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Molecular Imaging

This Group is focused on the development of molecular targets for radionuclide-mediated diagnosis and therapy of cancer. It includes both laboratory teams headed by Dr Jane Sosabowski and clinical consultants working in the Departments of Nuclear Medicine and Radiology at Barts and The London NHS Trust.

The Team has a long history of collaboration with the Imaging, Biotech and Pharmaceutical Industries including GE Healthcare, Bioscan, Celltech, Antisoma, Unilever, GlaxoSmithKline and others. Preclinical imaging really began here in 2006, when we were the first site in the world to have a preclinical SPECT/CT from Bioscan, which Imaging actively helped to develop.

Since then, the facility has acquired other preclinical imaging modalities (PET/CT, MRI, Ultrasound & optical), and has built extensive experience in the field. The Preclinical Imaging Facility has generated or contributed to over 40 scientific publications so far.

Available facilities include:

  • New specialised hot-labs for synthesis of PET, SPECT and therapeutic radiochemicals
  • Research Laboratories fully equipped for radiopharmaceutical development including five high pressure liquid radiochromatography work-stations, scintillation counters, digital autoradiography, and radio-ligand binding assays
  • MHRA-licensed aseptic suites for the preparation of radiopharmaceuticals
  • Category 2 biohazard tissue culture room
  • State-of-the-art small-animal multi-modality imaging scanners:
    • Bioscan / Mediso’s NanoSPECT/CT
    • Siemens Inveon PET/CT
    • PerkinElmer IVIS Lumina III
    • Bruker Icon 1T MRI scanner
    • Ultrasound

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Imaging Overview

In vivo Molecular Imaging in the Barts Cancer Institute

The Barts Cancer Institute possesses a number of instruments able to perform Molecular Imaging in small-animal models located in the Biological Services Unit at Charterhouse Square. Depending on demand, these are available for use by collaborating researchers both within and outside QMUL. A modest fee to help offset the service costs of the instrument will be requested.

Optical imaging

  • Perkin Elmer IVIS Lumina III - for bioluminescence and fluorescence imaging.
    High sensitivity, non radioactive imaging. Ideal for quick screening of cancer cells (in vitro) or therapeutic effect (in vivo).

Radionuclide imaging

  • Bioscan / Mediso NanoSPECT/CT - for single-photon emission Computed Tomography (SPECT)
  • Inveon PET/CT - for Positron Emission Tomography (PET)

Nuclear imaging is ideal for 3-dimensional high resolution imaging (down to 350µm for SPECT, and 1mm for PET) and deep tissue imaging.

Anatomical Imaging

  • Computerised Tomography (CT)
  • Bruker ICON 1T Magnetic Resonance Imaging (MRI)
  • Ultrasound

CT is ideal for bone imaging. MRI provides very good soft tissue contrast and is thus useful for e.g. tumour and brain imaging. Both CT and MRI can be combined with a perfusion (contrast) agent allowing e.g. cardiac imaging.

Comparison of small-animal imaging modalities

Type of Imaging
Modality
Resolution
Sensitivity
Quantitation
Time
Cost
Ultrasound Imaging
Ultrasound
50µm
V. Low
-
Minutes
Low
Nuclear Imaging
 
 
 
CT
50µm
V. Low
-
Minutes
Medium
PET
1mm
High
+++
Mins - tens of mins
High
SPECT
350µm
High
++
Tens of mins
High
Cerenkov
20µm - 5mm
(varies with depth & strength of signal)
High
+
Secs - mins
Low - medium
Optical imaging
Bioluminescence
20µm - 5mm
(varies with depth & strength of signal)
V. High
+
Secs - mins
Low
Fluorescence High + Secs - mins Low - medium
Magnetic resonance
MRI
25µm
Low
-
Tens of mins - hours
V. high

 

Optical Imaging

ivis

 bioSystem: Perkin Elmer - IVIS Lumina III used for:

- Bioluminescence

- Fluorescence imaging

- Cerenkov imaging

Bioluminescence imaging

Commonly used for Reporter Gene imaging

How does it work?

