Transcript Positive Contrast Agents

Module C: Computed
Tomographic Imaging
CT Imaging
Overview
can cause serious damage to the macromolecules of life
• In the middle of the spectrum are heat waves (infrared), visible light and UV rays. The
shorter UV rays can be damaging to life.
• X-rays (Röntgen rays) were discovered and artificially produced in the laboratory towards
the end of the 19th century.
Basic Difference between Major Modalities
CT: Synthesis of multiple X-ray images of a ‘slice’.
MRI: Imaging protons excited by radio waves.
Ultrasound: High - frequency ‘sound’ waves reflected
from tissue junctions.
CT
MRI
US
All these methods illustrate structure of the body in
some form of sectional view.
X Rays
X-rays are a part of the natural electromagnetic spectrum. All
electromagnetic waves travel at the same speed through vacuum –
300,000 km/sec.
A wave has two attributes – wavelength and frequency. The product
of the two equals the speed at which it travels.
Waves with longer wavelength (lower frequency) have lower energy.
The shorter the wavelength, greater the energy of the wave. At one
end of the spectrum we have radio waves with wavelengths
measured in metres, centimetres or millimetres (frequencies range
from few kHz to tens of mHz).
Use of X-rays for Various Applications
X Ray Tube Principles
Heater
Cathode
Window
Anode
• Artificially X rays are produced by decelerating highvelocity electrons. X-ray tube has a source of electrons,
a means of accelerating them to high velocities and
something to stop them so that they lose their energy.
• The electron source is the cathode, heated by a
filament.
• The anode has a positive voltage (thousands of volts)
and attracts the electrons so that they reach a high
velocity.
• The disc-like surface of the anode also stops the
electrons. The X-rays produced go out through the
window.
• Only a small fraction of the energy is in the form of Xrays, a lot is ‘wasted’ as heat. The anode is specially
designed to withstand the heat and the ‘tube’ also has
a cooling mechanism.
Key Point : X-rays are produced by deceleration of high velocity electrons.
Image Densities
In a nut shell
On films
 Bone – calcium – greater attenuation : white image
 Soft tissues
– less attenuation – gray image
 Air
– least attenuation, dark areas
However … thickness also matters!
In fluoroscopy the pattern is reversed.
A Matter of Contrast!
Dark blobs -bubbles of gas in the colon. Ordinarily, the
colon is invisible because it blends with the other viscera
in an X-ray image. Gas in the colon creates contrast.
Joints between
the articular
processes
Vertebrate:
Thin shell of
solid bone
and spongy
bone inside
Spine of a
vertebra is
at a lower
level than
its body
A Matter of Contrast
Diaphragm
blends with
the
abdominal
organs
Air between the liver and the right
dome of the diaphragm
Air under the diaphragm indicates that some abdominal hollow
organ has a perforation or rupture, causing gas to escape into the
peritoneal cavity
Key Point : Contrast can show structures which are otherwise invisible
Tomo = image // to long axis of the body
CT = image is transverse to the body
• Creating a cross-sectional tomographic plane of a body part
• A patient is scanned by an X-ray tube rotating around the body
• A detector assembly measures the radiation exiting the patients
CT Imaging
Overview
Voxel
Each pixel in the image
corresponds to the volume
of tissue in the body section
being imaged.
The voxel volume is a
product of the pixel area and
slice thickness
Hounsfield units: Each pixel within the matrix is assigned a
number that is related to the linear attenuation coefficient of the
tissue within each voxel
Hounsfield Units (HU)
• A relative comparison of x-ray attenuation of a voxel of
tissue to an equal volume of water.
• Water is used because it is in abundance in the body and
has a uniform density
• Water is assigned an arbitrary HU value of 0
• Tissue denser than water are given positive CT numbers
• Tissue with less density than water are assigned negative
CT numbers
• The scale of CT numbers ranges from -1000 for air to
+14,000 for dense bone
• Only – CT # in the body are Fat, Lung & Air
Hounsfield Scale
• On the CRT or LCD, each pixel within the image is assigned
a level of gray
• The gray level assigned to each pixel corresponds to the
CT number or Hounsfield units for that pixel
The CT Image
A CT image can be taken as a plain image or with the introduction
of a contrast medium. Like conventional X-ray images, bone
appears white, air black and soft tissues have intermediate
densities depending on their composition and thickness. However,
the contrast and resolution is better than in conventional
tomography.
