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Abstract

Although chemotherapeutic anticancer drugs have been developed and used in clinical practices for more than 80 years, there still exist many unsolved problems and limitations, including low bioavailability and high systemic toxicity. Moreover, different drugs usually do not share the same physicochemical properties and behave differently inside the body, which makes it difficult to combine multiple drugs to overcome resistance to one single drug or to achieve a synergetic effect. Nanoscale coordination polymer (NCP) is a nanoparticle platform that can load drugs with different physicochemical properties within a single particle by incorporating hydrophilic drugs inside its Zn-phosphate solid core and inserting hydrophobic drugs between its lipid bilayers. The drug-loaded particles are long-circulating and tumor-targeting. Evidence showed that when delivered by the NCP platform, drugs showed increased drug exposure and reduced systemic toxicity.Chapter 1 of this thesis discussed the current application and limitations of chemotherapeutic drugs and strategies to overcome the limitations, with a focus on nanoparticle formulation and prodrug design. Chapter 2 and Chapter 3 described two examples of using the NCP platform to deliver molecules that can cause immunogenic cell death. The combination of oxaliplatin and dihydroartemisinin showed high immunogenicity, while the combination of dihydroartemisinin and iron complexes triggered immunogenic ferroptosis. Both examples showed long circulation of loaded prodrugs and low toxicity with improved anticancer efficacy when compared to free drugs. They synergized with α-PD-L1 immunotherapy in immunosuppressive tumor models. Chapter 4 showed improvement of the well-established combination of cisplatin and paclitaxel therapy using the NCP platform. Detailed studies revealed the interaction between NCP particles and low-density lipoproteins and its influence on tumor-targeting effect of NCP particles. Chapter 5 further extended the scope of stable nanoparticles via self-assembly of amphiphilic molecules. Lysosome-targeting dyes self-assembled into nanoparticles and showed high tumor accumulation and great efficacy in photodynamic therapy.

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