1. ©2008 MagnaMedics MagnaMedics Sustainable and smart nanomaterials will enable nanotechnologies Paul J.A. Borm

2. ©2008 MagnaMedics MagnaMedics Chemelot campus, 800 ha, 80 companies Incl DSM, SABIC

3. ©2008 MagnaMedics MagnaMedics J. Miro, self-portrait CEO Products Production Profit Nanoparticles As tools Prof People Planet Papers Nanoparticles as Objects of study

4. ©2008 MagnaMedics MagnaMedics Intentionally produced NP -already on the market -Newly engineered Unintentionally produced NP -Combustion -Nucleation New products, applications High added value Nanomedicine: Intended exposure High dose, low risk No added value, extra cost Considerable health risks

5. ©2008 MagnaMedics MagnaMedics

6. ©2008 MagnaMedics MagnaMedics Country Target/ response NanoMaterialsC/AcNanoHSEReference World337/64 Carbon based Metal oxides 64/037 Gerritzen et al, 2006 Denmark165/11 Metal oxides Silica, polymers Carbon black 6/51 Tonning & Poulsen, 2007 Switserland197/43 Silica, TiO2 Metal oxides, Ag Carbon black 43/0N.D Schmid & Riediker, 2008 Zwitserland & Germany ?/40No info40/013 Helland et al, 2008 UK? /9No info7/2N.D.VRS, 2007 Netherlands98/8No info5/3N.D Mikkers et al, 2007 Netherlands122/37 Carbon black metal oxides silica 30/79 Borm et al (2008)

7. Risk = hazard x exposure Hazard: the “ability” of a chemical to cause harm Risk: the “probability” it will do so

8. ©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.

9. ©2008 MagnaMedics MagnaMedics Occupational hygiene strategies by approach

10. Risk = hazard x exposure Hazard: the “ability” of a chemical to cause harm Risk: the “probability” it will do so

11. ©2008 MagnaMedics MagnaMedics Combustion NP Engineered NP Nanomedicine Bulk industrial NP Epidemiology Toxicology ? ? Sources of evidence: a Bermuda Triangle

12. ©2008 MagnaMedics MagnaMedics Most of the evidence for human effects of NP is generated unintentionally using unintentionally produced combustion Nanoparticles. Effects of manufactured Nanoparticles have mainly been studied with a small set of particles already on the market for decades (carbon black, TiO 2, FeO) and more recently on carbon nanotubes. In words:

13. ©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

14. ©2008 MagnaMedics MagnaMedics Platelet aggregation by NP PM and carbon nanoparticles Have similar hazards

15. ©2008 MagnaMedics MagnaMedics

16. ©2008 MagnaMedics MagnaMedics Drug Matrix Linker Homing device Imaging tool Assembly Customized nanotools and Assemblies, based on Magnetic properties

17. ©2008 MagnaMedics MagnaMedics Drug delivery platforms on magnetic capture Applied successfully In animal studies. Krukemeyer et al (2008) In preparation

18. ©2008 MagnaMedics MagnaMedics Mitoxantrone-loaded Iron nanoparticles. Size: 120 nm Surface: dextrane Zeta-potential: -34 mV Load MT: 20 ug/mg Dose: 1 mg/kg BW Photo’s courtesy dr. Krukemeyer

19. ©2008 MagnaMedics 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

20. ©2008 MagnaMedics MagnaMedics No hair loss No gastro-intestinal complications Normal kidney function Temporal loss of leucocytes and thrombocytes. iron accumulation in the spleem

21. ©2008 MagnaMedics MagnaMedics Intravenous delivery of engineered NP Needs 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?

22. ©2008 MagnaMedics MagnaMedics

23. ©2008 MagnaMedics MagnaMedics MagnaFy: making devices visible Immobilize NP in polymers and composites Use magnetic properties and signal distortion: markers are magnified and easily visible No release of contrast agent in body Small volume and therefore no heating Application to existing medical devices

24. ©2008 MagnaMedics MagnaMedics Medical imaging-guidewires Application in renal stenting

25. ©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

26. ©2008 MagnaMedics MagnaMedics Data on toxicity of (drop-out) engineered nanoparticles from nanomedicine and its resulting conceptual understanding can be used as a benchmark for all nanomaterials: 1.Learn from properties of drop-outs 2.Learn from placebo groups 3.Effects at high (intentional) doses 4.Acute effects and chronic pathology 5.Use of sensitive and well-characterized models 6.Generate conceptual understanding 7.Bridge know-how to other materials and sectors Nanomedicine as a benchmark?

27. ©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.

28. ©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 user to another. You learn from our experience

29. ©2008 MagnaMedics MagnaMedics