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Abstract

Despite remarkable progress made in conventional therapies, cancer remains one of the deadliest disease in the world. Combination therapy with multiple chemotherapeutics is a successful strategy for treating many cancers. Nanoparticle-based therapeutics have gained popularity due to their many favorable properties, including their high payloads, tunable sizes, tailorable surface properties, controllable drug release kinetics, and improved pharmacokinetics. Recently, nanoscale coordination polymers (NCPs), self-assembled nanoparticles constructed from metal ions and organic bridging ligands, have been used as versatile platforms for cancer drug delivery. This work highlights the recent development of NCPs for simultaneous delivery of multiple chemotherapeutics for the treatment of various types of cancer. Chapter I introduces the challenges of treating cancers and summarizes current nanoplatforms in clinics and literatures. Chapter II presents a novel NCP containing oxaliplatin and gemcitabine for the treatment of pancreatic cancer. This work constitutes the first time that NCPs could incorporate multiple chemotherapeutics. In Chapter III, the development of NCP nanoparticles that efficiently deliver high payloads of carboplatin and gemcitabine. A strong synergistic effect was observed between carboplatin and gemcitabine against platinum-resistant ovarian cancer, SKOV-3 and A2780/CDDP, in vitro, while these particles exhibited long blood circulation and potently inhibit tumor growth in vivo when compared to free carboplatin and gemcitabine. Chapter IV introduces NCP nanoparticles carrying both cisplatin and gemcitabine for effective treatment of both small cell and non-small cell lung cancers. Synergy between cisplatin and gemcitabine was observed in vitro and superior potency and efficacy was found in vivo. In Chapter V, NCP containing cisplatin and gemcitabine was further enhanced with the addition of siRNAs on the surface of the particle to effectively target multidrug resistant genes. It was found that these NCP particles possesses efficient endosomal escape through a novel carbon dioxide release mechanism to completely eradicate subcutaneous cisplatin-resistant ovarian cancer tumors in vivo. Finally, Chapter VI concludes by reporting the synthesis, characterization and evaluation of NCP-based core-shell nanoparticles carrying oxaliplatin and photosensitizer pyrolipid in combination for chemotherapy and photodynamic therapy in colorectal cancers. These particles enable enhanced anti-tumor immunity for achieving superior anticancer efficacy in colorectal cancers and their potential applications in the treatment of metastatic colorectal cancer.

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