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3D Cell Modular Approach in Colon Cancer Therapeutics Using Nanoparticle-Mediated Photodynamic Treatment
thesisposted on 01.12.2019, 00:00 by Syeda Fatima Z Rizvi
Targeted drug therapies are becoming increasingly utilized for precision medicine, particularly towards cancer treatments. Optimized therapy is based on drugs’ selectivity and specificity towards cancerous tissues. We utilized bioluminescence to create light only within the cancer region and in the vicinity of the photoactive TiO2 nanoparticles by linking the enediol-modified TiO2 nanoparticles to firefly Luciferase and in doing so created biocomposites that upon activation induced apoptosis in cancer cells. Additionally, linkage with the C225 monoclonal antibody provided further selective targeting to the surface of HCT-116 colon cancer cells. The ensuing TiO2 nanoconjugates are 100% effective in 2D in vitro studies, but only partially (70%) effective in in vivo studies. Therefore, we designed a 3D cell model, mimicking tumor tissue at a microlevel, to bridge the gap and improve clinical efficacy. In doing so, our 3D cell model provided greater insight into tissue reactivity with TiO2 nanoconjugates, allowing for further optimization of the biocomposites. Tumor resistivity to drugs has been frequently linked to hypoxia. Thus, we incorporated the study of tumor hypoxia into our 3D cell model. Our results demonstrated the influential role of hypoxia in decreasing TiO2 nanoconjugate efficacy, limiting cell programmed death to the outer periphery of spheroids. The unique bioluminescent mechanism of TiO2 nanoconjugates furthermore allowed for in situ visualization in real-time of apoptosis in HCT-116 spheroids providing a holistic view of microtissue behavior during cell-programmed death. Our 3D cell model is a unique cell-based testing platform that can be adapted to study different types of cancer and other disease states. With further development, the 3D cell model also has the capability to reform the current drug development process and advance the study of targeted oncology therapeutics.