Transcript The Physical Chemistry of Technegas

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
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
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 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
Pulmonary Emboli (US statistics - 1985)
Dalen et al Prog Cardiovas Dis 1975
After an Edisonian effort - Technegas was created
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
Formation
Technegas aerosol
99mTc
A graphite furnace in
an argon atmosphere
3.5 sec sequence of evolution
So the Technegas
should behave
essentially like carbon
particles without any
metallic character
- What type of carbon?
Structure
Technetium is
shrink-wrapped
in graphite
Work done with Dr John Fitz Gerald, ANU
Transmission Electron Microscopy
of ground state Tc-99
bacterium
Structure
1 micron
encapsulates
Red blood cell
Technetium is
shrink-wrapped
in graphite
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
Particle Size vs. Activity
Log-normal distribution
-typical for gas phase formation
100
Particle count (arb.)
90
20
80
15
70
10
60
5
Cumulative activity (%)
25
Important factors
controlling particle size
• Burn temperature
• Burn time
50
0
2
3
4
5 6 7 89
2
3
4
5 6
100
Particle size (nm)
Work done with Dr Zoran Ristovski
Centre for Medical & Health Physics, QUT
Using an
electrostatic
classifier (TSI)
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
85°
water
graphite
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
NB.
Bone image
Is species
specific
RES - reticuloendothelial system – liver / spleen …
FibrinLite labelling of inflamed colon from
rats with spontaneous colitis
1 cm
200 nm
Transmission EM
Work done with Dr Gary Buffinton
Phase One Clinical study
After extensive
testing in animal
models,
FibrinLite
has commenced
clinical trials.
Distribution
of FibrinLite
in a normal
volunteer
1h post injection
3h post injection
Ant.
Contused muscle
FibrinLite
Clot seen with
ultrasound
two days
earlier
Distribution
of FibrinLite
in an
abnormal
volunteer
Ant.
Injection into foot vein
Post.
3h post injection
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
Liquid mercury
Encapsulate
(250nm)
Can have radio-tracer
particles with the same
affinity/function as a
radio-therapeutic particle
Gold
30-40nm carbon encapsulated
gold particles
Empty shell
without mercury
Also;
Beryllium
Cadmium
Yttrium
Magnesium
Copper
Rhenium
Silver
Sodium
Thallium
Holmium
Zinc and many others.
Liquid Mercury under vacuum
250 nm
before
after
Graphite in hard, contiguous and stable
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 al Amer. J Physiology (2005)
Deisel particulates increase susceptibility to lung infection
Castranova et al Enviro. Health Perspectives ,2001
Nanoscale measurements
From Oberdörster et al Particle and Fibre Toxicology 2005
Mostly! But remember Blue Man
From Oberdörster et al Particle and Fibre Toxicology 2005
Thanks to
Ross Stephens
David King
Gary Buffinton
Bill Burch