Protein Stabilization with Metal–Organic Frameworks for Drug Delivery and Catalysis

Chen, Yijing

doi:https://doi.org/10.21985/n2-4e5t-8107

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Protein Stabilization with Metal–Organic Frameworks for Drug Delivery and Catalysis

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Proteins are known to have diverse biomedical functions and excellent catalytic performance; however, they are also fragile outside living cells, challenging their use in industrial applications. Metal-organic frameworks (MOFs) are highly porous crystalline materials that consist of metal cluster nodes and organic linkers. With their rigid structures, MOFs can effectively prevent structural changes of proteins after encapsulation and further increase the protein's stability under different conditions. Importantly, the high surface areas and tunability of MOFs give rise to many possible structures which can achieve high protein loading capacities as well as concentrate the substrate to enhance reaction rates for catalysis. Therefore, one of the focuses of this thesis is the encapsulation of proteins with MOFs to enhance their stability in denaturing conditions that occur during the therapeutic protein delivery process. For that application, an insulin@MOF composite was designed and synthesized by encapsulating insulin in a MOF. The MOF can stabilize insulin in stomach acid by preventing its unfolding in an acidic environment while performing size exclusion towards the degradation enzyme existing in the stomach. After insulin@MOF reached the blood environment, MOF will start to degrade under the presence of phosphate ions and release a large amount of insulin from it. In addition, after DNA modification, the insulin@MOF nanoparticles show greatly enhanced colloidal stability and can penetrate the cells and enable the intercellular delivery of target large biomolecules. The other half of this thesis focuses on the stabilization of enzymes with MOFs for enhanced catalysis. Formate dehydrogenases (FDH), a class of enzymes that catalyze the reduction of CO2 to formic acid, show increased stability in both acidic and neutral environments upon encapsulation within a MOF. The regeneration of co-enzyme nicotinamide adenine dinucleotide (NADH) can be realized electrochemically via a modified fluorine-doped tin oxide (FTO) glass electrode. The photochemical NADH regeneration can also be achieved after MOF-modification with an electron mediator. With the coupling of the enzymatic CO2 fixation and the electrochemical or photochemical cofactor regeneration, formic acid can be produced using CO2 in the atmosphere and a catalytic amount of NADH at high efficiency. The mechanism of the enhanced catalytic performance of MOF-encapsulated enzyme was also investigated with different characterization instruments. From both experimental and simulation results, an enzyme Cytochrome c (Cyt c) shows structural changes in its heme-based active center during MOF encapsulation, likely resulting in enhanced accessibility of the active center to reaction substrates. In this thesis, proteins are encapsulated in and stabilized by MOFs for both protein delivery and enhanced biocatalysis applications. The mechanism of the enhanced performance of MOF encapsulated protein is also investigated.

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