Air in the stomach- As the patient is supine, the air rises to
the anterior side.
A
Right Kidney
R
L
Liver
R. Psoas major
R. post. vertebral
muscles
Pancreas
Infvena cava, with
left renal vein
crossing across aorta
Aorta
P
Left Kidney
Radio-opaque vs Radioactive
Positive contrast media are often described as radioopaque (“Opaque to X-radiation”).
CT Contrast media are NOT radioactive!
The confusion possibly arises from the fact that a
radioactive isotope of iodine (atomic mass 131) is
often used in diagnostic tests. Iodine is concentrated
by the thyroid gland. When it is radioactive iodine, the
thyroid gland emits radiation which can be used to
create an image of the thyroid gland.
Other radioactive isotopes are similarly used to “scan”
other organs, notably the liver.
Purpose of Contrast Media
• To enhance subject contrast or
render high subject contrast in a
tissue that normally has low subject
contrast.
Atomic Number
• Fat = 6.46
• Water = 7.51
• Muscle = 7.64
• Bone = 12.31
Radiographic Contrast : Influenced by…
• Radiation
Quality (KVP)
• Film Contrast
• Radiographic
object (Patient)
KVP
TYPE OF CONTRAST USED DETERMINES KVP RANGE
BARIUM
IODINES
90 – 120 kVp
70 – 80 kVp
(Ionic / Nonionic
Water or Oil)
Contrast Media
• Negative contrast
• (AIR OR CO2)
• Positive contrast
• (all others)
• Radiolucent
• Radiopaque
• Low atomic # material
• High atomic # material
• Black on film
• White on film
Types of Contrast Media
•
•
•
•
Radiolucentnegative contrast agent
x-rays easily penetrate
areas- appear dark on
films
Negative Contrast Media
• Air and gas
• complications
• emboli-air pockets in
vessels
• lack of oxygen
• Radiopaque• positive contrast agent• absorbs x-rays
• appears light
Positive Contrast Agents
• BARIUM
• IODINES
• BISMUTH
• GOLD
• GADOLINUM
Both + & - can be used in
same study
Most Common TYPES
OF CONTRAST material
• BARUIM Z# 56
• NON WATER SOLUABLE
• GI TRACT ONLY
INGESTED OR RECTALLY
• KVP 90 – 120*
•
•
•
•
•
•
•
•
•
IODINE Z# 53
WATER SOLUABLE
POWDER
LIQUID
INTRAVENOUS OR
Intrathecal
GI TRACT
Also OIL based
KVP BELOW 90*
Barium Meal
This is an oblique view of a barium
swallow.
Note the ribs on far side and the
vertebrae at lower right.
At the upper end of the picture the
barium paste mass is narrow,
indicating that the oesophageal
muscle is contracting to push the
‘bolus’ down.
At lower left notice that some barium
has entered the stomach and shows
as a larger mass.
avb
Barium Meal - Stomach
F
The outline of the stomach is
obvious. Observe the air bubble
in the fundus (F).
The blue
pylorus.
arrow
shows
the
Urography
These pictures show intravenous
urography. Note the lumbar vertebrae,
the outlines of the cavities (calyces) of
the kidney and the ureters, as also the
course of the ureter. In about an
hour’s time all the iodine compound
will be in the urinary bladder.
Key Points :
• In intravenous urography, the medium is
injected through a vein. It is too dilute in the
bloodstream.
• It is ‘concentrated’ in the urine by the
kidneys.
• This imaging method also indicates that
the kidney is functional!
CT Contrast Agents
Broad Categories of CT Contrast Agents
Small Molecule
Nanoparticle
Macromolecules
Blood pool CT contrast agents
(Confined to the intravascular space,
highlighting blood vessels)
Passive targeting agents
(Reticulo-endothelial system (RES) or
through the enhanced permeability
and retention (EPR) effect)
Active targeting agents
(Selectively accumulate on specific
cells and tissue by conjugation of
antibodies, peptides, or other ligands
onto the surface of nanoparticles)
Broadening the Horizon
Structural
Functional
Molecular
The ability of the CT to distinguish between different tissues is based on the fact that
different tissues provide different degrees of x-ray attenuation.
I0 =incident x-ray intensity;
I = transmitted x-ray intensity
χ = thickness of the absorber medium
µ = mass attenuation coefficient.
The most dominant factor impacting the mass attenuation coefficient is the
photoelectric effect, which is proportional to the third power of the atomic number of
the material (Z3).
