Towards the design of novel organic semiconductor-based contrast agents for targeting matrix metalloproteinases and the tumour microenvironment Ana-Maria Ivanus 1,2 , Alethea B. Tabor 1 , Graeme J. Stasiuk 2 , Bob C. Schroeder 1 1 Department of Chemistry, Faculty of Mathematical and Physical Sciences, University College London, United Kingdom 2 School of Biomedical Engineering & Imaging Sciences, Faculty of Life Sciences & Medicine, King’s College London, United Kingdom 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 plays a significant role in cancer, where they promote 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. 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 imaging probes are synthesised using isoindigo and isoindigo derivatives as the optically active probe with the scope of implementing photoacoustic imaging. The synthetic methodologies for incorporating solubilising, biocompatible linkers have been developed and optimised. UV-Vis absorption spectroscopy and photoluminescence spectroscopy are used for optical properties characterisation. Following the attachment of the macrocyclic chelator of choice (DOTA), cell stability is studied to evaluate the viability of our probes. Radiolabelling using 68 Ga is optimised for high radiochemical yields. Stability is assessed in bovine serum and cyto- and phototoxicity is evaluated in incubated cell lines. This talk will present the progress made towards the novel synthesis of near-IR-absorbing organic semiconductors functionalised with biocompatible handles. The handles enable the linkage of custom-made peptide sequences through “click chemistry”-type reactions for the improvement of solubility and enzyme specificity. These functionalisations also enable the attachment of macrocyclic chelators for radiolabelling. For every organic semiconductor synthesised, an assessment of the stability and cytotoxicity in vivo is presented, both before and after radiolabelling, therefore merging for the very first time the fields of organic semiconductor chemistry and radiochemistry for multimodal imaging platforms. In conclusion, the research presented illustrates the development of a novel library of multimodal imaging probes based on organic semiconductors with tuneable optical properties. Ultimately, this highlights the value of organic electronic materials in biomedical imaging, and their 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. References 1. H. Nagase, R. Visse and G. Murphy, Cardiovascular Research, 2006, 69 , 562–573. 2. T. Ma, P. Zhang, Y. Hou, H. Ning, Z. Wang, J. Huang and M. Gao, Advanced Healthcare Materials, 2018, 7 , 1800391. 3. D. Jung, S. Park, C. Lee and H. Kim, Polymers, 2019, 11 , 1693.
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