Metal-organic framework nanoprobes : new approaches to chemical sensing and phototherapy of alzheimer's disease

Abstract

Metal-organic framework (MOF) is a class of hybrid materials synthesized from metal cluster nodes and organic linkers that connect these nodes. This rapidly expanding class of structures presents advantages in various applications such as gas storage and separation, catalysis, sensing, cancer theranostics, and others. However, the applications of MOFs have not been extended in the fields including chemo-sensing and phototherapy of neurodegenerative diseases. The first part of this thesis is about Fe³⁺ colorimetric sensing based on Zn-MOF-74 nanodots. Zn-MOF-74 nanodots were successfully synthesized through a mild chemical reaction under room temperature and used as a chemo-sensor for highly sensitive and selective detection of Fe³⁺ in aqueous solution via a colorimetric approach. Conventional MOF-based chemo-sensors can act as a host and antenna to provide a rigid scaffold that protects fluorescent molecules inside the framework from self-quenching and also sensitize them to form tunable fluorescence. This often requires sophisticated apparatus and longer time. Our colorimetric approach is more convenient to observe the visual color change of the solution by naked eyes. The multiple functionalities of MOFs can also be used as nanomedicines not only for the phototherapy of tumors but also for neurological disorders such as Alzheimer's disease (AD). The second part of this thesis is regarding the photodynamic inhibition of Alzheimer's amyloid-β (Aβ) using porphyrin MOF PCN-224 nanoparticles. Porphyrin MOF PCN-224 nanoparticle of sub-100 nm size was synthesized and used to photo-catalyze the oxygen into ¹O₂ which can attenuate the neurotoxicity of Aβ by oxidizing the Aβ monomer and preventing it from aggregating into high-order oligomers and fibrils in the early stage. The porphyrin-based MOF showed strong light-to-oxygen generation capability due to the high percentage of exposed TCPP ligands in the framework and easy diffusion of molecular oxygen through the porous structure. The Aβ oxidized by photo-activated PCN-224 has low neurotoxicity when co-incubated with PC12 cells. In the third part of this thesis, A hybrid nanosystem composed of PCN-222 nanosheet and Indocyanine green - PCN-222@ICG was developed to realize the combinational phototherapy of AD. PCN-222 nanosheet inhibited the Aβ aggregation through the oxidization of the peptide by producing ¹O₂, whereas ICG prevent the Aβ aggregation by photothermal effect. Because of the high surface area of ultrathin PCN-222 nanosheet, the loading capacity of ICG on the PCN-222 was very high, thus the low concentration of nanoprobes exhibited a high inhibitory effect against Aβ aggregation. A BBB Transwell model consisted of hCMEC cells and human primary astrocytes and pericytes was built to examine the BBB permeability of this nanoprobe. Finally, with the newly emerging organ-on-a-chip technology, a brain-on-a-chip model was successfully built up through soft lithography. Human umbilical vein endothelial cells (HUVEC), human primary astrocytes, and pericytes were co-cultured in the chips that recapitulated human-relevant physiological BBB properties. Nanoprobes including MOF PCN-222@ICG and carbon dots modified with rabies virus glycoprotein (RVG) peptide had improved BBB permeability when assessed on the brain-on-a-chip model. Overall, this thesis described three MOF nanoprobes for chemo-sensing and AD phototherapy and reported a brain-on-a-chip platform for the assessment of BBB permeability for the PCN-222@ICG and carbon dots nanoprobes.