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Title: Development and evaluation of multifunctional colloidal composite nanoparticles for potential combined cancer cell diagnosis and therapy
Author: Martínez Pancorbo, P.
ISNI:       0000 0004 9355 8053
Awarding Body: University of Exeter
Current Institution: University of Exeter
Date of Award: 2020
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Nanomedicine includes detection, diagnosis and treatment of diseases at the cellular level and can be a valuable tool for highly specific medical interventions by utilising nanoscale objects. Cancer nanomedicine is one of the most successful research fields for exploring cancer at the cellular level. To find a suitable candidate for cancer theranostics (therapy and diagnosis) at an early stage and post-treatment (reemission), the cytotoxicity, imaging, and therapeutic capabilities of various classes of nanoparticles were investigated. Firstly, various nanoparticles were first obtained from WOx and iron oxides being processed under hydrogen (H2) + argon (Ar) gas heat treatment and membrane filtration. A colouration process from yellow to blue colour was obtained for WO3 nanoparticles (NPs) and an oxygen reduction process that led us to obtain metallic Fe NPs from γ-Fe2O3 NPs. Additionally, membrane filtration methods using ultrathin nanoporous membranes in microfluidic platforms were performed on γ-Fe2O3 polydisperse NPs. This novel application showed a consistent reduction in size distribution from these magnetic polydisperse NPs after filtration at 37 nm and 60 nm membrane pore sizes. Tangential and normal flow filtration (TFF and NFF, respectively) were used with ethanol and water solvents which showed the need to work at low concentrations for dense nanoparticles. TFF presented a higher degree of filtration at the cost of complexity, time and price. Secondly, these NPs were then investigated for their incorporation as the core in core-shell structures. Novel core-shell NP structures were designed with an intermediate tunable SiO2 layer (3-60 nm) using the Stober process and also a tunable Au outer shell (15-30 nm approximately) formed from 3.5 nm Au seeds obtained from the Turkevich method. WO3-SiO2-Au NPs were synthesised which are a new class of NP that contains a first in it class WO3 core with potential electrochromic functionalities. Coherent anti-Stokes Raman spectroscopy (CARS) and near-infrared (NIR) surface-enhanced Raman spectroscopy (SERS ) were performed as a proof of concept for potential medical imaging to locate the nanoparticles achieving single-cell resolution. SERS enhancement factor (EF) using 785 nm was approximately 103 for a 30 nm thick Au shell in a silicon wafer. Additional Raman signals were measured in liquid samples to evaluate obtaining a SERS EF of 771 with WOx core and 33 using γ-Fe2O3 core. It presented low toxicity at concentrations under 100 μg/mL after 24 h using human isolated at M D Anderson from a pleural effusion of a patient with invasive ductal breast carcinoma breast cancer cells (MDA-MB 231) in vitro. Finally, monodisperse γ-Fe2O3-SiO2-Au nanoparticles displayed a promising negative contrast for MRI in both T1 and T2 modes along with strong contrast under microcomputed tomography (μCT). Monodisperse γ-Fe2O3 cores, which have an average diameter of 11 nm following a gaussian distribution with a standard deviation of 3 nm, in γ-Fe2O3-SiO2-Au structures outperformed in all these imaging tests to polydisperse γ-Fe2O3 cores, which have a mode value at 31 nm following a Lorentzian distribution with a scale parameter of 29 ± 7 nm. Magnetic hyperthermia was achieved using γ-Fe2O3 cores confirmed the potential therapy functionality in water using AMFs at 515 kHz and 170 Oe, obtaining an increment of 7 °C in 23 min, which adds in total four functionalities with potential application for cancer nanotheranostics. Moreover, cell viability assays using monodisperse γ-Fe2O3-SiO2-Au nanoparticles showed almost negligible cytotoxicity in different nanoparticle concentrations (0-2000 μg/mL) and cell types (pericytes, embryonic kidney HEK293A and MCF10A human cells) in vitro. In conclusion, the thesis was able to demonstrate that WO3-SiO2-Au NP and γ-Fe2O3-SiO2-Au NP have the potential for further development as a tool in nanomedicine, although systemic toxicology and excretion pathways will have to be carefully studied next.
Supervisor: Zhu, Y. ; Stone, N. Sponsor: Engineering and Physical Sciences Research Council (EPSRC)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available