Sensitivity of the MRI to micro molar contrast agents' concentration
Sensitivity of the CT to millimolar contrast agents' concentration
Mass attenuation coefficients of iodine and
a selection of high-Z materials
looking at energies above the K-edge energy of a given high-Z element, these
elements exhibit a mass attenuation coefficient much higher than iodine.
CM based on high-Z materials may yield an increased contrast-to-noise ratio at equal
dose, which would allow for significant dose reduction when aiming for equal constant
contrast-to-noise ratio.
Clinically Approved CT Contrast Agents
Low-osmolality, nonionic contrast agents
Tissue Specific Small Molecule CT Contrast
Agents
compound 17
Representative upper GI
canine radiograph following
oral administration of a
conventional barium sulfate
suspension
J. Med. Chem., 2000, 43 (10), pp 1940–1948
Extensive, uniform, mucosal detail
and persistent coating of the small
intestines after oral administration.
Representative upper GI canine radiograph following oral
administration of an oil-in-water emulsion of
compound 17 (formulated at 22.0% w/v oil, 118 mg I/mL)
Glycosaminoglycan (GAG)
in cartilage is an indicator
of cartilage health
Anionic
Novel tissue-specific small-molecule iodinated CT contrast agents: (a) an anionic Ca2+
chelating contrast agent for bone micro-damage imaging
CECT in bovine osteochondral plugs. (A) Representative CECT images of control
and degraded samples (exposure to chondroitinase ABC for 8 h and for 30 h)
demonstrate an increase in CT attenuation of articular cartilage with increased
exposure to chondroitinase ABC. (B) Representative Toludine-blue stained sections
indicate a progressive loss of GAG (blue staining) from the ECM as indicated by
CECT in (A).
Cationic
In direct comparisons with
anionic contrast agents, the
cationic
contrast
agents
afforded higher equilibrium
concentrations
in
the
articular cartilage of ex
vivo rabbit femurs and thus
greater imaging sensitivity.
3D reconstruction of femur after exposure to CA4+.
Structures of a novel tissue-specific small-molecule iodinated CT contrast agent a
cationic contrast agent “CA4+” for cartilage tissue imaging
Linear regression analysis of average CT attenuation (in HU) vs GAG content of cartilage
(reported as [mg of GAG]/[mg of hydrated cartilage]) using the CA4+ contrast agent.
Issues?
• Nonspecific bio-distribution,
• Relatively small size -tend to undergo rapid renal
clearance from the body
• High osmolality and/or high viscosity of the contrast
media formulations can lead to renal toxicity and
adverse physiological effects
• High “per dose” concentrations are required
• High rates of extravasation and equilibration between
intravascular and extravascular compartments at the
capillary level --make it difficult to obtain meaningful
and clear CT images
Iohexol Containing Polymeric Nanoparticle
http://pubs.acs.org/doi/full/10.1021/ja405196f
A Direct Comparison Between Small Molecule
and NP Agents Containing Iohexol
(A) Serial fluoroscopic images of C57BL/6 mice
following jugular vein injection of 200 μL of
conventional iodinated contrast agent (iohexol)
solution (upper panel) and poly(iohexol) NP
solution (lower panel) at 250 mg iohexol/kg,
respectively. Images taken at 0 and 60 min after
injection were shown. Arrows indicated the
enhanced contrast in the bladder regions. (B) In
vivo circulation time of poly(iohexol) NP and
iohexol. 64Cu-labeled poly(iohexol) NP and
iohexol were injected intravenously through
the tail vein of mice. At various time points (5,
15, and 30 min and 1, 2, 4, 6, 8, 12, 24, and 48
h), blood was withdrawn intraorbitally, and the
radioactivity was measured by the γ-counter to
evaluate the systemic circulation of the
poly(iohexol) NP (red) and iohexol (blue) (n = 3)
MCF-7 Xenograft Study
A) Serial axial CT images of the MCF-7 tumors in mice following intratumoral injection of 200 μL of iohexol (upper
panel) and poly(iohexol) NPs (lower panel) at 50 mg iohexol/kg. Images were taken before injection as well as 5
min, 1 h, and 4 h post injection. Arrows indicate the enhanced contrast regions in the tumor bed. (B) Serial
sections of coronal CT images in MCF-7 xenografts bearing mice following the same treatment as described in (A).
