Contrast Agents and Next Generation CT Techniques - PowerPoint Presentation

Slide1

Contrast Agents and

Next Generation CT Techniques

Slide2

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)

Broad Categories of CT Contrast Agents

Slide3

Broadening the Horizon

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 intensityχ = 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 (Z

3).

Sensitivity of the MRI to micro molar contrast agents' concentration

Sensitivity of the CT to

milli

molar contrast agents' concentration

Slide4

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.

Slide5

Clinically Approved CT Contrast Agents

Low-osmolality, nonionic contrast agents

Slide6

Tissue Specific Small Molecule CT Contrast Agents

Representative upper GI canine radiograph following oral administration of a conventional

barium sulfate suspension

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) 

Extensive, uniform, mucosal detail and persistent coating of the small intestines after oral administration.

J. Med. Chem.

, 

2000

, 

43

 (10), pp 1940–1948

compound 

17

 

Slide7

Novel tissue-specific small-molecule iodinated CT contrast agents: (a) an anionic Ca2+ chelating contrast agent for bone micro-damage imaging

Glycosaminoglycan (GAG) in cartilage is an indicator of cartilage health

Anionic

Slide8

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).

Slide9

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 effectsHigh “per dose” concentrations are requiredHigh rates of extravasation and equilibration between intravascular and extravascular compartments at the capillary level --make it difficult to obtain meaningful and clear CT images

Issues?

Slide10

Iohexol

Containing Polymeric Nanoparticle

http://pubs.acs.org/doi/full/10.1021/ja405196f

Slide11

(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)

A Direct Comparison Between Small Molecule and NP Agents Containing

Iohexol

Slide12

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. 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

.

MCF-7

Xenograft Study

Slide13

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

Stability (shelf life/in-vivo)

Metals for CT Contrast Agents

Prerequisite features:

Coating

High Z metal

Homing agent

Z: 79

K-edge: 80.7 keV

Pros/Cons

+ Well studied metal

- Cost ($55/g.)

- High k-edge

Schirra, Pan et al

J. Mater. Chem.

, 2012, 22, 23071-23077

Au

Pan et. al.

Angew

Chem

Intl Ed.

2010,

Ed.

9635-39

Bi

Z: 83

K-edge: 90.8 keV

Pros/Cons

- Not water soluble

- High k-edge

Z: 70

K-edge: 61.3 keV

Pros/Cons

+ Well placed K-edge

+ Cost efficient (~$10/g.)

Pan, Schirra et al

ACS

Nano

.

2012,

6(4):3364-70.

Yb

Gd

Z: 64

K-edge: 50.2 keV

Pros/Cons

+ Well placed K-edge

+ Cost efficient

+ (In clinical practice)

- Known Safety issues

13

Slide14

Element

Atomic number

K-edge energy [

keV

]

X-ray mass attenuation coefficient at 100

keV

[cm

2

 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

K-edge energies and X-ray mass attenuation coefficients for heavy elements used in CT imaging

Slide15

Stable Xenon-enhanced Contrast CT

Uses the inert gas xenon to measure cerebral blood flow (CBF) in various brain regions

This technique uses stable non-radioactive 131Xe (At.#54; At. Wt. 131.293)An alternative to SPECTPatient inhales a mixture of xenon and oxygen over the period of a few minutes, allows measurement of their increased in density caused by the gas in brain tissue

Slide16

Can be incorporated into all existing CT technologies .

Can be used to determine local cerebral blood flow in an area as small as 1 x 1 x 5 mm

3 area Can be repeated within 20 mins, allowing the assessment of hemodynamic states including (in certain well-defined settings) Helps to evaluate acute stroke, occlusive vascular disease, carotid occlusion testing, vasospasm, arteriovenous malformations, and head trauma managementAdvantages

Slide17

Data are acquired during inhalation of a gas mixture containing 28%

131Xe and oxygen

A radio opaque, highly lipid soluble, diffusible indicator capable of crossing the blood brain barrier. It provides a measure of tissue perfusion with quantification based on a modification of the Fick’ principle.

VO2, oxygen consumption in ml of pure gaseous oxygen per minute. Ca, the oxygen concentration of blood taken from the pulmonary vein (representing oxygenated blood)

Cv

, the oxygen concentration of blood from an intravenous

cannula

(representing deoxygenated blood)

where CO = Cardiac Output, C

a

 = Oxygen concentration of arterial blood and

C

v

 = Oxygen concentration of mixed venous blood.

and hence calculate cardiac output.

Note that 

(C

a

 –

C

v

)

 is also known as the 

arteriovenous

oxygen difference

.

Slide18

Xenon-enhanced CT for Head Injury

Slide19

Disadvantages

Not FDA approved yet. Approved in the Europe

CT based perfusion imaging is considered investigational for all indications including the diagnosis and management of acute cerebral ischemia (stroke).Quantitative CBF studies can be difficult to perform in patients with associated pulmonary pathology since the technique is based on the assumption that the end-tidal xenon concentration is identical to the arterial concentration.

Slide20

Lymph Node Imaging with Bi

2

S3 NanoparticlesCT 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.

Slide21

Slide22

X-ray CT images of tumor-bearing mouse immediately (a), 2 h (b), 4.5 h (c), and 24 (d) after injection of Bi

2

S

3 

nanoparticles labeled with LyP-1. 

In vivo micro-CT volume reconstructions post–injection

polyethylene

glycol5000 coated Bi2S3 nanoparticles that

do not contain a peptide label.

