GOLDEN · Gold-Functionalized Devices and Engineered Nanoparticles: Bioorthogonal Tools for Unprecedented Biomedical Applications

Gold-Functionalized Devices and Engineered Nanoparticles: Bioorthogonal Tools for Unprecedented Biomedical Applications

The research program originated from the need for developing a safe therapeutic technology capable of mediating localised release of drugs exclusively at a damaged (non-cancerous) tissue or organ and for extended periods of time. The EU-funded GOLDEN project proposed to bypass the metabolic machinery of cells and produce bioactive molecules at specific locations within the body using metallic nanoparticles (NPs). Gold-based NPs serve as biocompatible catalysts and can be engineered to trigger release of systemically administered bioactive precursors into drugs (psychoactive agents). In this project, we used zebrafish as a model to test the efficacy of the GOLDEN NP-based strategy at activating dyes and neuromodulators in the brain, paving the way for the treatment of localised disorders and chronic pain. To achieve this, we developed a suite of chemical tools designed to optimize the catalytic property of Au-based devices, to mediate the release of a neuroactive agent directly in the brain of an animal, eventually reducing the adverse effects of systemic administration. Therefore, the main objectives were: 1. Development of Au-functionalized nanoparticles and microimplants with optimal catalytic capacity in biological media. 2. Development of inactive (caged) precursors of psycho-stimulants or depressants that are rapidly uncaged by Au catalysis in biocompatible conditions. 3. In vivo validation of the technology by testing its capacity to ―safely― increase or reduce zebrafish locomotor activity by intracranial release of psychoactive agents. Thanks to the successful completion of this research project, we reported the development of a truly-catalytic Au-polymer composite by assembling ultrasmall Au-NPs at the protein-repelling outer layer of a co-polymer scaffold via electrostatic loading. The developed bioorthogonal Au-based catalysts, coupled with activatable precursors of drugs/dyes, enabled the in situ generation of imaging and therapeutic agents. Expanding the scope of Au chemistry is paving the way to more advanced technologies and, in turn, is fostering the creation of first-in-class theranostic strategies to address unmet clinical needs. In addition, illustrating the in vivo-compatibility of the novel catalysts, we showed their capacity to uncage the anxiolytic agent fluoxetine at the central nervous system (CNS) of developing zebrafish, influencing their swim pattern. However, not only is it a safe method for the generation of bioactive compounds in designated anatomical areas, but this bioorthogonal strategy has enabled ―for the first time― modification of cognitive activity by releasing a neuroactive agent directly in the brain of an animal, offering a route for new applications beyond treating cancer or inflammation.

Data: CORDIS, © European Union