Zhang, Ziwei; (2021) Novel formulations for magnetic-resonance imaging guided theranostics. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Recent advances in bioimaging, biochemistry and bioinformatics have facilitated the development of personalized and precision medicine. Theranostics, a combination of imaging modalities and therapeutic agents, have garnered increasing attention in this context, thanks to their potential to monitor and control treatment for individual patients. An attractive strategy to achieve this goal involves the development of therapy guided by magnetic resonance imaging (MRI). MRI, possessing a number of benefits including a high degree of soft tissue contrast, low invasiveness, high depth of penetration and good spatial resolution, could offer advanced imaging-guided therapy enabling precise and time-resolved assessment of disease conditions and therapeutic progression. The goal of this PhD thesis is to develop novel formulations based on polymeric, inorganic or hybrid materials using two pharmaceutical fabrication techniques (electrohydrodynamic atomisation or spray drying), and explore their potential in MRI-guided chemotherapy. Five different types of formulation carrying MRI contrast agents and chemotherapeutic agents were fabricated. Chapter 3 reports the fabrication of pH-responsive formulations via electrodynamic atomization, loaded with superparamagnetic iron oxide nanoparticles (SPIONs) as contrast agents and the model chemotherapeutic carmofur. These platforms are able to protect the cargo from release acidic conditions representative of the stomach, while at neutral pH the relaxivity is tightly correlated to the extent of drug release. Chapter 4 describes a series of dual responsive systems with distinct morphology, comprising of pH-responsive Eudragit shells with SPIONs, and thermo-responsive core loading carmofur. The fibres are found to have better thermo-responsive properties compared to microparticles, and the relaxivity display clear linear relationships with drug release data. Chapter 5 focuses on using spray drying to fabricate nano-in-micro particles based on a synthetic polymer with an upper capital solution temperature. The microparticles encapsulate drug-loaded layered double hydroxide nanosheets, have thermo-sensitive release and relaxivity profile, and in vitro cell studies reveal that the formulations permit synergistic hyperthermia-aided chemotherapy. Chapter 6 details the preparation and characterization of four gadolinium doped layered double hydroxides to develop theranostic platforms carrying chemotherapeutics with high T1-relaxivity. In Chapter 7, polydopamine-coated polycaprolactone/poly(lactic-co-glycolic) acid nanofibers are developed via co-axial electrospinning, which are loaded with dug-loaded LDH nanocomposites in the core. In vitro studies reflect sustained release of chemotherapeutics, and highly effective cytotoxic effects on tumour cells with the polydopamine coated formulations, which was further enhanced at higher levels of glutathione.

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