Thesis Format
Integrated Article
Degree
Doctor of Philosophy
Program
Chemical and Biochemical Engineering
Supervisor
Zhang, Jin
Abstract
A nanostructure-based theranostic system offers a promising approach by integrating therapeutic and diagnostic functions into a single platform. However, significant challenges remain with these nanomaterials when used as theranostic systems, including (1) poor biocompatibility, (2) unsatisfied delivery outcome to targeted sites due to endothelial barriers such as the endothelial barrier and an uncontrollable drug release profile, and (3) low sensing performance. Therefore, this research aims to develop multifunctional nanostructures with unique physical and chemical properties and suitable surface modifications for enhanced barrier transportation, stimuli-responsive drug release and improved sensing performance for theranostic systems. First, the core shell upconversion nanoparticles (UCNPs) modified with cationic biopolymer, N, N, N-trimethyl chitosan (TMC), were developed and applied to overcome endothelial barriers. The results indicate that the transport percentage of the UCNPs@SiO2 with the surface modification of TMC through the in vitro endothelial barrier is twice higher than the one without TMC. Due to the efficient transport behavior, TMC has further been studied to develop a new nanosphere to facilitate the transport of hydrophobic drugs, curcumin, to across endothelial barriers efficiently. The results reveal that TMC nanospheres significantly extend the release of curcumin over a 72-hour period, with curcumin transport across the endothelial barrier being 26.7% greater than that of the untreated system, indicating improved barrier permeability. In addition, a hybrid TMC-based magnetic nano-system was designed to further control the drug releasing while efficiently crossing the tissue barrier. The results show that the hybrid magnetic nano-system releases 50% more curcumin under AMF exposure for six hours compared to the non-exposed system, and numerous openings appear at the paracellular tight junction sites, suggesting effective stimuli-responsive drug release and improved barrier transport. Finally, CdSe/ZnS quantum dots (QDs)-based Förster resonance energy transfer (FRET) sensor was continuously developed for quickly detecting human tear glucose for the non-invasive diagnosis of diabetes. It shows high selectivity to glucose and good sensitivity at the range of 0.01-1 mM, with a limit of detection of 0.01 mM. In summary, suitable surface modification of nanostructures with special optical and magnetic properties is critical to overcoming the limitations of theranostic systems.
Summary for Lay Audience
Theranostic system is a well-designed platform that combines diagnosis and therapeutics together. It can simultaneously deliver drug to targeted organs or tissues and monitor the real time therapeutic effects either by biological imaging or sensing for diagnosis. That makes the system narrow the gap between diagnostics and therapeutics, improve disease management and prevent overtreatment. Nanomaterials are materials with one of the size dimensions less than 100 nm and have been investigated to develop nanostructured theranostic systems, because of their high specific surface area, special and tunable physical and chemical properties, and stronger interactions with biomarkers. However, there are significant challenges associated with using these nanomaterials in theranostic applications, including (1) limited biocompatibility, (2) ineffective delivery to targeted sites due to barriers like the endothelial barrier and uncontrolled drug release, and (3) low sensing performance. Therefore, this research focuses on developing multifunctional nanostructures to enhance barrier penetration, to enable stimuli-responsive drug release, and to improve sensing capabilities for theranostic applications.
First, a cationic polymer, TMC, has been synthesized and coated on the surface of UCNPs, which showed enhanced barrier transportation ability than the one without TMC coating. Based on this, TMC was further explored to develop a new nanosphere designed to transport hydrophobic drugs, curcumin, more effectively across endothelial barriers. The findings revealed that TMC nanospheres extended curcumin release over 72 hours, with a 26.7% improvement in curcumin transport across the barrier compared to untreated systems. Additionally, a hybrid TMC-based magnetic nano-system was designed to further control drug release and efficiently transport tissue barriers. The results demonstrated that this hybrid magnetic nano-system released 50% more curcumin under AMF exposure for six hours compared to non-exposed systems, and noticeable openings at paracellular tight junction sites suggested improved barrier transport. Finally, a QDs-based FRET sensor was developed for rapid, non-invasive detection of glucose in human tears for diabetes diagnosis. The sensor showed high selectivity for glucose and good sensitivity in the 0.01-1 mM range. In summary, suitable surface modification of nanostructures with special optical and magnetic properties is critical to overcoming the limitations of theranostic systems.
Recommended Citation
Lu, Chao, "Tailoring the interface between hybrid nanostructures and cells for stimuli-based theranostic systems" (2024). Electronic Thesis and Dissertation Repository. 10386.
https://ir.lib.uwo.ca/etd/10386