Typically a gene encoding for an enzyme such as luciferase is inserted into tissues of the animal model of interest. Cells expressing the gene are allowed to grow for the desired period of time. A substrate for the enzyme (eg. luciferin) is then administered to the animal. The reaction between the enzyme and substrate results in emission of light by the cells expressing the luceriferase. This light is detected by the IVIS device; essentially a very sensitive CCD camera.

The limitation of this modality resides in the physical property of light and tissues: as light doesn’t travel well through tissue, 2 identical signal strengths will give different quantification results depending on how deeply set they are in the animal.

What can it be used for?

Essentially to monitor gene expression in vivo. The simplest applications use the luciferase expression as a marker of cell viability. If, for example, expression is limited to tumour cells growing in the animal, the effect of therapeutic interventions on tumour size can be determined by measuring their effect on the amount of bioluminescence produced. If used as part of a multi-cistronic vector, then the signal can be used to monitor the function of control elements or other genes in the construct.

Pros and Cons

Pros: Relatively straightforward to use, high sensitivity, quick acquisitions, no radiation

Cons: low resolution, quantity of light emitted varies depending on signal strength & depth in tissue, quality of substrate injection (for BLI). This physical limitation (ie how light travels through tissue) renders this method difficult to quantify reliably (especially in longitudinal studies).

Fluorescence imaging

Used in either direct imaging or indirect imaging modes.

How does it work?

Direct fluorescence imaging is similar to bioluminescence imaging expect that it uses a gene that codes directly for a fluorescent protein such as GFP. The difference is that the protein needs to be excited by external photons of the required wavelength. The downside is that this produces auto-fluorescence by non-target tissues which increases the level of background.

Indirect fluorescence uses an exogenous fluorescent marker that is administered to the animal prior to imaging. The marker will bind to target tissues (such as receptors) and produce an enhanced fluorescent signal from these tissues. However background fluorescence will also arise from non-targeted marker as well as from auto-fluorescence. This latter phenomenon can be reduced by using fluorophores which absorb and emit in the Near Infra-red range (NIR imaging).

What can it be used for?

Direct fluorescence is used to monitor gene expression in vivo. Indirect fluorescence imaging can be used to measure levels of expression of target molecules to which the fluorescent marker binds in vivo. It is also possible to design fluorophores which are normally quenched but become activated as a result of a molecular event in vivo – eg. enzymatic cleavage. This potentially permits changes in expression of many biochemical processes to be monitored in vivo.

Pros and Cons

Pros: Relatively straightforward to use, high sensitivity,

Cons: low resolution, high background can be a problem.

The fluorophore to be used should be well chosen. For example, GFP emits green light which is stopped by haemoglobin. Therefore GFP imaging is not very sensitive. Red emitting fluorophores (especially near infra-red) tend to travel better through tissue, ie more appropriate for deeper tissue imaging.


Overall, optical imaging is good for superficial tissues, less for deep-seated organs.

Radionuclide imaging

Two types of Radionuclide Imaging are available at BCI:

  • Single-photon emission tomographic (SPECT)
  • Positron emission tomographic (PET)

How does it work?

PETmouse

Both modalities depend upon radiotracers for imaging. The biodistribution of the radiotracer is imaged using specialised SPECT or PET cameras. After administration (usually IV). these radiotracers interact with molecular targets in vivo resulting in localisation of radioactivity at the target site however some degree of non-targeted radioactivity will always occur resulting in background radioactivity.

The images obtained therefore depend on the efficiency of targeting and the rate and route of clearance of non-targeted tracer. This, in turn, depends upon the physico-chemical properties of the molecule: size, charge, hydrophilicity etc. To help assist interpretation of the images obtained, these scanners are interfaced with CT scanners which provide anatomical localisation of the functional images obtained.

What can it be used for?

PET (positron-emitting isotopes) 

- Normally very short-lived with half-lives of minutes or a few hours. They require specialised skills and facilities for their preparation. PET tracers can interact with trans-membrane transport systems such as glucose, amino-acid or nucleotide transporters and map their activity in vivo. PET imaging is most often used to assess changes of the levels of these metabolic functions in disease and as a result of their treatment.

SPECT (gamma-emitting isotopes)

- Half-lives in the range of several hours, to days to weeks. They also require specialised facilities to produce but are somewhat easier to prepare than PET tracers. SPECT tracers can bind to extracellular receptors or markers on target tissues and also be used to measure regional organ function such as cardiac, hepatic or renal function. SPECT imaging is most widely used in pre-clinical radiopharmaceutical development (prior to clinical application) but can also be used to study changes certain biochemical functions during disease progression or treatment.


