Photonic Sensing and Dual-mode Bio-Imaging with Rare Earth Upconversion Nanoparticles

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Cardiovascular diseases (CVD) which include acute myocardial infarction (AMI) and stroke are the main cause of premature deaths in the world. The nature of CVD demands efficient and simultaneous detection of biomarkers earlier than current approaches that are incapable or time consuming. Atherosclerosis is an inflammatory disease, and inflammatory marker high-sensitivity C-reactive protein (CRP), has been shown to identify additional individuals who are at risk. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is also a marker of vascular inflammation. Thus screening with for example both Lp-PLA2 and hs-CRP may provide a better risk assessment for CVD and stroke than using either test alone. In this project we have chosen four biomarkers NT-proBNP, LpPLA2, GFAP and IL6 for implementing a multiple biomarker detection and measurement system. Traditional diagnostic tools currently used for detection and assessing atherosclerotic plaques have their limitations regarding the less contrast images received even from modern techniques such as CT and MRI. Although recent advances in imaging techniques together with proteomics and metabolic profiling have enhanced the feasibility of patient screening for the diagnosis, they are not suitable for the "point-of-care" where the early diagnosis may benefit primary prevention and treatment of these diseases. The "gold standard" cardiac angiography is an invasive method with risks associated with the catheterization procedure and there is no reliable non-invasive method to identify and quantify the severity of atherosclerotic plaque formation. Ultrasound scan is currently used for detecting plaque burden non-invasively, particularly in the carotids, but there is no currently available interpretation of this that allows differentiation of unstable vs stable plaques.In this interdisciplinary project, we will develop lanthanide doped up-conversion nanoparticles (UCNPs) and biomolecular conjugate based assays for the rapid and simultaneous detection and imaging of key biomarkers - for CVD and atherosclerosis. UCNPs have specific excitation and emission wavelengths, and the individual fluorescent lanthanide ions are very sensitive to environmental alterations around them. The project aims to create a scalable manufacturing process for rare earth (RE) upconversion nanoparticles (UCNP) suitable for photoluminescence based rapid bio-sensing and bio-imaging that also preclude signal noise due to autofluorescence (fluorescence from tissues). The crystallinity and RE doping concentration of the UCNPs need improvement for high output visible light emission under infrared laser excitation while being biologically safe. We propose to scale up the manufacturability of the UCNPs suitable for commercial exploitation. These nanoparticles with intense visible light emission under near infrared excitation will be surface functionalised with -Affimers to be suitable for biologically safe and targeted laser based as well as magnetic (MRI) imaging of tissues and organs. Affimers are synthetic binding proteins, developed at the University of Leeds and marketed by Avacta Lifesciences. As a further development, these particles suitably functionalised will be used to create lab-on-a-chip device for simultaneous and rapid sensing of CVD biomarkers. By bringing together imaging and sensing modalities, this project proposes to develop methodologies for identifying, monitoring and finally detecting atherosclerotic tissues. The methodology developed in the project might also be applicable to various forms of cancer biomarker detection and tissue imaging.