Targeted Bismuth Nanoparticles

Slide23

Energy Resolved CT

Slide24

24

Conventional CT:

The HU measurement is a weighted average of the beam absorption over the entire range of beam energies

Energy-resolved CT: Multiple narrow sections of the energy spectrum are sampled simultaneously, providing a range of energy-dependent HU across the spectrum.

As each material has a specific measurable X-ray spectrum, imaging allows for multiple materials to be quantified and differentiated from each other simultaneously

Dual Energy CT:

Commercially available dual energy systems measure two materials and some dual energy research machines measure up to three materials.

Are Hounsfield Units (HU) Energy Dependent?

Slide25

(

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 X-ray 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 outer-shell electrons, producing a characteristic X-ray (

Photoelectron effect

).

Interactions of X-ray with matters

Slide26

26

Mass attenuation coefficients of several materials as function of X-ray energy

Excitation of a 1s electron occurs at the K-edge, while excitation of a 2s or 2p electron occurs at an L-edge

(A) Mass attenuation coefficients of a variety of elements. (B) Photon energy distribution generated from the X-ray tube of a CT scanner run at 80 or 140 kV.

Slide27

27

Spectral/multi energy CT has the potential to distinguish different materials by K-edge characteristics.

K-edge imaging involves the two energy bins on both sides of a K-edge.

Energy discriminating photon counting detectors

Advanced Detector Technology

Slide28

http://www.healthcare.siemens.com/computed-tomography/technologies-innovations/ct-dual-energy/technical-specifications

The Selective Photon Shield ensures dose neutrality by eliminating spectral overlap. This makes Dual Energy as dose-efficient as any single 120 kV scan.

Dual Energy CT

During a Dual Source Dual Energy scan, two CT datasets are acquired simultaneously with different kV and mA levels, allowing to visualize differences in the energy-dependence of the attenuation coefficients of different materials.

These images are combined and analyzed to visualize information about anatomical and pathological structures.

Slide29

Attenuation Difference is the Key

Slide30

One Basic Reason for Use of Dual Energy CT: Material Differentiation

By scanning a patient at two different energy spectra (e.g. at 56 kV and 76 kV), the attenuation difference of the same material is different.

Iodine has higher attenuation difference, compared to bone. Scanning allows the computer to process bone and iodine content on images differently.Routine Use of Dual-energy CT for Material Differentiation Creation of 3D vascular images ("Direct Angio") by easy removal of bony structures

Plaque analysis (calcified vs. soft plaques)

Lung perfusion

Virtual unenhanced scan (creation of unenhanced scan from enhanced images by deleting iodine content from the images)

Calculi characterization (uric acid vs. others)

Slide31

http://www.dsct.com/index.php/clinical-applications-dual-energy-ct/

Use the spectral properties of iodine to differentiate it from other dense materials in the dataset (similar to magnetic resonance angiography (MRA)).

With Dual Energy CT, it is possible to identify bone by its spectral behavior and to erase it from an angiogram. Then, the iodine in the vessels remains the only dense material in the dataset and a MIP can be calculated from a CT angiogram to closely resemble an MRA.

Additionally, it is possible to detect those voxels that contain both calcium and iodine and add them back to the dataset.

Calcified plaques of atherosclerotic vessels can thereby be switched on and off in the dataset to visualize both the residual lumen and the plaque distribution.

Dual Energy in Angiography

Slide32

Differentiation of Tendons and Ligaments

Tendons and ligaments have weak spectral properties, presumably due to the densely packed collagen.

It is possible to identify thick tendons and ligaments in Dual Energy CT datasets and to display them separately, for example, to visualize the tendons of the wrist and identify ruptures.

However, signal-to-noise ratio is not sufficient to depict thin ligaments; thus the clinical value of this application is limited.

Slide33

Coronary Thrombus Imaging by Spectral CT

Nanobeacons (Au, Bi,…) bind to fibrin

Conventional CT is unable to selectively image materialsSpectral CT enables material specific imaging of suitable metals

New Nanobeacons and advances in statistical image reconstruction methods improve coronary fibrin imaging

Nanobeacons target

fibr

in of thrombus on ruptured plaque

Fibrin

Ca deposit

Plaque formation

non-separated attenuation from

nanoparticle

and Ca

Selective imaging of nanoparticles

Slide34

Quantitative Tissue Differentiation

Targeted bismuth

nanocolloids distinguishes fibrin

microdeposits from calcium

Pan et. al.

Angew

Chem

Int

Ed. 9635-9639 (2010)

Human Coronary phantom

Spectral CT image of a fibrin clot phantom with embedded calcium chloride (white arrow) targeted (green arrow) in a glass tube (blue arrows denote wall).

Ca-separated

Specimen

removal

Hospitaltour.com

Carotid

Enderectamy

Specimen

Calcium

red

& Bismuth

Gold

)

Soft tissue invisible due to low X-ray attenuation

Local Bi-

conc

~0.1 g/cm

3

Slide35

Targeting in situ Clots (Thrombus)

in Rabbits

Slide36

Slide37

(A) Structure of Au–high-density lipoprotein (HDL), a macrophage targeted CT contrast agent. (B) Negative stain transmission electron microscopy characterization of the nanoparticle. (C) Spectral CT image of an artery phantom. (D) Spectral CT image of an atherosclerotic mouse acquired 24 h after injection with Au–HDL and directly after injection of an iodine

nanoemulsion

. In (C) and (D) gold (yellow), iodine (red) and photoelectric (blue) images are overlaid on a Compton image (grayscale).