Fototermal, Fotodinamık Ve Kemodinamık Terapi İçin İnorganik Nanopartiküllerin Sentezi Ve Karakterizasyonu

Abstract

Metastasis and treatment resistance, which are major challenges in oncology, limit the effectiveness of current treatment protocols. Copper (Cu), due to its Fenton-like activity, and cerium (Ce), due to its high redox cycle and catalase- like activity, stand out as promising, cost effective, and readily available materials for nanoparticulate therapeutic approaches aimed at increasing reactive oxygen species (ROS) production to enhance damage to tumor cells by overcoming the resistance of the hypoxic tumor microenvironment. In this study, multifunctional synergistic therapeutic agents based on Cu and Ce were designed to overcome the current limitations of cancer treatments. These agents, developed as mesoporous copper (II) oxide nanorods and hollow cerium oxide nanoparticles, demonstrated a strong synergistic effect against tumor cells by integrating chemodynamic, photodynamic, photothermal, and starvation therapies. Through surface modifications of the nanorods and nanoparticles, multiple functionalities such as hydrogen peroxide production, catalase-like activity, oxygen bubble formation, and heat generation were achieved. Consequently, an environment was created that enhances oxidative stress in the tumor microenvironment, triggering cell death. Additionally, starvation therapy induced through glucose consumption disrupted the energy metabolism of tumor cells, increasing their sensitivity to treatment. Mesoporous copper (II) oxide nanorods (CuO) were synthesized via heterogeneous nucleation on polymeric nanoparticles and functionalized with a CaO₂ nanoshell coating (CuO@CaO₂). The decomposition of the nanoshell in aqueous media activated the Cu(I)/Cu(II) cycle through the generation of H₂O₂, significantly increasing glutathione (GSH) depletion. The decomposition of H₂O₂ through catalase-like activity resulted in the formation of O₂ bubbles, propelling the CuO@CaO₂ nanorods like nanomotors. In addition to catalase activity, these nanostructures exhibited peroxidase- and oxidase-like activities. The peroxidase-like activity of CuO@CaO₂ nanorods potentiated the chemodynamic effect in the tumor microenvironment by using self-generated H₂O₂ to enhance the production of toxic hydroxyl (•OH) radicals. When exposed to near-infrared (NIR) laser irradiation, the nanorods exhibited high photothermal conversion properties due to significant temperature increases. Through photothermal therapy (PTT), GSH depletion was enhanced, and •OH radical production was further optimized, improving chemodynamic function. The therapeutic potential was evaluated against T98G cells by loading chlorin e6 (Ce6) onto the nanorods. Using CuO@CaO₂@Ce6 nanorods, the synergistic combination of photodynamic therapy (PDT), PTT, and chemodynamic therapy (CDT) resulted in over 90% cell death in vitro. To further increase oxygen levels in the tumor microenvironment, hollow and mesoporous CeO₂ nanoparticles (H-CeO₂) exhibiting catalase-like activity were synthesized using a stage shape-templating protocol. These nanoparticles were loaded with Ce6 through adsorption and coated with a thin polydopamine (PDA) layer. The PDA shell facilitated PTT conversion upon exposure to an 808 nm NIR laser. By immobilizing glucose oxidase (GOx) onto H CeO₂@Ce6@PDA nanoparticles, glucose in the tumor microenvironment was converted into H₂O₂ and gluconic acid. The conversion of glucose into the tumor-toxic •OH radical demonstrated the CDT effect of these nanoparticles. Glucose consumption induced starvation in tumor cells, increasing ROS production in the tumor microenvironment and enhancing PDT efficacy. The in vitro synergistic effects of starvation therapy (ST), PDT, and PTT, without the use of any drugs, were tested on T98G glioblastoma cells, resulting in over 90% cell death. In conclusion, two novel synergistic therapeutic agents were developed within the scope of this thesis, representing a significant step toward designing effective cancer treatment strategies.