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Preclinical Molecular Imaging using Multi-Isotope Digital Autoradiography - Techniques and Applications

Örbom, Anders LU (2013)
Abstract (Swedish)
Popular Abstract in Swedish

Bildgivande system har en allt mer framträdande roll inom sjukvård och medicinsk forskning. En del av dessa system fungerar genom att en patient eller ett försöksdjur injiceras med ett läkemedel märkt med ett radioaktivt ämne, och sedan mäts den strålning som detta ämne avger för att skapa en bild av var ämnet, och därmed läkemedlet, befinner sig. Det finns både system som mäter fördelningen av radioaktivitet i tre dimensioner hos levande individer (till exempel PET- eller SPECT-kameror) och sådana som mäter fördelningen på en mer detaljerad nivå i tunna vävnadssnitt som är tagna från avlivade försöksdjur; den senare metoden kallas för autoradiografi.

Den idag mest använda tekniken för... (More)
Popular Abstract in Swedish

Bildgivande system har en allt mer framträdande roll inom sjukvård och medicinsk forskning. En del av dessa system fungerar genom att en patient eller ett försöksdjur injiceras med ett läkemedel märkt med ett radioaktivt ämne, och sedan mäts den strålning som detta ämne avger för att skapa en bild av var ämnet, och därmed läkemedlet, befinner sig. Det finns både system som mäter fördelningen av radioaktivitet i tre dimensioner hos levande individer (till exempel PET- eller SPECT-kameror) och sådana som mäter fördelningen på en mer detaljerad nivå i tunna vävnadssnitt som är tagna från avlivade försöksdjur; den senare metoden kallas för autoradiografi.

Den idag mest använda tekniken för autoradiografi baseras på plattor med fosfor-kristaller som fungerar ungefär som en svart-vit fotografisk film. De exponeras under en viss tid för vävnadsprovet med det radioaktiva ämnet, och sedan framkallas bilden med hjälp av en speciell utrustning. Det nya system som utvärderas och används i den här avhandlingen är istället en kiselbaserad halvledardetektor, och fungerar lite som en digital färgvideokamera jämfört med fosforplattorna. Det kan se signalerna från det radioaktiva preparatet i realtid, mäta när i tiden strålningen avges och vilken ”färg”, d.v.s. energi, den har.

Detektorsystemet testades och olika egenskaper mättes. Det visade sig ha en låg bakgrundssignal, god förmåga att för många, men inte alla, radioaktiva ämnen avgöra vilka energier som mättes, samt korrekt kunna mäta relativt starkt radioaktiva prov. Detaljnivån, d.v.s. upplösningen, i bilden jämfördes med fosforplattorna genom att en mycket tunn radioaktiv tråd avbildades på båda systemen. Kiseldetektorn hade en högre upplösning än fosforsystemet även om skillnaden inte var drastisk.

Systemet applicerades i en rad djurmodellstudier med antikroppar märkta med radioaktiva ämnen som känner igen vissa strukturer på celler i till exempel cancertumörer eller åderförkalkningsplack. Det observerades att i en råttmodell av koloncancer tar sig antikropparna först in i och behandlar tumören med strålning, men efter något dygn finns radioaktiviteten i områden av ärrvävnad i tumören där den kanske inte gör så stor nytta. Andra antikroppar testades i musmodeller av prostatacancer där de visade sig visserligen hitta tumören, men på grund av tumörens struktur och att antikroppar är relativt stora m.m. ofta ha väldigt svårt att nå in till tumörens inre. I en del av dessa studier användes flera antikroppar eller andra molekyler samtidigt och de märktes då med olika radioaktiva ämnen, som i bilden kunde separeras genom deras olika energi, eller hur snabbt de avger sin strålning. Ett sådant exempel var när en antikropp specifik mot åderförkalkningsplack testades samtidigt med en ospecifik antikropp och ett sockerliknande ämne som ackumuleras vid inflammation. Där kunde vi i en jämförelse se att den specifika antikroppen togs upp mer i plack än i omkringliggande kärlvägg. Detta i högre grad än det sockerliknande ämnet, men liknande den ospecifika antikroppen.

Sammantaget visade studierna att autoradiografi med ett modernt instrument som kan separera signalen från olika radioaktiva ämnen har mycket att tillföra i studier där man tar fram nya läkemedel eller diagnostiska preparat, men att teknik och metod fortfarande behöver utvecklas. (Less)
Abstract
Molecular imaging, both in vivo and ex vivo, is playing an increasingly important role in preclinical medical research. When using radionuclide-labeled tracers, e.g. in the development of radiopharmaceuticals for diagnostic imaging or for radionuclide therapy, quantitative in vivo imaging can be performed using emission tomography. Quantitative autoradiography of thin tissue sections is employed to obtain high-resolution images of the radioactivity distribution ex vivo, commonly using photo¬graphic film or a storage phosphor screen.

The aim of the work presented in this thesis was to evaluate the potential of digital auto-radiography with multi-radionuclide imaging capabilities to contribute to pre¬clinical, small-animal, research... (More)
Molecular imaging, both in vivo and ex vivo, is playing an increasingly important role in preclinical medical research. When using radionuclide-labeled tracers, e.g. in the development of radiopharmaceuticals for diagnostic imaging or for radionuclide therapy, quantitative in vivo imaging can be performed using emission tomography. Quantitative autoradiography of thin tissue sections is employed to obtain high-resolution images of the radioactivity distribution ex vivo, commonly using photo¬graphic film or a storage phosphor screen.

The aim of the work presented in this thesis was to evaluate the potential of digital auto-radiography with multi-radionuclide imaging capabilities to contribute to pre¬clinical, small-animal, research studies using radiolabeled targeting molecules for diagnosis or therapy.

