Coordination Nanoparticles for Tumor Microenvironment-Responsive Cancer Therapy

Abstract

Coordination nanoparticles, especially layered double hydroxide and metal-organic frameworks, have attracted great attention for biomedical applications. These categories of nanomaterials stand among various conventional reagents for several outstanding features, their versatile composition allows the flexible construction or substitution of the core elements, subsequently enable the integration of multiple functions. These nanohybrids can often be derived from facile and controllable syntheses, which will result in a tunable size/morphology, hence the resultants can be tailored with specificity and serve for particular purposes. Moreover, by virtue of the metal elements within the structure, hydroxide bones or coordination bonds can be readily degraded while subjected to certain biological conditions, e.g., mild acidity in the solid tumor. It indicates a potential satisfactory biodegradability, which is critical and desirable for biological applications. Most importantly, potent catalytic reactivity relies upon rational design. The nanohybrid can be engineered with a trigger that responds sensitively to tumor microenvironments, e.g., elevated hydrogen peroxide level. This thesis has firstly summarized current prevalent catalytic nanomedicines and the corresponding paradigms achieved by layered double hydroxide and metal-organic frameworks, current challenges and perspectives were also proposed. In Chapter 3, a novel approach was used to enhance nanoparticle colloidal stability. Various reaction conditions have been investigated to optimize synthesis. Characterizations illustrated the fundamental mechanism behind the PEGylation. Further tests also revealed that the PEGylated nanoparticles had a decreased protein adsorption, enhanced cellular uptake, and negligible cytotoxicity. In the following chapter, an iron(II)-incorporated nanocatalyst was then synthesized with this PEGylation strategy. It was observed that the resultant demonstrated an ultrathin two-dimensional nanosheet morphology. The as-synthesized PEG/Fe-LDH displayed extremely high affinity and reactivity regarding the catalytic decomposition of H2O2, and abundant amount of •OH was detected. More importantly, desirable biodegradability was observed on PEG/Fe-LDH. While proceeded to in vitro and in vivo studies, significant cancer cell growth suppression was observed, which can be attributed to the high responsiveness to H2O2. Bearing H2O2-responsive catalytic reaction in mind, an Mn-based MOF was designed and tested in Chapter 5. The resultant significantly alleviated tumor hypoxia, and an enhanced photodynamic therapy has been successfully established.