Both PET and SPECT can also be used for reporter gene imaging to monitor the expression of genes that encode for enzymes or transporters for which the radiotracers are substrates.

Pros and Cons

Pros: Medium to high sensitivity combined with moderate to good resolution. Provides quantitative information on both deep-seated and peripheral tissues. Directly translatable to clinical imaging modalities.

Cons: Complex and expensive imaging procedures to perform, uses radiation, needs expertise and experience to acquire and analyse data.

Anatomical Imaging

tumourvessels

Although used primarily in low  (several 100 µm) resolution for anatomical localisation of radioisotope images, the CT scanners interfaced to the SPECT and PET imaging systems can also be used for stand-alone CT imaging with resolutions down to 30 µm.

Although used primarily in low (several 100 µm) resolution to serve as anatomical reference of radioisotope images, the CT scanners interfaced to the SPECT and PET imaging systems can also be used for stand-alone CT imaging with a resolution down to 30 µm.

At our site, we have several modalities for anatomical imaging:

  • Computed Tomography (CT)
  • Magnetic Resonance Imaging (MRI)
  • Ultrasound (US)

How does it work?

CT

The subject to be imaged is placed between an X-Ray source and a digital detector. X-rays penetrate the subject while rotating around it, and the detector measures the X-ray attenuation by the object (attenuation by bone is particularly high). A computer then reconstructs the tomographic signal in to a 3D image.

MRI

In, Magnetic Resonance Imaging (MRI), a signal is produced by a combination of a static magnetic field, additional smaller electromagnetic (“gradient”) fields and radiofrequency pulses. They all act on the nuclei of hydrogen atoms. In particular abundant and small molecules produce a strong signal, i.e. in vivo predominantly water and fat molecules. Variation in water and fat content but also differences in the microenvironment affect the signal intensity. In addition, complex series of gradient and radiofrequency pulses have been developed that produce various contrast patterns. Thus MR imaging can be tailored to specific research interests.

US

Ultrasound uses high frequency sound waves and their echoes. The technique is similar to the echolocation used by bats, whales and dolphins, as well as SONAR used by submarines.

The ultrasound machine transmits high-frequency (1 to 5 megahertz) sound pulses into the body of the subject using a probe. The sound waves travel through the body and hit a boundary between tissues (e.g. between fluid and soft tissue, soft tissue and bone). Some of the sound waves get reflected back to the probe, while some travel on further until they reach another boundary and get reflected. The reflected waves are picked up by the probe. The machine then calculates the distance from the probe to the tissue or organ (boundaries) using the speed of sound in tissue (5,005 ft/s or1,540 m/s) and the time of the each echo's return (usually on the order of millionths of a second).

The machine displays the distances and intensities of the echoes on the screen, forming a 2D image.

What can it be used for?

CT
CT is mainly used to obtain an anatomical reference to “locate” radioactive signal. However, used on its own, and at times with contrast agents, it can provide valuable information on organs and bones. CT can be used to observe a wide range of structures:
- tumours (e.g. lung tumour)
- organ perfusion (with the use of contrast agent)
- bone structures
- nanoparticles
- implants
MRI

MRI provides the best contrast for soft tissue analysis (ie tumours or organs). It can also be used with contrast agents, and can provide valuable biologic information (perfusion, diffusion etc).

US

Ultrasound, like MRI, provides better contrast than CT in soft tissue. However, you only get 2D information, and the analysis of the images requires a trained eye.

Pros and Cons

CT

Pros: good for dense object imaging (ie bone), fairly fast acquisition
Cons: expensive equipment, low contrast (not too good for soft tissue without the use of contrast agent), subject exposure to XRays which potentially could affect tissues if repeated imaging is carried out.

MRI

Pros: good for soft tissue imaging, harmless to the body of the subject
Cons: expensive equipment, low throughput, requires a high degree of expertise in order to use it to its full potential

US

Pros: good for soft tissue imaging, harmless to the body of the subject
Cons: only 2D images, requires training to be able to analyse the images and detect what you are looking for.

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