Stimuli-responsive nanomaterials for controlled delivery by light, magnetic and electrical triggers

The use of nanomaterials for biomedical applications is an emerging and important field. This is particularly true of advancements in targeted and controlled drug delivery, which offer several important improvements over traditional drug administration. The clinical efficacy of small-molecule therapeutics is currently limited by many factors, including: poor solubility, inefficient cellular uptake, overly rapid renal clearance and an inability to target only desired locations such as diseased tissues. The use of nanocarriers for drug delivery may greatly improve the efficacy over traditional therapeutics by lowering the total dosage, limiting the exposure to affected areas only, and giving greater temporal control over drug elution. These materials often make use of both organic and inorganic components, exploiting the unique and useful properties of each constituent to achieve novel, synergistic functions. This dissertation presents a study of nanocomposites comprising the three most important materials in this field: titania, iron oxides and polypyrrole. Titania is a strong photocatalyst, iron oxides provide useful responses to applied magnetic fields, and polypyrrole is a polymer with unique electrochemical properties. Studies in this dissertation were aimed at combining these three materials to create a novel structure that is responsive towards light, magnetic fields and electrical stimulation to serve as an enabling platform for the loading and release of biologically interesting compounds. These nanomaterials have been paired with amino acids L-lysine and Lglutamic acid, two organic molecules of interest due to their ability to bind to DNA and proteins, and to form prodrugs that exhibit enhanced performance compared to traditionally administered medicines. Two model compounds have been loaded and released on these carriers: Ketoprofen, an important anti-inflammatory that is traditionally hindered by its limited cellular uptake levels; and fluorescein isothiocyanate, a fluorescent dye molecule that is a common tool used in this field for nanocarrier location and easy visualisation of release-related kinetics. First, an investigation into the effect of pH on the binding of amino acids to titania, iron oxide and polypyrrole is presented with a view towards optimising the functionalised material for subsequent loading and release of the model drugs (in this case, amine-reactive molecules). The release mechanism of photo-activated TiO2 is studied in detail with a particular focus on the competition between the cleavage of bonds versus organic degradation on the catalyst’s surface. Both mechanisms are currently reported in literature and studies were aimed at identifying the more dominant pathway in the system developed alongside understanding the crucial role of reaction time scales on this photochemistry. Then, the pH-tuneable flocculation of the amino acid-functionalised nanoparticles via electrostatic attractions is exploited to create a novel, anisotropic assembly of iron oxides. These filaments display a dynamic and unique response towards a rotating magnetic field by creating local microscale vortices. This motion is used to enhance local delivery rate of molecules through magnetic-field triggered microscale mixing. Finally, this anisotropic iron oxide structure is combined with polypyrrole to create a unique, novel material that possesses directional conductivity, a photothermal response, and magnetic field-triggered release of loaded molecules at enhanced and controllable rates compared with traditional diffusion-limited systems. Thesis Organisation A detailed review of literature is given in Chapter 1 Background and Literature Review. This comprises an introduction to metal oxide nanomaterials and their role in nanomedicine (Section 1.2), magnetic nanomaterials and their unique magnetic field responsive character (Section 1.3), synthesis of metal oxide nanomaterials (Section 1.4), functionalisation strategies (Section 1.5), intrinsically conductive polymers (Section 1.6), and biocompatibility (Section 1.7). The key research questions arising from this literature review and associated research aims are presented in Section 1.8. The results of experiments on the effect of pH on amino acid functionalisation of TiO2 and Fe3O4 will be presented in Chapter 2. Chapter 3 investigates the flocculation effect of this functionalised material and presents a method to exploit this for self-assembly of Fe3O4 under a magnetic field to create novel, anisotropic structures. An analogous functionalisation of PPy with amino acids is presented in Chapter 4. Finally, the findings of previous chapters are combined to produce a composite material of amino acid-functionalised, lightresponsive, conductive and magnetically responsive material that is presented in Chapter 5. Conclusions and recommendations for future work will be presented in Chapter 6. Methods and materials are given at the end of each chapter where appropriate. References will follow at the end of the document. List of publications Journal Papers T. Zhang, P. Costigan, N. Varshney, A. Tricoli, RSC Advances 2016, 6, 3384333850. T. Zhang, M. A. Go, C. Stricker, V. R. Daria, A. Tricoli, J. Mater. Chem. B 2015, 3, 1677-1687. J. Ou, F. Wang, Y. Huang, D. Li, Y. Jiang, Q. -H. Qin, Z. Stachurski, A. Tricoli, T. Zhang, Colloids and Surfaces B: Biointerfaces 2014, 117, 466-472. Conference Proceedings T. Zhang, M. A. Go, C. Stricker, V. R. Daria, A. Tricoli, Journal of Materials Chemistry B 2015, 3, 1677-1687. In Submission K.Bruggeman, T.Zhang, A.Tricoli, D.Nisbet, Pharmaceutical Research, “Reverse UV-Triggered Growth Factor Delivery from TiO2 Nanoparticles in a SelfAssembling Peptide Hydrogel”