Nanoparticles

Nanoclusters have at least one dimension between 1 and 10 nanometers and a narrow size distribution. Nanopowders are agglomerates of ultrafine particles, nanoparticles, or nanoclusters. Nanometer-sized single crystals are often referred to as nanocrystals.

Nanoparticle research is currently an area of intense scientific interest due to a wide variety of potential applications in biomedical, optical and electronic fields.

In nanotechnology, a particle is defined as a small objectthat behaves as a whole unit in terms of its transportand properties. It is further classified according to size (diameter):fine particles between 100 and 2500 nanometers, ultrafine particles between 1 and 100 nanometers(nanoparticles).

MoleculesAlthough the size of most molecules would fit into the above outline, individual molecules are usually not referred to as nanoparticles.

Although nanoparticles are generally considered an invention of modernscience, they actually have a very long history. Nanoparticles were usedby artisans as far back as the 9th century in Mesopotamia for generatinga glittering effect on the surface of pots.

Licurgo’s pot

Green (reflection light)Red (trasmission light)Silver and gold nanoaparticles(Ag, Au 70 nm).

One of the first exampleof nanotechnologies!

Background

As these nanoparticlesget smaller, the coloursshift from red, through yellow and green, to blue.

As early as 500 AD, glass artisans were making stained glass windows with vibrant reds and yellows.

These colours were much moreluminous and durable than dyes could produce, and were the products of “coinage metal”nanoparticles imbedded in the glass.

In a subsequent paper, the author (Turner) points out that:

Michael Faraday provided the first description, in scientific terms, of the optical properties ofnanometer-scale metals in his classic 1857 paper.

"It is well known that when thin leaves of gold or silver are mounted upon glass

and heated to a temperature which is well below a red heat (~500 °C), a

remarkable change of properties takes place, whereby the continuity of the

metallic film is destroyed. The result is that white light is now freely transmitted,

reflection is correspondingly diminished, while the electrical resistivity is

enormously increased."

Metal, dielectric, and semiconductor nanoparticles have been formed, as well ashybrid structures (e.g., core-shell nanoparticles).

Nanoparticles made of semiconducting material may also be labeled quantum dotsif they are small enough (typically sub 10 nm) that quantization of electronic energylevels occurs.

Such nanoscale particles are used in biomedical applications as drug carriers or imaging agents.

Composition

Shapes

Nanoparticles may or may not exhibit size-related properties that differ significantlyfrom those observed in fine particles or bulk materials.

Properties

Nanotoxicity

The toxicity, like many properties of nanomaterials, differ from their macroscale characteristics

Researchers at Rice University under Prof. Jennifer West, havedemonstrated the use of 120 nm diameter nanoshells coated with gold tokill cancer tumors in mice. The nanoshells can be targeted to bond to cancerous cells by conjugatingantibodies or peptides to the nanoshell surface. By irradiating the area of the tumor with an infrared laser, which passesthrough flesh without heating it, the gold is heated sufficiently to cause death to the cancer cells.

Biomedical Applications

Nanoparticles of cadmium selenide (quantum dots) glow when exposed toultraviolet light. When injected, they seep into cancer tumors. The surgeoncan see the glowing tumor, and use it as a guide for more accurate tumorremoval.

Biomedical Applications

To use nanoparticles in vivo, one often selects polymers known to be non-toxic.

Polyglycolic-lactic acid (PGLA) is a good example.

Nanoparticles of this materialcan be dosed with specifictherapeutic agents and injectedinto biological systems.

Toxicity

Superparamagnetic iron oxide (SPION) was shown to enhance medical magnetic imaging.

However, normal SPION is toxic.

When coated with a sugar derivative (Pullulan), it was found to be non-toxic.

Biomaterials 2005, 26, 1565.

Specific Toxicity – Cell Apoptosis

The surface coating of nanoparticlesis crucial to determining their properties.

In particular, the surface coating can regulatestability, solubility and targeting.

For biological applications, the surface coating should be polar to give high aqueous solubility and prevent nanoparticle aggregation. In serum or on the cell surface, highly charged coatings promote non-specificbinding, while polyethylene glycol (PEG) linked to terminal hydroxyl or methoxygroups repel non-specific interactions.

Nanoparticles can be linked to biological molecules which can act as addresstags, to direct the nanoparticles to specific sites within the body,or specificorganelles within the cell, to follow specifically the movement of individual proteinor RNA molecules in living cells.

Functionalization

The polymer nanoparticle can be modified with a bio-nanosensor to chemically recognise a cancer cell.

The surface of the particle is “decorated” with aptamers.

An aptamer is a small “piece of DNA” that is developed to specifically bind to a cancer cell.

With the aptamer in place, the nanoparticles adhere to the cancer cell, and release the drug at the site where it is required.

Drug release

Drug release from a nanoparticle is slow and steady over time.

Specific uptake occurs when a nanoparticle has surface “chemistry” that binds to specific sites on the cell walls.

Mostly, this is engineered.

Specific Uptake

Non Specific Uptake

Non-specific uptakeis due to the characteristics of thenanoparticle, but will be taken up by any cell wall.

This is a general toxicity.

Nanoparticles present possible dangers, bothmedically and environmentally.

Nanostars of vanadium(IV) oxide

Most of these are due to the high surface to volume ratio, which can make the particles very reactive or catalytic.

However, free nanoparticles in the environment quickly tend to agglomerateand thus leave the nano-regime, and nature itself presents manynanoparticles to which organisms on earth may have evolved immunity(such as salt particulates from ocean aerosols, terpenes from plants, or dustfrom volcanic eruptions).

They are also able to pass through cell membranes in organisms, and their interactions with biological systems are relatively unknown.

Safety

According to the San Francisco Chronicle,

"Animal studies have shown that some

nanoparticles can penetrate cells and

tissues, move through the body and brain

and cause biochemical damage they also

have shown to cause a risk factor in men for

testicular cancer. But whether cosmetics and

sunscreens containing nanomaterials pose

health risks remains largely unknown,

pending completion of long-range studies

recently begun by the FDA and other

agencies.“

SEM micrograph of amorphous colloidal silicaparticles (average particle diameter 600 nm).

Diesel nanoparticles have been found to damage the cardiovascular system in a mouse model.

There is presently debate about whether they have health risks akin to asbestos:

“Our data demonstrate that asbestos-like pathogenic behaviour

associated with CNTs conforms to a structure–activity

relationship based on length, to which

asbestos and other pathogenic fibres

conform.” Nature Nano. 2008, 3, 423.

Carbon Nanotubes: An Asbestos Debate

Nanomaterials in Biological Systems

Mozzarella

In food (es. mozzarella) titanium dioxide (TiO2) is a well-known and approvedadditive as effective white pigment (food coloring E171). We do not know the real size (distribution) of the particles.

In 2006 media articles prominentlyreported the presence of nanoscaledtitanium dioxide in confectionery suchas aMars chocolate bars, Twix and M&M’s.

NANOPRODUCTS Clothing, cosmetics, food containers and even plush toysincorporate silver nanoparticles for their antibacterial abilities.

So the Virginia Tech researchers decided to use x-ray transmission electron microscopy, an extremely sensitive technique that can identify both composition and structure. With micrographs of sludge from a Midwest treatment plant, they identifiednanoparticles 5 to 20 nm in diameter and determined that the particles had a 2-to-1 silver-to-sulfur ratio. The scientists also obtained a crystal structure to confirm that the particles were Ag2S.