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Abstract

Metal-organic frameworks (MOFs) have emerged as a new class of hybrid molecular materials with potential for a broad range of applications. When scaled down to the nanosize, nanoscale metal-organic frameworks (nMOFs) have been explored for applications in diagnosis, imaging, and biomedicine by virtue of their structural and functional tunability. In this dissertation, we have further demonstrated the use of nMOFs in cancer therapies and pH sensing in live cells. Chapter 1 briefly introduces the basic concepts of nMOFs and their potential applications. I also provide brief overviews on cancer, photodynamic therapy (PDT), checkpoint blockade immunotherapy, and RNA interference. Chapter 2 describes the rational design of the first porphyrin-based nMOF, DBP-Hf, for PDT of resistant head and neck cancer. The nMOF displays greatly enhanced PDT efficacy both in vitro and in vivo, representing a new class of promising PDT agents for resistant cancer treatment. Chapter 3 reports the design of first chlorin-based nMOF, DBC-Hf, with even more enhanced PDT efficacy. By virtue of the improved photophysical properties comparing to its porphyrin counterpart, DBC-Hf outperforms DBP-Hf in PDT of two colon cancer mouse models. Chapter 4 details the design of another chlorin-based nMOF for combination of PDT and checkpoint blockade immunotherapy. A small molecular inhibitor of indoleamine 2,3-dioxygenase is encapsulated into the MOF channels to alter the tumor microenvironment, which synergizes with the nMOF-mediated PDT to elicit systemic antitumor immune response. The synergistic combination therapy achieves effective local and distant tumor rejection in colorectal cancer models. Chapter 5 describes the first use of an nMOF as a co-delivery system of chemotherapeutics and small interfering RNAs (siRNAs). A cisplatin prodrug was encapsulated into the pores of the nMOF and pooled siRNAs were loaded onto the nanocrystal surface by coordination to the metal sites, leading to an order of magnitude enhancement in chemotherapeutic efficacy in vitro. Chapter 6 illustrates the first use of an nMOFs for intracellular pH sensing in live cells. Fluorescein isothiocyanate was covalently conjugated to an nMOF to exert ratiometric pH-sensing. Live cell imaging studies revealed endo and exocytosis of the nMOF and endosome acidification in real time.

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