New Frontiers for Triple Negative Breast Cancer Detection and Treatment: From Mechanical Biomarkers to Specific Nanoparticle Entry for Robotically Controlled Laser-Induced Hyperthermia

Uzonwanne, Vanessa

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New Frontiers for Triple Negative Breast Cancer Detection and Treatment: From Mechanical Biomarkers to Specific Nanoparticle Entry for Robotically Controlled Laser-Induced Hyperthermia

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This thesis presents the results of a combined experimental, computational, and theoretical study of triple negative breast cancer (TNBC) cells and non-tumorigenic breast cells. It explores the interactions of these cells with biosynthesized gold nanoparticles (GNP), PEG-coated GNP (GNP-PEG), triptorelin functionalized GNP (GNP-TRP), and triptorelin-conjugated PEG-coated GNP (GNP-PEG-TRP) that are relevant to the treatment of triple negative breast cancer. Salient conclusions arising from the study of the adhesion, entry, and photothermal properties of GNP, GNP-PEG, GNP-TRP, and GNP-PEG-TRP in TNBC/non-tumorigenic cells are presented. The adhesion is studied at the nanoscale using atomic force microscopy (AFM) experiments. The AFM measurements showed that the GNP-TRP and GNP-PEG-TRP have higher adhesion to TNBC than non-tumorigenic breast cells. The increased adhesion of GNP-TRP and GNP-PEG-TRP to TNBC is also attributed to the overexpression of LHRH receptors on the surfaces of TNBCs. Finally, a three to nine-fold increase in the adhesion is predicted between triptorelin-functionalized PEG-coated gold nanoparticles (GNP-PEG-TRP) and TNBC cells. Hence, the experimental observation indicates that specific receptor-ligand adhesion facilitates the targeting of TNBC cells with GNP-PEG-TRP. These results highlight the potential to develop Triptorelin functionalized PEG-coated gold nanoparticles into tumor-specific photothermal agents and drug carriers. Next, the entry of GNP, GNP-PEG, GNP-TRP, and GNP-PEG-TRP into TNBC and non-tumorigenic cells were studied using in vitro nanoparticle entry experiments and thermodynamics-kinetics models to predict the wrapping times and optimal cluster size of uptake into TNBC cells. This nanoparticle entry study provides new insights into these biosynthesized nanoparticles' selectivity, clustering, wrapping time, and optimum sizes. In addition, these results highlight the role of receptor density distribution and cluster surface energy in nanoparticle uptake into TNBC and non-tumorigenic breast cells. Specifically, the nanoparticle cluster size distribution results in TNBC (MDA-MB-231, MDA-MB-468) and non-tumorigenic breast cells (MCF 10A) were consistent with the theoretical models. Interestingly, the cluster size distribution of all nanoparticles in the cells increased as a function of metastatic cells. This increase in the cluster size distribution is attributed to the overexpression of LHRH receptors on the surfaces of both TNBC cells. Lastly, this thesis presents an experimental and finite element (FE) study of the photothermal effects of GNP, GNP-PEG, GNP-TRP, and GNP-PEG-TRP in TNBC using in-vitro laser-nanoparticle hyperthermia (41ºC - 45ºC) experiments on TNBC cells and tissue models. The heating effects of near-infrared (808 nm) laser interactions with the different gold nanoparticles are explored using a fluid and a tissue model. Also, the influence of robotics-assisted laser positioning on hyperthermic heating in tissue was investigated. Results from the laser-nanoparticle interactions were validated using finite element analysis (FEA) and found to be consistent with the experimental results. Notably, all the biosynthesized gold nanoparticles achieved hyperthermia and thermal ablation temperatures in water. Furthermore, the photothermal conversion efficiency of the gold nanoparticles decreased with surface modification. Finally, the robotics-controlled laser positioning assisted heating in tissue reveals that axial and rotational laser interactions with the biosynthesized gold nanoparticles yield temperatures suitable for hyperthermia in tissue. The implications of the results are discussed for the development of a laser-nanoparticle-based medical robotics system for the specific hyperthermia treatment of TNBC.

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