Functionalization of harmonic nanoparticles for drug release and multimodal imaging applications

Cancer is among the leading causes of death worldwide, and as knowledge of the disease continues to grow there is an increasing interest towards precision medicine: more specifically towards the theranostics field, i.e the development of targeted molecular probes combining specific diagnosis and treatment modalities. The theranostic paradigm involves merging, in a single agent, specific tumor biomarker targeting, multimodal imaging techniques which allow to overcome the inherent limitations of classical methods, and the controlled delivery of anticancer compounds. This strategy thus aims at high diagnosis sensitivity for earlier tumor detection and the reduction of off-target effects, which are critical factors in patient survival rates. In this context, inorganic nanoparticles emerge as promising tools owing to their surface properties, which are amenable to post-functionalization, and their imaging properties.The goal of this project is to usher in the development of such multimodal theranostic tools based on harmonic nanoparticle (HNP) materials. These metal oxide nanomaterials, characterized by a crystalline structure lacking inversion symmetry (e.g LiNbO3), exhibit a non-linear optical response by generating second- and third- harmonic signals upon laser excitation. A silica-based coating layer allows for improved biocompatibility of the inorganic HNPs and for the introduction of surface azide moieties, which are exploited for subsequent functionalization through bioorthogonal copper-free click reaction with cyclooctyne-modified ligands, or standard copper-catalyzed click chemistry with alkyne-modified ligands.Light-sensitive drug carriers are produced by the grafting of chemotherapeutics to the surface of HNPs through photosensitive tethers based on coumarinyl moieties. Irradiation of the HNPs with near-infrared (NIR) light allows switching between imaging and treatment modalities by tuning of the excitation energy. Excitation at high wavelengths (> 1000 nm) is used for multi-harmonic detection, while lower wavelengths (~800 nm) results in the harmonic emission of ultraviolet light, inducing cleavage of the phototrigger and release of the therapeutic cargo.In addition, the HNPs can be covalently conjugated to a lanthanide (III) chelate, potentially acting as an MRI/X-ray contrast agent or a luminescent probe depending on the lanthanide atom chosen while maintaining the intrinsic optical properties of HNPs, thereby paving the way for multimodal imaging.In summary, this project aims at developing a theranostic nanoplatform for controlled therapeutic cargo delivery upon NIR irradiation and multimodal detection by combing optical and magnetic resonance imaging, based on nanoparticle platforms functionalized by bioorthogonal reactions. Those nanoprobes have the potential to provide a high level of sensitivity for the early detection of cancer, and high potency for in vivo cancer treatment.