©2008 MagnaMedics

MagnaMedics

Sustainable and smart nanomaterials will enable nanotechnologies

Paul J.A. Borm

©2008 MagnaMedics

MagnaMedics

Chemelot campus,800 ha, 80 companiesIncl DSM, SABIC

©2008 MagnaMedics

MagnaMedics

J. Miro, self-portrait

CEO

ProductsProductionProfit

NanoparticlesAs tools

Prof

PeoplePlanetPapers

Nanoparticles as Objects of study

©2008 MagnaMedics

MagnaMedics

Intentionally produced NP-already on the market

-Newly engineered

Unintentionally produced NP-Combustion-Nucleation

New products, applicationsHigh added value

Nanomedicine:Intended exposureHigh dose, low risk

No added value, extra costConsiderable health risks

©2008 MagnaMedics

MagnaMedics

©2008 MagnaMedics

MagnaMedics

CountryTarget/response

NanoMaterials C/Ac NanoHSE Reference

World 337/64Carbon basedMetal oxides

64/0 37Gerritzen et al, 2006

Denmark 165/11Metal oxidesSilica, polymersCarbon black

6/5 1Tonning & Poulsen, 2007

Switserland 197/43Silica, TiO2Metal oxides, AgCarbon black

43/0 N.DSchmid &Riediker,2008

Zwitserland & Germany

?/40 No info 40/0 13Helland et al, 2008

UK ? /9 No info 7/2 N.D. VRS, 2007

Netherlands 98/8 No info 5/3 N.DMikkers et al, 2007

Netherlands 122/37Carbon blackmetal oxidessilica

30/7 9Borm et al(2008)

Risk = hazard x exposure

Hazard: the “ability” of a chemical to cause harm

Risk: the “probability” it will do so

©2008 MagnaMedics

MagnaMedics

Company policies for handling nanomaterials

• Defined by 9 out of 32 companies (24%)• Others on project level

• 3 most important elements:– Pre-emptive choice on specific nanoparticles– Handling all nanomaterials as toxic substances (safety principle)– Choices on the physical form of nanoparticles

Borm, Houba & Linker (2008) Survey on best practices in handling nanomaterials in Dutch industry.

©2008 MagnaMedics

MagnaMedics

0%

20%

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60%

80%

100%

120%

per

cen

tag

e o

f co

mp

anie

soverall

particles

particles & matrix

embedded in matrix only

Occupational hygiene strategies by approach

Risk = hazard x exposure

Hazard: the “ability” of a chemical to cause harm

Risk: the “probability” it will do so

©2008 MagnaMedics

MagnaMedics

Combustion NP

Engineered NPNanomedicine

Bulk industrial NP

Epidemiology

Toxicology?

?

Sources of evidence: a Bermuda Triangle

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MagnaMedics

Most of the evidence for human effects of NP is generated using unintentionallyunintentionally produced combustion Nanoparticles.

Effects of manufactured Nanoparticles have mainlybeen studied with a small set of particles alreadyon the market for decades (carbon black, TiO2, FeO)and more recently on carbon nanotubes.

In words:

©2008 MagnaMedics

MagnaMedics

General paradigms in nanoparticle toxicity based on inhalation

• Size matters for many dynamic and kinetic issues.• Inflammation is the key hallmark in effects.• Surface area is the best metric for inflammation. For

other effects no such consensus is present.• At fine size, aggregates of nanoparticles have a larger

effect than one fine particle of the same material.• Aggregates of nanoparticles cannot be dissociated in

epithelial lining fluid. Does that impede single NP uptake?

• Size is the main driver for current studies.• Little data is available that allow bridging to other

routes of exposure or materials

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MagnaMedics

Platelet aggregation by NP

PM and carbon nanoparticlesHave similar hazards

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MagnaMedics

Technology& ServicesMagCustom: Customized Beads and Materials

©2008 MagnaMedics

MagnaMedics

DrugMatrix

Linker

Homingdevice

Imagingtool

Assembly

Customized nanotools andAssemblies, based on Magnetic properties

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MagnaMedics

Drug delivery platforms on magnetic capture

Applied successfullyIn animal studies.

Krukemeyer et al (2008)In preparation

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MagnaMedics

Mitoxantrone-loadedIron nanoparticles.Size: 120 nmSurface: dextraneZeta-potential: -34 mVLoad MT: 20 ug/mgDose: 1 mg/kg BW

Photo’s courtesy dr. Krukemeyer

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MagnaMedics

Patient KL, treated with mitoxantrone-FF(100 mg/m2) liver metastasis reduced from 14.9 to 8.0 cm3

30.05.2008 04.07.2008

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MagnaMedics

Liver function

0

20

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100

120

-2 0 1 2 3 4 14 30

Time (days)

GOT

GPT

AP

y-GT

• No hair loss• No gastro-intestinal complications

• Normal kidney function• Temporal loss of leucocytes and thrombocytes.

• iron accumulation in the spleem

©2008 MagnaMedics

MagnaMedics

Intravenous delivery of engineered NPNeeds to study a series of questions:

• what happens to the FeO particles upon release from coatings?

• Is the surface active to bind endogenous proteins?

• Are NP being degraded/excreted or reach other targets.

• Do circulating FeO particles affect platelet aggregation, thrombosis or any other vascular condition?

©2008 MagnaMedics

MagnaMedics

Technology& ServicesMagCustom: Customized Beads and Materials

©2008 MagnaMedics

MagnaMedics

MagnaFy: making devices visible

Immobilize NP in polymers and compositesUse magnetic properties and signal distortion: markers are magnified and easily visibleNo release of contrast agent in bodySmall volume and therefore no heatingApplication to existing medical devices

©2008 MagnaMedics

MagnaMedics

Medical imaging-guidewires Application in renal stenting

©2008 MagnaMedics

MagnaMedics

MagnaFy: Biocompatibility and safety

Coated rods were found to be biocompatible in blood samples.

No wearing of markers in guide-wires after application in vivo

In worst-case damage of marker would cause release of iron-oxide nanoparticles. The iron oxide nanoparticles in our coating our non-toxic and biocompatible to relevant target systems.

Iron oxides are used as SPIONS and injected on purpose as contrast agent.

Matrix, iron-oxide and hydrophilic coating are fully biocompatible.

Residence time of devices is usually low ( < 15 min) and are removed from the body

No release from device as applied in active imaging

©2008 MagnaMedics

MagnaMedics

Data on toxicity of (drop-out) engineered nanoparticles fromnanomedicine and its resulting conceptual understandingcan be used as a benchmark for all nanomaterials:

1.Learn from properties of drop-outs 2.Learn from placebo groups3.Effects at high (intentional) doses4.Acute effects and chronic pathology5.Use of sensitive and well-characterized models6.Generate conceptual understanding7.Bridge know-how to other materials and sectors

Nanomedicine as a benchmark?

©2008 MagnaMedics

MagnaMedics

NanoMedicine mar help to fullfil Nanotechnology essential needs:

Guide to safe and sustainable (nano)materials

Set standards for handling and best-practices

Generate amended regulation and tests, through it sensitive models

May create success stories that show the benefit-risk balance in a proper way.

©2008 MagnaMedics

MagnaMedics

NanoScreen: our solution to your question

Content: • Screen your product for nanoparticles and

exposure potential • Screen and monitor your workers for particle

exposure and uptake• Screen the biocompatibility of your products and

components.• Screen your best-practices

A business to business service from one userto another. You learn from our experience

©2008 MagnaMedics

MagnaMedics