Arrows indicate the enhanced contrast regions in the bladder. (C) Enhanced density (ΔHU) of tumors at 5 min, 1 h,
and 4 h after injection of poly(iohexol) NPs or iohexol.
Metals for CT Contrast Agents
Prerequisite features:
•High payload (>500k metal atoms/NP)
•High atomic number (Z)
•Metal with well-positioned K-edge energy
•Biocompatible surface
•Defined in vivo characteristics
•Bio-elimination
Homing agent
•Stability (shelf life/in-vivo)
Z: 83
K-edge: 90.8 keV
Bi
Pros/Cons
- Not water soluble
- High k-edge
Pan et. al. Angew Chem Intl Ed.
2010, Ed. 9635-39
Au
Yb
Coating
High Z metal
Gd
Z: 79
K-edge: 80.7 keV
Z: 70
K-edge: 61.3 keV
Z: 64
K-edge: 50.2 keV
Pros/Cons
+ Well studied metal
- Cost ($55/g.)
- High k-edge
Pros/Cons
+ Well placed K-edge
+ Cost efficient (~$10/g.)
Pros/Cons
+ Well placed K-edge
+ Cost efficient
+ (In clinical practice)
- Known Safety issues
Schirra, Pan et al J. Mater. Chem., 2012,
22, 23071-23077
Pan, Schirra et al ACS Nano.
2012, 6(4):3364-70.
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K-edge energies and X-ray mass attenuation
coefficients for heavy elements used in CT
imaging
Element
Atomic
number
K-edge energy
X-ray mass attenuation
[keV]
coefficient at 100 keV [cm2 g−1]
I
53
33.2
1.94
Ba
56
37.4
2.20
Au
79
80.7
5.16
Pt
78
78.4
4.99
Gd
64
50.2
3.11
Yb
70
61.3
3.88
Dy
66
53.8
3.36
Lu
71
63.3
4.03
Ta
73
67.4
4.30
Bi
83
90.5
5.74
Nanoparticle of Bismuth
Experimental CT opacity of bismuth solutions as a function of concentration. The
horizontal dashed lines indicate the opacities of air, water and 2.36 M (300 mg I ml-1)
iodine contrast agent, for comparison. Inset: X-ray fluoroscopy of tubes containing PBS,
0.5 M Bi2S3 nanoparticle suspension (BPNPs) and 2.36 M iodine contrast agent
(Iopromide).
Lymph Node Imaging with Bi2S3 Nanoparticles
CT imaging of a lymph
node of a mouse with the
BPNP imaging agent. a,b,
Three-dimensional
volume renderings of the
CT data set, the length of
the reconstruction is 3.8
cm. c, Coronal slice
(length of the slice
2.3 cm). d, Transverse slice
at the height indicated by
the horizontal lines in b.
The maximal diameter of
the mouse 1.8 cm.
Tungsten Oxide Nanoparticles
In vivo X-ray transverse CT images of tumor
(a1 and a2) and 3-D renderings of in vivo CT
images (b1 and b2) before (a1 and b1) and
after (a2 and b2) intratumoral injection of
PEGylated WO2.9 NRs (20 mg/kg).
Scientific Reports 4, Article number: 3653 doi:10.1038/srep03653
Anti-CD-4-Targeted Gold Nanoparticles
CT images of mice before (a, b) and after (c, d) injection of gold nanoparticles. While little
contrast enhancement is observed for the mouse administered with nonspecific
immunoglobulin G (IgG)-conjugated nanoparticles (a, c), anti-CD-4-targeted nanoparticles
show clear contrast enhancement of inguinal lymph nodes (c, d).
Interactions of X-ray with matters
(i) A portion of X-rays is transmitted without interaction.
(ii) The energy of the incident X-ray is absorbed by an atom, and then X-ray with
the same energy is emitted with a random direction (Coherent scattering).
(iii) When the incident X-ray collides with outer-shell electrons, a portion of the Xray energy is transferred to the electron, and the X-ray photon is deflected with
a reduced energy (Compton scattering).
(iv) When the incident X-ray transfers its energy to inner-shell electron, the electron
is subsequently ejected, and the vacancy of the electron shell is filled by outershell electrons, producing a characteristic X-ray (Photoelectron effect).
Spectra CT
(a) Schematic drawing of third-generation CT. CT images are acquired during the rotation of
an X-ray tube and an array of detectors. (b) Schematic attenuation profiles of voxels.
Measured X-ray intensity can be expressed as sum of the attenuation along the path of X-ray.