Functionalization of second harmonic generation nanoparticles for theranostic applications

Nowadays, cancer is one of the leading causes of death in developed countries. The actual medical tools to detect cancer at early stage suffer to their low sensitivity. The design of multimodal nanodevices for in vivo imaging offers the perspective of cancer detection of cancer at a very early stage. The recent progress in the development of stimuli-responsive nanocarriers allows to achieve higher concentration in tumor site and reduces the side effects of active molecules. The combination of controlled release of therapeutics and imaging properties in a single nanocarrier has a great potential for theranostic applications. In this context, harmonic nanoparticles, which are composed by non-centrosymmetric materials, can be easily imaged by their second harmonic generation signal in multiphoton imaging platforms and functionalized with photosensitive systems for controlled-drug delivery.

The research project focused on the development of functionalized second-harmonic nanoparticles that exhibited imaging properties for theranostic application. The first part devoted to the development of photosensitive molecules based on coumarinyl and ortho-nitrobenzyl moieties and thereafter, several cargos molecules (tryptophan, organic dyes and anticancer drugs) where covalently conjugated to these tethers via carbamate or ester linkages. The coating of the harmonic nanoparticles, BiFeO3 and LiNbO3 via formation of silica shell increased their biocompatibility. The coated nanoparticles were functionalized with photo-responsive tethers via covalent linkage through biorthogonal click reactions.

The ability of the phototrigger to induce the selective release of the caged compound was first evaluated under UV-light excitation. The amount of uncaged molecule was quantified by UHPLC-MS. Excitation of these functionalized harmonic nanoparticles in the near IR region generated second harmonic UV emission and subsequent selective release of the caged compound. This strategy was first evaluated with tryptophan as model cargo using femtosecond pulsed laser. NIR irradiation and functionalized nanoparticles exhibited good biocompatibility in vitro. The methodology was applied to the controlled delivery of anticancer drug (erlotinib and chlorambucil). The suitability of this methodology for the decoupled imaging of cancer cells and exposure to uncaged molecular cargos was investigated in vitro by tuning the excitation wavelength in multiphoton imaging setup.

In summary, harmonic nanoparticles were functionalized with several photosensitive tethers bearing molecular cargos that can be released in a controlled and selective manner upon UV- or NIR-light irradiation. In addition, the system exhibited high potency for in vivo and ex vivo cancer treatment.