Nanoformulation of metal complexes : intelligent stimuli-responsive platforms for biomedical applications

• Main Author: Hu, Ming
• Other Authors: Xing Bengang
• Format: Theses and Dissertations
• Language: English
• Published: 2019
• Subjects: Science::Chemistry
• Online Access: https://hdl.handle.net/10356/89207; http://hdl.handle.net/10220/49335
• Institution: Nanyang Technological University

So far, precise theranostic demonstrated great possibility for effective therapeutics and diagnosis towards a variety of human diseases. As one type of commonly used agent, metal complexes have gained considerable successes in clinical applications for their rich and versatile properties for instance rich redox states, coordination numbers, preferential ligand and photo-induced ligand exchange processes etc. which can facilitate the rational design of therapeutic and sensing agents. In spite of these, limitations such as severe side effects, lack of specificity and inevitable toxicity have largely hampered their biomedical applications. To this end, innovative strategies to improve the pharmacokinetics as well as specificity of therapeutic and sensing agents based on traditional metal complex are highly demanded. Recently, nanotechnology has gained considerable attentions mainly due to their ability to reduce drug’s side effect as well as enhanced pharmacokinetics and drug loading efficiency. Due to the favorable physical and chemical properties of nanostructures, the nanoformulation of metal complex has been demonstrated effective approaches to address the issues of currently used metal complex, especially those based on the stimuli-responsive therapeutic strategies allow on-demand treatment and imaging of diseases with excellent control over time, space and dosage. In this dissertation, we introduced some strategies which endowed traditional metal complex with stimuli-responsive properties for further advance their application as therapeutic and sensing agents. Firstly, a NIR-light mediated strategy was developed to activated photo-sensitive Re(I) complex for its cytotoxic effect. To this end, the metal complex was incorporated onto light converting nanoparticles. Owing to the great spatial-temporal resolution of light irradiation, upon NIR stimulation, Re(I) complex can be locally activated within pathological side by upconverted UV light from nanoparticles and exert cytotoxic effect for precise treatment against both drug-susceptible and drug-resistant cancer cells, minimizing unwanted photo damage. Secondly, we introduced another stimuli-sensitive strategy for selective sensing illicit drug Gamma-hydroxybutyric acid (GHB). Upon substrate-specific enzyme recognition of GHB, reduced nicotinamide adenine dinucleotide (NADH) would be generated. As an ubiquitous reducing agent, the resulting NADH molecule can promote the reduction of gold(III) complex and form gold nanoparticles (AuNPs). The distinct transformation from molecular metal complex into nanoscaled particles can be easily monitored through either spectrometer or naked-eye observation, allowing specific sensing of GHB. Thirdly, we designed a strategy for long term sensing and imaging in response to reducing cellular environment. Typically, we designed a lanthanide based molecular probe which can respond to reducing environment. Once reduced, this lanthanide probe would undergo intermolecular cross linking and form dimer structure. The resulted dimer would subsequently assemble into nanoscaled particles which can potentially accumulate within cells for long term intracellular sensing and imaging purpose. Lastly, we provided an effective approach to site-specifically localize luminescent complex on cell surface through metabolic labelling and biorthogonal reaction. Upon stimulation by NIR illumination, the intense emission from the complex could activate the light-responsive membrane channel and allow precise manipulation of ion flux both in vitro and in vivo. This strategy could not only provide new strategies towards the manipulation of membrane activities and relevant biological processes in vitro and in vivo, and it would also promote in-depth understanding of the physiological roles of cell membrane in live settings. In summary, these proposed intelligent system in this dissertation could provide new prospectives for the precision therapeutics and diagnosis based on their stimuli-responsive properties. We believe these current work could promote innovations in this research field and facilitate the advance in biomedical research and scientific community.