Research

Luminescent Conjugated Oligo- and Polythiophenes

Aim

Materials and molecules that combine the modalities of therapy and diagnostic imaging, so called “theranostics” are of great interest for combating a variety of diseases such as Alzheimer´s disease and cancer. In this regard, the aim of our research is to developed novel molecular tools, luminescent conjugated oligo- and polythiophenes (LCOs and LCPs) (Fig. 1a and 1b), that can be utilized to gain novel insight regarding fundamental pathological mechanisms underlying distinct disease, as well as for developing novel diagnostical tools and therapeutic inventions towards these disease.

Background

Conjugated polymers have been used as tools for detection of biological events, as these molecules provide a direct link between spectral signal and different biological processes. The detection schemes of conjugated polymers are mainly employing the efficient light harvesting properties or the conformation sensitive optical properties of the conjugated polymers. The latter is particularly observed for conjugated polymers with a repetitive flexible thiophene backbone (Fig. 1a and 1b), as a conformational restriction of the thiophene rings leads to a distinct optical finger print from these fluorescent dyes. Most conventional techniques, such as antibodies, are limited by their reliance on the detection of a certain biomolecule, whereas LCOs and LCPs are identifying a particular structural motif or a distinct conformational state of a biomolecule. Hence, LCOs and LCPs offer the possibility to monitor the biochemical activity of biological events on the basis of a structure-function relationship rather than on a strictly molecular basis. Molecular tools for imaging and therapeutic agents need to be exceptionally target-specific in a complex environment, such as tissue.  In recent studies (see list of publications), we have been able to show that LCOs and LCPs can function as target specific chameleons that change their color depending on the structural motif of a distinct target molecule even in a complex environment, such as cells and tissue. This intrinsic property makes these molecules useful as selective probes for identifying and distinguishing protein deposits (Fig. 1c-e), the pathological hallmark of protein aggregation diseases such as Alzheimer’s disease, and for specific identification of distinct cells (Fig. 1f and 1g).

Figure 1. Schematic structures of LCPs (a) and different chemically defined LCOs (b). Examples showing how LCOs with distinct chain length (pentamers or heptamers) can be used to study biological processes, such as optical in vivo imaging of protein aggregates in transgenic mouse models by two-photon microscopy (c) or differentiation of protein aggregates with distinct age (d). e) The anionic pentameric LCO, p-FTAA (top), which can be implemented for specific staining of protein aggregates in tissue (bottom). Image of a brain tissue section from a patient with Alzheimer’s disease (AD). Notably, the two pathological hallmarks of AD, A-beta aggregates (green arrows) and neurofibrillary tangles (red arrows) can easily be distinguished due to the emitted light from p-FTAA. f). The cationic pentameric LCO, p-HTMI (top), which can be implemented for specific staining of neural stem cells or cancer stem cells (bottom). The neural stem cells can easily be separated from other cells due to the strong green emission from p-HTMI. g) The zwitter-ionic pentameric LCO, p-HTES (top), which can be implemented for specific staining of cancer cells (bottom). The neural stem cells can easily be separated from other cells, including cancer stem cells, due to the strong green emission from p-HTES. All of the staining was performed in PBS.

Our research

Our theranostic approaches include therapeutic strategies, such as chemotherapy, PDT, and radiation therapy combined with one or more imaging functionalities for both in vitro and in vivo studies. Recent advancement of non-invasive imaging techniques offers the possibility to visualize the dynamics and biochemical activity of pathological or biological processes in real-time. Magnetic resonance imaging (MRI) and positron emission tomography (PET) can be used in organ to the full body scale, whereas resolution at the cellular and molecular level is obtained using optical imaging. LCOs can be chemically modified to recognize a specific structural motif and might for instance be used for specific identification of distinct biological targets, such as protein aggregates or distinct cells (Fig. 1). By the development of novel LCOs and through merging the LCO technique with other technological platforms, we aim at developing novel smart multimodal imaging agents, i.e. experimental tools that can be used to gain basic novel insights regarding fundamental disease related biological mechanisms ranging from the molecular level to the organ full body scale. Furthermore, such imaging agents can be utilized as non-invasive molecular diagnostic tools for a wide range of diseases. In addition to their applications toward molecular imaging and diagnostics, the molecular scaffolds can also be explored for therapeutics. As the LCOs identifies and strikes at disease associated molecular targets, we foresee that the LCOs can be utilized as pharmacaphores for a) direct interference with disease related molecular processes; b) transporters/carriers for known therapeutically effective agents; c) molecular scaffolds for creating high-avidity pharmaceuticals.

The main focus of our research is to synthesize novel molecular tools and implement these tools within molecular biology and medicine. Most of our research project has a focus on chemical biology and involves multidisciplinary collaborations with research disciplines such as organic chemistry, physics, biochemistry, molecular biology and medicine.

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Last updated: Fri Oct 26 09:33:51 CEST 2012