The characteristics of a digital autoradiography system employing a double-sided silicon strip detector were investigated with regard to spatial resolution, detection sensitivity, background and noise, system dead time, and the ability to resolve energy spectra. This system, although it has a smaller field of view, was found to perform favorably compared to a storage phosphor system. Methods of separating the contributions from several radionuclides imaged simultaneously were developed and evaluated.

The intratumoral distribution of 177Lu-labeled monoclonal antibodies (mAbs) over time was studied in a syngeneic rat model of colon carcinoma at both therapeutic and lower activity levels. The activity was initially found in the tumor periphery, then in areas of viable, antigen-expressing cells, and at 24-48 h and later in areas of granulation tissue and low antigen expression. A point-dose kernel was used to calculate the absorbed-dose rate distribution in tumor sections, which was found to be twice the section mean in areas with high activity accumulation.

The distributions of 111In- and 177Lu-labeled mAbs targeting intercellular adhesion molecule 1 were studied in a xenograft model of human prostate cancer, and compared with a control mAb as well as clinically used 18F-labelled tracers using small animal SPECT/CT and PET/CT, as well as multi-radionuclide digital auto¬radio¬graphy. Results from this study, and those from an 125I-labelled mAb compared with a co-injected smaller antibody fragment labeled with 131I, both targeting carcino¬embryonic antigen, confirmed that barriers to tumor penetration by macro-molecules are a major problem, especially in radioimmunotherapy. A mAb against free prostate-specific antigen was also studied.

Using multi-radionuclide digital autoradiography, the plaque-to-aorta contrast of a mAb targeting oxidized low-density lipoprotein was observed to be higher than that of 18FDG in slide mounted aortas from atherosclerotic mice.

These studies show that digital autoradiography, including multi-radionuclide imaging, has the potential to provide novel data for preclinical imaging studies, but that further development and optimiz¬ation of the method are needed. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Senior Lecturer Green, Alan J., University College London Cancer Institute, London, UK
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Autoradiography, Radioimmunotherapy, Antibodies, Molecular Imaging, Multi-Radionuclide Imaging, Silicon-strip detector
defense location
The lecture hall, 3rd floor in the new radiotherapy building, Klinikgatan 5, Lund
defense date
2013-12-18 09:00
ISBN
978-91-7473-778-3
language
English
LU publication?
yes
id
1c65f87f-aaeb-4b3c-9000-1984b788e632 (old id 4173493)
date added to LUP
2013-11-25 09:52:21
date last changed
2016-09-19 08:45:18
@phdthesis{1c65f87f-aaeb-4b3c-9000-1984b788e632,
  abstract     = {Molecular imaging, both in vivo and ex vivo, is playing an increasingly important role in preclinical medical research. When using radionuclide-labeled tracers, e.g. in the development of radiopharmaceuticals for diagnostic imaging or for radionuclide therapy, quantitative in vivo imaging can be performed using emission tomography. Quantitative autoradiography of thin tissue sections is employed to obtain high-resolution images of the radioactivity distribution ex vivo, commonly using photo¬graphic film or a storage phosphor screen.<br/><br>
The aim of the work presented in this thesis was to evaluate the potential of digital auto-radiography with multi-radionuclide imaging capabilities to contribute to pre¬clinical, small-animal, research studies using radiolabeled targeting molecules for diagnosis or therapy.<br/><br>
The characteristics of a digital autoradiography system employing a double-sided silicon strip detector were investigated with regard to spatial resolution, detection sensitivity, background and noise, system dead time, and the ability to resolve energy spectra. This system, although it has a smaller field of view, was found to perform favorably compared to a storage phosphor system. Methods of separating the contributions from several radionuclides imaged simultaneously were developed and evaluated.<br/><br>
The intratumoral distribution of 177Lu-labeled monoclonal antibodies (mAbs) over time was studied in a syngeneic rat model of colon carcinoma at both therapeutic and lower activity levels. The activity was initially found in the tumor periphery, then in areas of viable, antigen-expressing cells, and at 24-48 h and later in areas of granulation tissue and low antigen expression. A point-dose kernel was used to calculate the absorbed-dose rate distribution in tumor sections, which was found to be twice the section mean in areas with high activity accumulation.<br/><br>
The distributions of 111In- and 177Lu-labeled mAbs targeting intercellular adhesion molecule 1 were studied in a xenograft model of human prostate cancer, and compared with a control mAb as well as clinically used 18F-labelled tracers using small animal SPECT/CT and PET/CT, as well as multi-radionuclide digital auto¬radio¬graphy. Results from this study, and those from an 125I-labelled mAb compared with a co-injected smaller antibody fragment labeled with 131I, both targeting carcino¬embryonic antigen, confirmed that barriers to tumor penetration by macro-molecules are a major problem, especially in radioimmunotherapy. A mAb against free prostate-specific antigen was also studied.<br/><br>
Using multi-radionuclide digital autoradiography, the plaque-to-aorta contrast of a mAb targeting oxidized low-density lipoprotein was observed to be higher than that of 18FDG in slide mounted aortas from atherosclerotic mice.<br/><br>
These studies show that digital autoradiography, including multi-radionuclide imaging, has the potential to provide novel data for preclinical imaging studies, but that further development and optimiz¬ation of the method are needed.},
  author       = {Örbom, Anders},
  isbn         = {978-91-7473-778-3},
  keyword      = {Autoradiography,Radioimmunotherapy,Antibodies,Molecular Imaging,Multi-Radionuclide Imaging,Silicon-strip detector},
  language     = {eng},
  school       = {Lund University},
  title        = {Preclinical Molecular Imaging using Multi-Isotope Digital Autoradiography - Techniques and Applications},
  year         = {2013},
}