Polymeric Nanocarriers for the Visualization and Quantification of Molecular Release

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The overarching aim of the current proposal is to develop a technology platform that can follow and quantify molecular release mechanisms (e.g. drug release) by incorporating a switchable fluorescent moiety which is able to simultaneously visualise and quantify payload delivery. The development of polymeric nanoparticles as drug delivery vehicles has facilitated effective targeted release strategies for a variety of therapeutics. When combined with imaging agents, these nanoparticles allow for the visualization of the biodistribution of a molecular payload. However, the majority of these systems do not report on the release of the drug from the carrier, an important facet which is crucial to the design of optimized payload delivery systems and will enable an in-depth understanding of biological effects. The sought project will develop novel polymeric nano-carriers which can show where, when and how much molecular payload is delivered to a specific target site. Featuring a strong polymer chemical focus, this will be achieved through the incorporation of a nitroxide-fluorophore couple into the delivery system. When a fluorophore is held in close proximity to a nitroxide, the fluorophore enters a profluorescent state and a complete quenching of the fluorescence is observed. When the load is released from the carrier - through stimuli-induced scission of a covalent linkage - separation of the nitroxide and fluorophore moieties will occur and an immediate increase in fluorescence will be observed, thereby allowing the quantification of the delivery. The molecules will be designed such that the switch on of one fluorophore will be related to the release of one delivered molecule, leading to a quantifiable measure of release. In order to realize such an ideal, a number of chemical challenges have been identified that are at the core of the current proposal and will be addressed, leading to a more profound understanding of the mechanisms by which delivery from polymeric nanocarriers is achieved. The concept will be evidenced in in vitro as well as in vivo studies to demonstrate its practical applicability.