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Author ORCID Identifier
Open Access Dissertation
Doctor of Philosophy (PhD)
Year Degree Awarded
Month Degree Awarded
Vincent M. Rotello
Chemicals and Drugs | Nanomedicine
Bioorthogonal chemistry offers versatile strategies for monitoring and modulating biomolecules in their native environments through abiotic chemical reactions. Bioorthogonal catalysis via transition metal catalysts (TMCs) provides the controlled activation of anticancer therapeutics, which mimics the enzymatic amplifications. However, the direct use of TMCs in living systems faces challenges such as instability, poor solubility, and low biocompatibility. Engineering the structure of TMCs can partially solve the problems, but the rapid clearance of small molecules hurdles the in vivo applications. Therefore, embedding TMCs in/onto nanomaterials to obtain bioorthogonal nanozymes enhances stability, solubility, biocompatibility, and the presence of the catalysts in biological environments for drug activation.
In this thesis, I screened a library of surface-functionalized gold nanoparticles (AuNPs) to check their effect on immune cells. I chose the positively charged with hydrophilic headgroup one to hydrophobic TMCs. AuNPs insulate the catalyst from the deactivating environment. The surface ligands of AuNPs were further engineered to generate stimuli-responsive nanozymes by harnessing the formation and proteolysis of the protein corona. Moreover, the cationic-charged nanozyme exhibited prolonged stability both in vitro and in vivo, allowing for localized drug activation. The localized cancer therapy mediated by nanozymes efficiently reduced the growth of aggressive breast cancer and avoided acute liver damage, a common off-target effect of chemotherapy. The nanozymes were also applied for anticancer immunotherapy by polarizing macrophages to anticancer phenotype through activating the precursor of an immune modulator.
Other than gold nanoparticles, I functionalized zinc sulfite nanoparticles as the scaffold to integrate degradability and enhanced catalysis for anticancer drug activation. I also developed a scalable polymeric-based nanozyme that resisted serum poisoning for cancer killing. Overall, this dissertation presents the promising potential of fabricating bioorthogonal nanozymes for localized anticancer therapy.
Zhang, Xianzhi, "TRANSITION METAL CATALYST (TMC)-EMBEDDED BIOORTHOGONAL NANOZYMES FOR ANTICANCER THERAPEUTICS" (2023). Doctoral Dissertations. 2878.
Available for download on Sunday, November 26, 2023