Rizk, Marwa Mohamed Ibrahim Elsayed; (2024) Theranostic MRI-active responsive polymer-mesoporous silica nanocomposites for hepatocellular carcinoma. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis presents a comprehensive approach to address the complicated challenges in advanced-stage treatment and early diagnosis of hepatocellular carcinoma (HCC). A multifunctional thermo-responsive system was designed using mesoporous silica nanoparticles (MSNs) as the foundational platform, loaded with doxorubicin HCl or sorafenib tosylate, and Gd3+-DOTA chelates for sensitive and more accurate MRI. MSNs grafted with thermo-responsive polymers enable precise drug release and water gating, reflecting cargo release through MRI signal changes. This innovative approach aims to provide an all-in-one solution for HCC management, balancing advanced treatment options, improved bioavailability, and precise early-stage diagnostics. In this thesis we focused on optimising drug-loading capacity within MSNs for both hydrophilic doxorubicin and hydrophobic sorafenib tosylate. By carefully considering factors such as pore channel chemistry, loading methods, solvent selection, and pore size, effective drug loading has been achieved. This optimisation served as a foundation for more efficient drug delivery systems, ultimately improving therapeutic effectiveness. Moreover, this project delved into enhancing Gd-DOTA MRI-active theranostic MSNs. We investigated factors influencing MRI signals, including the placement of Gd-chelates within the pore channels and the influence of drug loading. Furthermore, this thesis explored the fine-tuning of the transition temperature of UCST polymers, crucial for biomedical applications, by manipulating monomer ratios and polymerisation times. This optimisation approach holds promise for future biomedical applications, contributing to progress in the field. Furthermore, we have successfully grafted thermo-responsive polymers and linkers onto MSNs, enabling controlled drug release. These advancements, combined with promising results in cell viability assessments, suggest the potential of these theranostic systems for targeted cancer treatment. This represents significant progress in controlled drug release, ultimately leading to improved therapeutic outcomes. In summary, this research significantly advances the field of stimuli-responsive theranostics for HCC. Key contributions include optimised drug loading techniques, refined MRI contrast agents, fine-tuning of transition temperatures for biomedical applications, and successful grafting strategies enabling controlled drug release.

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