Functionalization of Nanoparticles for Targeted Cancer Imaging and Diagnosis

At present time, cancer is the leading cause of death in developed countries. The medical imaging tools currently used in clinics such as radiology, nuclear magnetic resonance imaging, microscopy and endoscopy are not able to reach the sensitivity necessary to detect cancers in their earliest stages. The detection and identification of rare circulating individual cells and early cancer metastasis is of the utmost importance to reduce cancer mortality. The development of nanotechnology-based medical diagnostic tools could provide a qualitatively new level of sensitivity and accuracy for the detection of malignant diseases. In this project, the synthesis of functionalized nanoparticles with small targeting molecules that can capture cell entities for the detection of breast, lung and prostate cancers was thus investigated. The research project focused on the chemical development of coated and functionalized second harmonic nanoparticles, displaying unique optical properties. First, the synthesis of hetero-bifunctional poly(ethylene glycol) (PEG) able to covalently coat the nanomaterial and bind to the targeting molecules was performed. The coating of nanoparticles with α-triethoxysilyl-ω-azido and -ω-amino PEG was evaluated on iron oxide nanoparticles (IO NPs) as proof of concept. Coated NPs demonstrated to be non-cytotoxic and stable overtime in biological medium. Similar results were obtained with bismuth iron oxide NPs (BFO NPs) expressing second harmonic generation property. The functionalization of coated NPs was then established with drugs and ligands to specifically target cancer cells biomarkers. Preliminary modification of the selected ligands (e.g. c(RGDfK), Erlotinib, Lapatinib, and an inhibitor of prolyl-endopeptidases) with spacers and a biotin label was undertaken in order to assess their binding specificity to tumor cells. The two best candidates, c(RGDfK) and the inhibitor of prolyl-endopeptidases were modified to contain a simple or strain-cyclic alkyne for the conjugation to the NP's surface through bioorthogonal click reactions. Biological evaluations demonstrated that the ligand-functionalized IO and BFO NPs bind to human cancer cells through target-specific interactions. In summary, chemical modifications of nanoparticles were implemented using two different materials and several targeting ligands, demonstrating the flexibility of this methodology. Functionalized NPs were demonstrated to be biocompatible, stable over-time and suitable for the labelling of cancer cells through specific interactions with extracellular biomarkers overexpressed in tumors.

Gerber, Sandrine
Juillerat-Jeanneret, Lucienne
Lausanne, EPFL
Other identifiers:
urn: urn:nbn:ch:bel-epfl-thesis6248-2

Note: The status of this file is: EPFL only

 Record created 2014-08-19, last modified 2018-03-17

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