BREAST CANCER DETECTION: FROM TUMOR-SPECIFIC NANOPARTICLES TO CELL MECHANICS

Abstract

This thesis presents combined experimental and theoretical studies of cancer cell mechanics and peptide-enhanced nanoparticle entry/adhesion to triple negative breast cancer (TNBC) cells.

The adhesive interaction between functionalized nanoparticles and biological cells is critical for effective cancer targeting. A combination of atomic force microscopy (AFM) and simulation approaches are used to evaluate the adhesion and molecular origin of adhesive interactions, respectively, between Triptorelin (a Luteinizing Hormone-Releasing Hormone (LHRH) agonist)-conjugated poly-(ethylene glycol) (PEG)-coated magnetite nanoparticles (Triptorelin-MNPs) and breast cells. AFM results show that Triptorelin-MNPs have a fourteen-fold greater work of adhesion to TNBC cells than to normal breast cells. Hence, the experimental observation indicates that specific receptor-ligand adhesion facilitates Triptorelin-MNPs to target TNBC cells. In addition, the simulations reveal that the adhesive interactions are dominated by van der Waals forces and electrostatic interactions. Both experimental and computational studies suggest that PEG serves as an effective coating that enhances adhesive interactions to breast cancer cells. These results highlight the potential to develop Triptorelin-MNPs into tumor-specific MRI contrast agents and drug carriers.

To investigate Triptorelin-MNP cluster entry mechanism and cellular uptake efficacy, thermodynamics and kinetics modeling and optical/confocal fluorescence microscopy are used to show that Triptorelin ligands enhance the uptake of Triptorelin-MNPs into TNBC cells. The trends in the predicted cluster entry times (into TNBC cells) and the size ranges of the engulfed nanoparticle clusters (within the TNBC cells) are shown to be consistent with experimental observations.

Finally, a cell mechanics approach is explored for TNBC cell detection. This involves the use of a shear assay technique, in parallel with digital image correlation and a Maxwell model for the measurements of viscoelastic properties as effective biomarkers. The reduced cell viscoelastic properties (e.g. moduli and viscosities) of TNBC cells are associated with the reduction of actin filament structural components, and the loss of actin organization. These results suggest that the shear assay technique may serve as an effective screening tool for TNBC cell detection.