Final Activity Report Summary - MOREDITH (Molecular Recognition for Diagnosis and Therapy)
A network of research groups at the Delft University of Technology and the Erasmus University Rotterdam provided research training to 12 early stage researchers on molecular imaging and therapy through the research project MOREDITH.
The aim of molecular imaging is to investigate cellular and molecular events involved in normal and pathological processes. Two major classes of diagnostic techniques are radiodiagnostics and Magnetic resonance imaging (MRI). The latter has a high spatial resolution; however its use in molecular imaging is seriously hampered by its low sensitivity because of the MRI contrast agents. An approach to overcome the sensitivity problem is to apply vectorised contrast agents, which can bring a high payload of the reporting group, i.e. of paramagnetic metal ions, responsible for the enhancement of the MRI image contrast, to the site of interest.
A contrast agent for molecular imaging is usually built up from a reporter group and a targeting vector, which are both attached to a carrier. In the MOREDITH project, the goal was to design each of these modules for optimal efficiency with respect to contrast enhancement. Three artificial targeting vectors were selected, which were able to recognise receptors that were over-expressed in tumours, namely bis-phosphonate, boronate and the octapeptide octreotide. Synthetic routes were developed to attach these compounds either directly to a reporter group, i.e. a complex of a paramagnetic metal ion, or to a carrier. Multiplication of the effect of the recognition of a receptor could be obtained via attaching a few targeting vectors and many reporter groups to the carrier. Several carriers were investigated, such as liposomes, the polysaccharide inulin, dendrimers and calixarenes. The resulting contrast agents were all efficient positive contrast agents, giving bright spots in the image.
An extremely high efficiency could be obtained with nanoparticulate systems, which had the advantage of combining the functions of carrier and reporter. Lanthanide oxide particles with a diameter of about 50 nm appeared to have excellent efficiency in contrast enhancement. These agents were negative contrast agents that were giving dark spots. Their efficiency appeared to increase at higher magnetic fields, greater than 1.5 T, which are nowadays applied in MRI to an increasing extent. Work to cover these particles with a coating and attachment of targeting vectors was in progress by the time of the project completion.
The first of the developed systems that was selected for further animal studies was a bis-phosphonate targeting vector attached to a lanthanide chelate. In this case the selected lanthanide was radioactive Lu-177, which allowed for gamma-imaging and positron emission tomography or single-photon emission computed tomography (PET-SPECT) diagnosis. The bone-targeting complexes underwent an early and selective retention in the skeleton. After the excretion of about 25 % of the initial dose via the kidneys, the radioactivity was exclusively present in the skeleton. Relatively high amounts of radioactivity were observed in the epiphyseal plates and teeth, which were places of fast growth in rats. Therefore, these agents were promising for both the diagnosis of calcious tissue and palliation of bone pain.
The research on this and other systems which was developed as part of MOREDITH project was anticipated to be continued in several follow-up projects. The insights and expertise in MOREDITH was evaluated as forming a firm basis for that future research.
The aim of molecular imaging is to investigate cellular and molecular events involved in normal and pathological processes. Two major classes of diagnostic techniques are radiodiagnostics and Magnetic resonance imaging (MRI). The latter has a high spatial resolution; however its use in molecular imaging is seriously hampered by its low sensitivity because of the MRI contrast agents. An approach to overcome the sensitivity problem is to apply vectorised contrast agents, which can bring a high payload of the reporting group, i.e. of paramagnetic metal ions, responsible for the enhancement of the MRI image contrast, to the site of interest.
A contrast agent for molecular imaging is usually built up from a reporter group and a targeting vector, which are both attached to a carrier. In the MOREDITH project, the goal was to design each of these modules for optimal efficiency with respect to contrast enhancement. Three artificial targeting vectors were selected, which were able to recognise receptors that were over-expressed in tumours, namely bis-phosphonate, boronate and the octapeptide octreotide. Synthetic routes were developed to attach these compounds either directly to a reporter group, i.e. a complex of a paramagnetic metal ion, or to a carrier. Multiplication of the effect of the recognition of a receptor could be obtained via attaching a few targeting vectors and many reporter groups to the carrier. Several carriers were investigated, such as liposomes, the polysaccharide inulin, dendrimers and calixarenes. The resulting contrast agents were all efficient positive contrast agents, giving bright spots in the image.
An extremely high efficiency could be obtained with nanoparticulate systems, which had the advantage of combining the functions of carrier and reporter. Lanthanide oxide particles with a diameter of about 50 nm appeared to have excellent efficiency in contrast enhancement. These agents were negative contrast agents that were giving dark spots. Their efficiency appeared to increase at higher magnetic fields, greater than 1.5 T, which are nowadays applied in MRI to an increasing extent. Work to cover these particles with a coating and attachment of targeting vectors was in progress by the time of the project completion.
The first of the developed systems that was selected for further animal studies was a bis-phosphonate targeting vector attached to a lanthanide chelate. In this case the selected lanthanide was radioactive Lu-177, which allowed for gamma-imaging and positron emission tomography or single-photon emission computed tomography (PET-SPECT) diagnosis. The bone-targeting complexes underwent an early and selective retention in the skeleton. After the excretion of about 25 % of the initial dose via the kidneys, the radioactivity was exclusively present in the skeleton. Relatively high amounts of radioactivity were observed in the epiphyseal plates and teeth, which were places of fast growth in rats. Therefore, these agents were promising for both the diagnosis of calcious tissue and palliation of bone pain.
The research on this and other systems which was developed as part of MOREDITH project was anticipated to be continued in several follow-up projects. The insights and expertise in MOREDITH was evaluated as forming a firm basis for that future research.