Towards novel organic semiconductor-based contrast agents for targeting matrix metalloproteinases and the tumour microenvironment Ana-Maria Ivanus 1 , Alethea B. Tabor 1 , Graeme J. Stasiuk 2 , Bob C. Schroeder 1 1 University College London, UK, 2 King’s College London, UK Matrix metalloproteinases (MMPs) are a family of enzymes that are crucial in extracellular matrix remodelling. 1 Their upregulation is involved in a significant number of ageing-related diseases such as cardiovascular disease or rheumatoid arthritis. MMPs upregulation also play a significant role in cancer, where they promote the tumour cell growth, tissue invasion, abnormal extracellular matrix reordering, and ultimately the development of the tumour microenvironment. 2 Therefore, these crucial enzymes can serve as important biomarkers when assessing and targeting malignant tumours. However, there is little development in the use of MMP-specific contrast agents that employ multimodal diagnosis and treatment techniques. The aim of this research project is to synthesise a library of multifunctional probes consisting of a radio-labelled organic semiconductor-based fluorophore, conjugated to a dark quencher via an MMP-cleavable short peptide. Our hypothesis is that in the MMP-rich tumour microenvironment, the quencher coupled to the recognised peptide is detached from the probe, and the fluorophore restores its emission properties, adding desirable temporal resolution to the imaging probe. These novel contrast agents will allow the monitoring of their diffusion using positron emission tomography, while employing optical imaging techniques using the near-IR biological window for high specificity in-depth tissue penetration. 3 The poster will present the progress made towards the novel synthesis of an organic semiconductor functionalised with biocompatible handles that enable the linkage of custom-made peptide sequences for the improvement of solubility and specificity. Moreover, these functionalisations also enable the attachment of macrocyclic chelators to access radiolabelling and assess the stability and cytotoxicity in vivo , therefore merging for the first time the fields of organic semiconductor chemistry and radiochemistry. This work is complemented by an in silico assessment of the fluorophore’s optical properties, as well as its ability to bind to the MMP active site, evaluating any issues such as steric hinderance. Ultimately, this research highlights the value of organic electronic materials in biomedical imaging, and its potential to be applied as cheaper, better-performing theranostic tools, opening new avenues in the imaging and diagnostics of both cancer and ageing-related disorders. 4 References 1. Nagase, H.; Visse, R.; Murphy, G., Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 2006, 69 (3), 562-73. 2. Ma, T.; Zhang, P.; Hou, Y.; Ning, H.; Wang, Z.; Huang, J.; Gao, M., "Smart" Nanoprobes for Visualization of Tumor Microenvironments. Adv Healthc Mater 2018, 7 (20), e1800391. 3. Jung, D.; Park, S.; Lee, C.; Kim, H., Recent Progress on Near-Infrared Photoacoustic Imaging: Imaging Modality and Organic Semiconducting Agents. Polymers (Basel) 2019, 11 (10). 4. Li, J.; Pu, K., Development of organic semiconducting materials for deep-tissue optical imaging, phototherapy and photoactivation. Chem Soc Rev 2019, 48 (1), 38-71.
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