Using carbon particulates in the clinical setting:

benefits and hazards

Tim SendenThe Browitt Nanoparticle Laboratory

Dept Applied Mathematics

Research School of Physics and Engineering

• A case study: Technegas a ventillation diagnostic • Technegas as a platform for injection• There’s carbon, and then there’s carbon….

Diesel particulates/fullerenes

Summary

Types of particulate carbon

Two types of bonds sp2 and sp3

• Graphite / graphene

• Fullerenes (bucky balls – nanotubes)

• Diamond

• “Amorphous” soot

• Glassy carbon

Early ‘80s Bill Burch sought a radio-aerosol for ventilation studies of the lung. A ‘smoke’ was a good candidate.

Dr Bill BurchInventor and

Nuclear Medicine physicist

Generic curve…but chemistry needs to be defined

R. Rogers, 1976

Diameter, microns

Depends on water saturation and surface energy

Pulmonary Emboli (US statistics - 1985)

After an Edisonian effort - Technegas was created

Dalen et al Prog Cardiovas Dis 1975

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

• Fate of most inspired particles is the gut

Gamma sequence of Technegas on the mucocillary escalator(see website for animation)

Clinical studies - Pulmonary Emphysema

X-ray MRI

SPECT

Technegas penetrates the furthest spaces of the lungs – why? Surface chemistry

An academic non-commercial website

FormationTcCn Initial:

Material sitson surface

(room temp tosimmer temp).

First reduction:

Carbon combines with pertectnetate

(630-850 °C)

Evaporationand vapour

condensation:Co-condensation of Tc and

C species. Surface of Tc platelets is covered with C

species. (crucible temp: 2550°C)

TcVIIgraphitecrucibleGas phase:CO + CO2TcKTcO4KTcO2TcGas phase:KO 2 Second

reduction:Final reduction to

metal(850-1000 °C)

TcIII Cooling:Both TcC and Tc

coexist in carbon-rich phase

0TcTcTcC+ technegasparticles

Gas phase:

3.5 sec sequence of evolution

A graphite furnace inan argon atmosphere

So the Technegas should behave essentially like carbon particles without any metallic character- What type of carbon?

99mTc

Technegas aerosol

Structure Transmission Electron Microscopyof ground state Tc-99

Technetium isshrink-wrappedshrink-wrapped

in graphite

Work done with Dr John Fitz Gerald, ANU

Red blood cell

bacterium

encapsulates

1 micron

-Globulin

Structure

Transmission Electron Microscopy

of ground state Tc-99

Technetium isshrink-wrappedshrink-wrapped

in graphite

Work done with Dr John Fitz Gerald, ANU

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 !

Particle Size vs. Activity

Important factors controlling particle size

• Burn temperature• Burn time

25

20

15

10

5

02 3 4 5 6 7 8 9

1002 3 4 5 6

100

90

80

70

60

50

Particle size (nm)

Work done with Dr Zoran RistovskiCentre for Medical & Health Physics, QUT

Using an electrostatic

classifier (TSI)

Log-normal distribution-typical for gas phase formation

Graphite particles aredifficult to disperse in

water

The Browitt Precipitron, 1995

Hydrophilized Technegasdisperses to produce

FibrinLite

Graphite coating is;contiguous, inert & contiguous, inert &

hardhard

Rod Browitt - 1998

watergraphite

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

FibrinLite - Rabbit RES biodistribution

RES - reticuloendothelial system – liver / spleen …

NB.Bone imageIs speciesspecific

FibrinLite labelling of inflamed colon from rats with spontaneous colitis

Transmission EM

200 nm

1 cm

Work done with Dr Gary Buffinton

Phase One Clinical study

After extensive testing in animal

models,FibrinLite

has commenced clinical trials.

Ant.1h post injection 3h post injection

Contused muscle

Distribution of FibrinLite in a normal

volunteer

Ant.

Injection into foot vein

FibrinLite

Distribution of FibrinLite

in an abnormal volunteer

3h post injection

Clot seen with ultrasound

two days earlier

Post.

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)

Encapsulation of Other Isotopes

Rhenium Silver Sodium Thallium Holmium Zinc and many others.

Gold

30-40nm carbon encapsulated gold particles

Empty shellwithout mercury

Liquid mercuryEncapsulate

(250nm)

Can have radio-tracer particles with the same affinity/function as a

radio-therapeutic particle

Also; Beryllium Cadmium Yttrium Magnesium Copper

Liquid Mercury under vacuum

250

nm

Graphite in hard, contiguous and stable

before

after

Not all carbon particles are the same

Need to take into account:• Allotrope• Roughness / curvature• degree of agglomeration• Porosity• Surface chemistry• polydispersity• adsorbates

Deisel particulates increase susceptibility to lung infectionCastranova et al Enviro. Health Perspectives ,2001

Bucky tubes cause pulmonary fibrosis and granulomasShevdova et al Amer. J Physiology (2005)

Nanoscale measurements

From Oberdörster et al Particle and Fibre Toxicology 2005

From Oberdörster et al Particle and Fibre Toxicology 2005

Mostly! But remember Blue Man

Ross Stephens

David King

Gary Buffinton

Bill Burch

Thanks to