Surface functionalization of metal oxide harmonic nanoparticles for targeted cancer imaging

Cancer is a major health burden worldwide and the leading cause of death in industrialized countries. Early detection is a primary factor of survival and remission rate. Classical imaging methods such as magnetic resonance imaging, ultrasound imaging and microscopy lack in sensitivity for early detection of precancerous lesions. Recent and rapid progresses in nanotechnologies have paved the way for the development of new tools for diagnosis and targeted treatment of cancer. Taking advantage of their surface properties for post-conjugation coupled to their optical characteristics, nanoparticles could provide new level of sensitivity for the detection and imaging of tumors. The investigation of functionalization of nanoparticles with small molecules for the targeting of cancer biomarkers was thus an important aim of this thesis. Secondly, the synthesis of a new multimodal probe coupling magnetic resonance imaging and multiphoton microscopy was also investigated.

This work focuses on the development and application of synthetic pathways for small molecules targeting neoplastic cells and tumor microenvironment. Erlotinib and an inhibitor of fibroblast activation protein α were selected for their specific interactions with the epithelial growth factor receptor, present on the surface of lung cancer cells, and cancer-associated fibroblasts respectively. Those molecules where first modified with a biotin residue to assess their biocompatibility and their affinity for the targeted biomarker. The targeting ligands were further equipped with a cyclooctyne moiety for coupling with coated nanoparticles through bioorthogonal reaction.

Nanoparticles based on non-centrosymmetric crystals were selected for their optical properties. Polymeric or inorganic coating, based on poly(ethylene glycol) derivatives and (3-aminopropyl)triethoxysilane respectively, were applied to decorate the nanomaterials with azide moieties. The resulting azides were used to perform copper-free click reaction with the modified targeting ligands. The conjugated nanoparticles where then assessed for their selective association to the targeted biomarker. Nanoparticles decorated with an inhibitor of fibroblast activation protein α revealed target-specific association to the enzyme. In vitro investigation of the association of Erlotinib-tagged nanoparticles to epithelial growth factor receptor positive cells is ongoing.

Finally, a gadolinium complex was modified with an alkyne functional group for copper-catalyzed [3 + 2]-cycloaddition to the surface of coated nanoparticles. The functionalized nanoparticles were further assessed for their efficiency as magnetic resonance imaging contrast agent. Results revealed that conjugation of the gadolinium complex to the nanomaterial afforded a potent T1 contrast agent without affecting its optical properties.

To summarize, several nanosystems were prepared through bioorthogonal reactions. The first part of this thesis presents the synthesis of two small molecules and subsequent coupling to coated nanoparticles for targeted tumor imaging. The second part of this work, discusses the preparation of a new multimodal device for magnetic resonance imaging coupled to multiphoton microscopy. Those nanoprobes may provide new sensitivity levels for the study and the early detection of cancers.