Using carbon particulates in the clinical setting: benefits and hazards

1. Using carbon particulates in the clinical setting:benefits and hazards Tim Senden The Browitt Nanoparticle Laboratory Dept Applied Mathematics Research School of Physics and Engineering

2. Summary • A case study: Technegas a ventillation diagnostic • Technegas as a platform for injection • There’s carbon, and then there’s carbon…. Diesel particulates/fullerenes

3. Types of particulate carbon Two types of bonds sp2 and sp3 • Graphite / graphene • Fullerenes (bucky balls – nanotubes) • Diamond • “Amorphous” soot • Glassy carbon

4. Early ‘80s Bill Burch sought a radio-aerosol for ventilation studies of the lung. A ‘smoke’ was a good candidate. Dr Bill Burch Inventor and Nuclear Medicine physicist Depends on water saturation and surface energy Generic curve… but chemistry needs to be defined Diameter, microns R. Rogers, 1976

5. Pulmonary Emboli (US statistics - 1985) Dalen et al Prog Cardiovas Dis 1975 After an Edisonian effort - Technegas was created

6. Clinical studies • In 20 years from initial patenting; • >2.2 million administrations worldwide • >200,000 administrations / annum • 44 countries world-wide • >85% certainty in diagnosis of PE V/Q scan

7. Fate of most inspired particles is the gut Gamma sequence of Technegas on the mucocillary escalator (see website for animation)

8. MRI X-ray Clinical studies - Pulmonary Emphysema SPECT Technegas penetrates the furthest spaces of the lungs – why? Surface chemistry

9. An academic non-commercial website

10. Technegas aerosol A graphite furnace in an argon atmosphere 99mTc Formation 3.5 sec sequence of evolution So the Technegas should behave essentially like carbon particles without any metallic character - What type of carbon?

11. Technetium is shrink-wrapped in graphite Transmission Electron Microscopy of ground state Tc-99 Structure Work done with Dr John Fitz Gerald, ANU

12. Technetium is shrink-wrapped in graphite bacterium Structure 1 micron encapsulates Red blood cell g-Globulin Transmission Electron Microscopy of ground state Tc-99 The chief advantage of a radio-particle over a radio-labelled drug is huge increase in specific acitivity. A drug might have only one radioactive atom per molecule – a radioparticle might have 10,000 to a million ! Work done with Dr John Fitz Gerald, ANU

13. Log-normal distribution -typical for gas phase formation Particle Size vs. Activity • Important factors controlling particle size • Burn temperature • Burn time Using an electrostatic classifier (TSI) Work done with Dr Zoran Ristovski Centre for Medical & Health Physics, QUT

14. Graphite coating is; contiguous, inert & hard Graphite particles are difficult to disperse in water The Browitt Precipitron, 1995 Hydrophilized Technegas disperses to produce FibrinLite Rod Browitt - 1998 water 85° graphite

15. FibrinLite - Binding to Thrombus • In 1996 Dr Hari Nair at Canberra Hospital postulated that Technegas particles should show an affinity for fibrin • - showed ex vivo labelling of clot in blood circuit Gamma image

16. FibrinLite - Rabbit RES biodistribution NB. Bone image Is species specific RES - reticuloendothelial system – liver / spleen …

17. 1 cm 200 nm FibrinLite labelling of inflamed colon from rats with spontaneous colitis Transmission EM Work done with Dr Gary Buffinton

18. Ant. After extensive testing in animal models, FibrinLite has commenced clinical trials. Phase One Clinical study Distribution of FibrinLite in a normal volunteer 1h post injection 3h post injection Contused muscle

19. FibrinLite Clot seen with ultrasound two days earlier Distribution of FibrinLite in an abnormal volunteer Ant. Post. 3h post injection Injection into foot vein

20. Opsonisation • Dr Ross Stephens has shown that other adhesion proteins can be involved: Fibronectin, vitronectin, fibrinogen… • Explains the fate in the liver / spleen • Most inorganic particles introduced into the circulatory system end up in the liver / spleen (unless specially coated in PEG, dextrans, etc)

21. Liquid mercury Encapsulate (250nm) Can have radio-tracer particles with the same affinity/function as a radio-therapeutic particle Gold Empty shell without mercury Encapsulation of Other Isotopes 30-40nm carbon encapsulated gold particles Also; Beryllium Cadmium Yttrium Magnesium Copper Rhenium Silver Sodium Thallium Holmium Zinc and many others.

22. Liquid Mercury under vacuum before 250 nm after Graphite in hard, contiguous and stable

23. Not all carbon particles are the same • Need to take into account: • Allotrope • Roughness / curvature • degree of agglomeration • Porosity • Surface chemistry • polydispersity • adsorbates Bucky tubes cause pulmonary fibrosis and granulomas Shevdova et alAmer. J Physiology (2005) Deisel particulates increase susceptibility to lung infection Castranova et alEnviro. Health Perspectives ,2001

24. Nanoscale measurements From Oberdörster et alParticle and Fibre Toxicology 2005

25. Mostly! But remember Blue Man From Oberdörster et alParticle and Fibre Toxicology 2005

26. Thanks to Ross Stephens David King Gary Buffinton Bill Burch