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Multimodal tools for Molecular Imaging, Diagnostics and Therapeutics

Final Report Summary - MUMID (Multimodal tools for Molecular Imaging, Diagnostics and Therapeutics)

Novel molecular imaging agents and therapeutics are essential for combating diseases, since such molecules can be utilized for clinical diagnostics and treatment of distinct disorders. Furthermore, multimodal molecules that combine two different imaging modalities or the modalities of therapy and diagnostic imaging, so called “theranostics”, can be developed. The overall goal of this project was to develop multimodal tools for molecular imaging, diagnostics and therapy and special emphasis was put on translational research for the development and validation of functionalized luminescent conjugated oligomeric thiophene derivatives (LCOs) that via chemical design and modern imaging technology can give rise to entirely new and innovative methodologies for molecular theranostics of protein aggregation diseases, such as Alzheimer´s disease, cancer and bacterial infection.

LCOs can be chemically modified to recognize a specific structural motif and in this project we have developed a library of LCOs that can be utilized for specific identification of distinct biological targets, such as protein aggregates the pathological hallmark of a wide range of diseases. These smart multimodal imaging agents have been employed as experimental tools for obtaining basic novel insights regarding fundamental disease related biological mechanisms underlying Alzheimer´s disease and prion disease. From a clinical perspective, we have also identified LCOs that recognize a broader subset of disease associated protein aggregates than conventional probes that are used in routine clinical diagnostic of protein aggregation diseases. Overall, the LCOs have been very useful for obtaining novel information regarding heterogenic populations of protein aggregates, a phenomenon that is believed to be associated with the diverse clinical picture of these diseases. Hence, the LCOs might be applied as novel diagnostic tools for protein aggregation diseases. In this regard, we have also modified the LCO molecular scaffold towards non-invasive molecular diagnostic techniques, such as positron emission tomography (PET) and magnetic resonance imaging (MRI), with the aim of providing imaging tools that can be used for sensitive non-invasive clinical diagnostic of protein aggregation diseases. Such tools will also be essential for evaluating novel therapeutic inventions towards these diseases.

In addition to their applications toward molecular diagnostics of protein aggregation diseases, the library of LCOs has also been utilized to explore any potential therapeutic effects of this class of molecules towards these diseases. In this regard, we have identified properly functionalized LCOs that can inhibit prion propagation and thereby delay the progress of the disease. These important findings will be explored further towards other neurodegenerative diseases such as Alzheimer´s and Parkinson´s disease.

A wide range of studies have shown that bacteria express proteinaceous extracellular fibers having a structure similar to the protein aggregates observed in protein aggregation disease and these extracellular fibrils are a crucial component in bacterial biofilm formation, a key element in the infection process of the bacteria. In this project, we have also developed LCOs that can be utilized for real-time optical imaging of the bacterial biofilm formation, as well as detection of specific components of the biofilm. Thus, molecular tools for studying yet another pathological process, bacterial biofilm, has been provided and we foresee that these tools will aid in studying the molecular details of bacterial infection, as well as be utilized for the development of novel diagnostics tools to monitor bacterial infections. We have also identified properly functionalized LCOs that can be used to identify distinct cell types in a novel fashion and these molecules can be implemented as tools for studying stem cells and tumour associated cells in a more refined manner. As a continuation of these observations, the LCOs can now be implemented as novel optical tools that can be utilized to gain basic insights regarding fundamental cancer related biological mechanisms and as non-invasive molecular diagnostic tools for cancer tumours. In addition, these LCOs might also serve as “guided missiles” aimed at cancer associated molecular targets and offer a novel strategy for targeted drug delivery of anti-cancer therapies.

In summary, the project has generated novel multimodal imaging tools that can be utilized to gain basic novel molecular insights regarding fundamental diseases associated molecular mechanisms of distinct diseases. In addition, the proof of concept for applying oligothiophenes as therapeutically active agents towards protein aggregation disease has also been shown. The continuation of these findings will be focused towards developing these molecular tools further with the aim of providing novel non-invasive clinical diagnostic tools and therapeutically active agents towards protein aggregation diseases, cancer and bacterial infection.